Dubiously increased FT4 and FT3 levels in clinically euthyroid patients: clinical finding or analytical pitfall?

OBJECTIVES: We systematically investigated normally or subclinically increased thyroid stimulating hormone (TSH) values associated with unexpectedly increased thyroxine (FT4) and free triiodothyronine (FT3) in findings of patients without any thyroid disease. Moreover, we looked for alternatives to overcome such states with an improved diagnostic procedure and to investigate the pathogenetic background of the respective patients. METHODS: Samples with TSH concentrations within the range of 0.4-10 mU/L combined with increased concentrations of FT4 (n=120; Cobas, Roche) were collected over a period of around six years. Cobas FT4 results were compared with measurements from Liaison (DiaSorin) and Architect (Abbott) FT4 assays. For further validation all samples were measured for total thyroxine (TT4) (Cobas, Roche). Finally, FT3 and TT3 as complementary parameters were measured in samples with leftover material. To overcome potential analytical disturbances from stimulating heterophilic antibodies, we used heterophilic blocking tubes (HBTs). RESULTS: From the 120 samples with increased FT4 concentrations by Cobas, 51/120 were also increased by Liaison, and 26/120 by Architect. However, the measurement of TT4 indicated only n=10/120 increased values. The number of increased FT3 (n=71) measurements was higher in Architect>Cobas>Liaison (28>27>9). TT3 levels of 70/71 samples were within the reference interval. HBTs were inappropriate to reduce unspecific immunoreactivity in our samples. No clear pathogenetic background could be elucidated in the anamnesis of individual patients. CONCLUSIONS: To overcome dubious constellations of TSH, FT4, and FT3, it is helpful to measure TT4 and TT3 for control or to use an immunoassay with an alternative assay design for the respective parameters.

Effects of temporary low-dose galactose supplements in children aged 5-12 y with classical galactosemia: a pilot study.

BACKGROUND: Classical galactosemia is caused by severe galactose-1-phosphate uridyltransferase deficiency. Despite life-long galactose-restriction, many patients experience long-term complications. Intoxication by galactose and its metabolites as well as over-restriction of galactose may contribute to the pathophysiology. We provided temporary low-dose galactose supplements to patients. We assessed tolerance and potential beneficial effects with clinical monitoring and measurement of biochemical, endocrine, and IgG N-glycosylation profiles. METHODS: We enrolled 26 patients (8.6 ± 1.9 y). Thirteen were provided with 300 mg of galactose/day followed by 500 mg for 2 wk each (13 patient controls). RESULTS: We observed no clinical changes with the intervention. Temporary mild increase in galactose-1-phosphate occurred, but renal, liver, and bone biochemistry remained normal. Patients in the supplementation group had slightly higher leptin levels at the end of the study than controls. We identified six individuals as "responders" with an improved glycosylation pattern (decreased G0/G2 ratio, P < 0.05). There was a negative relationship between G0/G2 ratio and leptin receptor sOb-R in the supplementation group (P < 0.05). CONCLUSION: Temporary low-dose galactose supplementation in children over 5 y is well tolerated in the clinical setting. It leads to changes in glycosylation in "responders". We consider IgG N-glycan monitoring to be useful for determining individual optimum galactose intake.

Influence of external, intrinsic and individual behaviour variables on serum 25(OH)D in a German survey.

The objective of the present study was to identify external, intrinsic or behavioural factors that significantly influenced serum 25-hydroxyvitamin D (25(OH)D) concentrations in a German survey. Data from 3061 participants in the Cooperative Health Research in the Region of Augsburg, Germany (KORA) F4 survey were used to relate potential determinants to measured mean serum 25(OH)D concentrations using multivariable regression models. The factors significantly associated with hypovitaminosis D (defined as 25(OH)D<25 nmolL(-1)) were season (winter, spring and autumn), urban environment and high body mass index. In contrast, times spent in sunny regions, hours per day spent outdoors in the summer as well as additional oral intake were associated with higher 25(OH)D concentrations. These results suggest that mainly ambient UV exposure but also individual behaviour are the most important determinants for personal 25(OH)D concentrations. The analyses further showed that in winter 43% of subjects were vitamin D deficient and 42% insufficient. Even in summer over half the population has insufficient vitamin D status with 8% deficient and 47% insufficient. Therefore measures to mitigate widespread vitamin D insufficiency such as regular short-term sun exposure and/or improved dietary intake/supplementation recommendations by public health bodies need to be considered.

Effect of calcium phosphate and vitamin D3 supplementation on bone remodelling and metabolism of calcium, phosphorus, magnesium and iron.

BACKGROUND: The aim of the present study was to determine the effect of calcium phosphate and/or vitamin D3 on bone and mineral metabolism. METHODS: Sixty omnivorous healthy subjects participated in the double-blind, placebo-controlled parallel designed study. Supplements were tricalcium phosphate (CaP) and cholecalciferol (vitamin D3). At the beginning of the study (baseline), all subjects documented their normal nutritional habits in a dietary record for three successive days. After baseline, subjects were allocated to three intervention groups: CaP (additional 1 g calcium/d), vitamin D3 (additional 10 µg/d) and CaP + vitamin D3. In the first two weeks, all groups consumed placebo bread, and afterwards, for eight weeks, the test bread according to the intervention group. In the last week of each study period (baseline, placebo, after four and eight weeks of intervention), a faecal (three days) and a urine (24 h) collection and a fasting blood sampling took place. Calcium, phosphorus, magnesium and iron were determined in faeces, urine and blood. Bone formation and resorption markers were analysed in blood and urine. RESULTS: After four and eight weeks, CaP and CaP + vitamin D3 supplementations increased faecal excretion of calcium and phosphorus significantly compared to placebo. Due to the vitamin D3 supplementations (vitamin D3, CaP + vitamin D3), the plasma 25-(OH)D concentration significantly increased after eight weeks compared to placebo. The additional application of CaP led to a significant increase of the 25-(OH)D concentration already after four weeks. Bone resorption and bone formation markers were not influenced by any intervention. CONCLUSIONS: Supplementation with daily 10 µg vitamin D3 significantly increases plasma 25-(OH)D concentration. The combination with daily 1 g calcium (as CaP) has a further increasing effect on the 25-(OH)D concentration. Both CaP alone and in combination with vitamin D3 have no beneficial effect on bone remodelling markers and on the metabolism of calcium, phosphorus, magnesium and iron. TRIAL REGISTRATION: NCT01297023.

Effect of reducing the n-6/n-3 fatty acid ratio on the maternal and fetal leptin axis in relation to infant body composition.

OBJECTIVE: To investigate the effect of reducing the n-6/n-3 fatty acid ratio in maternal nutrition on the maternal and cord blood leptin axis and their association with infant body composition up to 2 years. DESIGN AND METHODS: 208 healthy pregnant women were randomized to either a dietary intervention to reduce the n-6/n-3 fatty acid ratio from 15th week of gestation until 4 months postpartum or a control group. Leptin, soluble leptin receptor and free leptin index were determined in maternal and cord plasma and related to infant body composition assessed by skinfold thicknesses up to 2 years. RESULTS: The intervention had no effect on either the maternal or fetal leptin axis. Maternal leptin in late pregnancy was inversely related to infant weight and lean body mass (LBM) up to 2 years, after multiple adjustments. Cord leptin was positively related to weight, body fat, and LBM at birth, and inversely associated with weight, BMI, fat mass, and LBM at 2 years and weight gain up to 2 years. The contribution of cord leptin to infant outcomes was overall stronger compared with maternal leptin. CONCLUSIONS: Both, maternal and fetal leptin were associated with subsequent infant anthropometry with a greater impact of fetal leptin.

Exenatide-induced reduction in energy intake is associated with increase in hypothalamic connectivity.

OBJECTIVE: Glucagon-like peptide-1 receptor agonists such as exenatide are known to influence neural activity in the hypothalamus of animals and to reduce energy intake. In humans, however, significant weight loss has been observed in only a subgroup of patients. Why only some individuals respond with weight loss and others do not remains unclear. In this functional magnetic resonance imaging (fMRI) study, we investigated differences in hypothalamic connectivity between "responders" (reduction in energy intake after exenatide infusion) and "nonresponders." RESEARCH DESIGN AND METHODS: We performed a randomized, double-blinded, placebo-controlled, cross-over fMRI study with intravenous administration of exenatide in obese male volunteers. During brain scanning with continuous exenatide or placebo administration, participants rated food and nonfood images. After each scanning session, energy intake was measured using an ad libitum buffet. Functional hypothalamic connectivity was assessed by eigenvector centrality mapping, a measure of connectedness throughout the brain. RESULTS: Responders showed significantly higher connectedness of the hypothalamus, which was specific for the food pictures condition, in the exenatide condition compared with placebo. Nonresponders did not show any significant exenatide-induced changes in hypothalamic connectedness. CONCLUSIONS: Our results demonstrate a central hypothalamic effect of peripherally administered exenatide that occurred only in the group that showed an exenatide-dependent anorexigenic effect. These findings indicate that the hypothalamic response seems to be the crucial factor for the effect of exenatide on energy intake.

Dietary supplementation with trans-11- and trans-12-18 : 1 increases cis-9, trans-11-conjugated linoleic acid in human immune cells, but without effects on biomarkers of immune function and inflammation.

Trans-fatty acid intake is associated with an increased risk of CHD and diabetes. The effects of single trans-fatty acid isomers are largely unexplored. The present study examined the effects of a 6-week supplementation with two trans-18 : 1 isomers (trans-11 and trans-12) in human subjects on immune cells, several inflammatory and immunological biomarkers (for example, IL, TNFalpha, C-reactive protein, adiponectin, intercellular adhesion molecule-1, prostacyclin, phagocytic process). Following a 2-week adaptation period without supplements, the test group (n 12) received vaccenic acid (trans-11-18:1) and trans-12-18 : 1 in equal amounts (6.0 g/d) for 6 weeks. The control group (n 12) consumed an oil without trans-fatty acids and conjugated linoleic acids (CLA). Samples were collected at the end of both periods. Trans-11- and trans-12-18 : 1 were significantly increased in cellular lipids. The endogenous synthesis of cis-9, trans-11-CLA from trans-11-18 : 1 was demonstrated via increased CLA in cellular lipids of the test group. Generally, trans-isomer supplementation did not affect either inflammatory biomarkers (for example, IL-6, IL-8, TNFalpha) or immune function (for example, phagocytosis) during the present study. The dietary supplementation of trans-11- and trans-12-18 : 1 (6 g/d) and their accumulation in leucocytes had no effects on biomarkers of inflammation and immune function. However, because of the limited data on the safety of trans-fatty acid intake and effects of individual trans isomers on human health (for example, trans-9-18 : 1, trans-10-18 : 1) at present, it is prudent to reduce trans-fat intake in general.