Objectives-To describe the interrelationships of thyroid functions based on trimester-specific concentrations in healthy, iodine-sufficient pregnant women across trimesters, and postpartum.Methods-Circulating total 3,5,3′-triidothyronine (T 3 ) and thyroxine (T 4 ) concentrations were determined simultaneously using liquid chromatography tandem mass-spectrometry (LC/MS/MS). Free thyroxine (FT 4 ), thyroid-stimulating hormone (TSH), and thyroglobulin (Tg) were measured using immunoassay techniques. Linear mixed effects models and correlations were calculated to determine trends and associations, respectively, in concentrations.Results and conclusions-Trimester-specific T 3 , FT 4 , TSH, and Tg concentrations were significantly different between the first and third trimesters (all p < 0.05); second and third trimester values were not significantly different for FT 4 , TSH, and Tg (all p > 0.25) although T 3 was significantly higher in the third, relative to the second trimester. T 4 was not significantly different at any trimester (all p > 0.80). With two exceptions, analyte concentrations tended not to be correlated at each trimester and at 1-year postpartum. One exception was that T 3 and T 4 tended to be associated (all p < 0.05) at all time points except the third trimester (ρ = 0.239, p > 0.05). NIH Public Access

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Background-Most clinical chemistry laboratories measure free thyroxine (FT4) by an analogue (direct) method. Nevertheless, the validity of analogue FT4 immunoassays has been questioned and patient's results using this approach frequently do not fit in with the clinical presentation. Because of these problems we routinely send out all direct free T4's that are < 2.5th percentile and many that are > 97.5th percentile for measurement by equilibrium dialysis, the gold standard method. In approximately half of these cases, the FT4 by equilibrium dialysis was normal. We developed a rapid, reliable free T4 method employing isotope dilution tandem mass spectrometry and compared our results with both the analogue (direct) free T4 and equilibrium dialysis procedures.Methods-An API-4000 tandem mass spectrometer (Sciex, Toronto, Canada) equipped with TurboIonSpray and Agilent HPLC system was used employing isotope dilution with deuterium labeled internal standard (IS=L-thyroxine-d 2 ). Serum was filtered through the Centrifree YM-30 ultrafiltration device by centrifugation, IS added to the ultrafiltrate, and 400 μL injected onto a C-18 column. After washing, the switch valve is activated and a methanol gradient allows for elution of both T4 and the IS into the LC/MS/MS system. Quantitation was by MRM analysis in the negative mode. Equilibrium dialysis was performed by the Nichols method and analogue free T4 results were obtained on the Dade Dimension RxL.Results-The within-day and between-day CV's were < 7.1% at all concentrations tested. The results correlated well with equilibrium dialysis (Eq Dial=0.971 MS+0.041, n =68, Syx=1.381, r =0.954). A poor correlation was found with the analogue (direct) free T4 method (IA=0.326 MS +6.27, n =154, Syx=1.96, r =0.459). Conclusions-Samples can be processed in batches of 30. The free T4 tandem MS method has a rapid turn-around-time vs the equilibrium dialysis procedure, with a chromatographic run time of 8 min per sample. NIH Public Access

Missense mutations have been identified in the coding region of the extracellular calcium-sensing receptor (CASR) gene and cause human autosomal dominant hypo-and hypercalcemic disorders. The functional effects of several of these mutations have been characterized in either Xenopus laevis oocytes or in human embryonic kidney (HEK293) cells. All of the mutations that have been examined to date, however, cause single putative amino acid substitutions. In this report, we studied a mutant CASR with an Alu-repetitive element inserted at codon 876, which was identified in affected members of families with the hypercalcemic disorders, familial hypocalciuric hypercalcemia (

The calcium-sensing receptor (CASR), a member of the G-protein coupled receptor family, is expressed in both parathyroid and kidney, and aids these organs in sensing extracellular calcium levels. Inactivating mutations in the CASR gene have been described in familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT). Activating mutations in the CASR gene have been described in autosomal dominant hypoparathyroidism and familial hypocalcemia. The human CASR gene was mapped to Chromosome (Chr) 3q13.3-21 by fluorescence in situ hybridization (FISH). By somatic cell hybrid analysis, the gene was localized to human Chr 3 (hybridization to other chromosomes was not observed) and rat Chr 11. By interspecific backcross analysis, the Casr gene segregated with D16Mit4 on mouse Chr 16. These findings extend our knowledge of the synteny conservation of human Chr 3, rat Chr 11, and mouse Chr 16.

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We studied family members of a large kindred expressing both familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT) and found, by PCR amplification of the extracellular calcium-sensing receptor (CASR) gene exons and flanking intronic sequences, that FHH individuals were heterozygous for a g to t substitution in the last nucleotide of intron 2 (IVS2-1G>T). Defects in messenger RNA splicing were investigated by illegitimate transcription of the CASR gene in lymphoblastoid cells from an FHH affected individual, as well as by transfection of a CASR minigene harboring this mutation into HEK293 cells. The mutation resulted predominantly in exon III skipping causing a shift in exon IV reading frame and introduction of a premature stop codon leading to a predicted truncated protein of 153 amino acids. Interestingly, it was noted that exon III splicing is not 100% efficient in parathyroid, thyroid, and kidney; an exon III-deleted transcript is produced approximately 15% of the time. This is the first description of a splice site mutation in the CASR gene and provides an explanation of the clinical phenotype of the patients.

Objective: Severe gestational hypertriglyceridemia is a rare disease, and there are no published guidelines to assist the clinician in management. However, due to the elevations in lipids that occur during pregnancy, this condition is encountered in clinical practice and presents a therapeutic dilemma. We report the successful management and treatment of a patient with severe gestational hypertriglyceridemia and conducted a review of the literature regarding treatment modalities.Methods: We conducted a search in PubMed from 1990 to 2018 for the following terms: "severe hypertriglyceridemia in pregnancy;" "management of hypertriglyceridemia in pregnancy;" "apheresis for severe gestational hypertriglyceridemia;" "TPN for severe gestational hypertriglyceridemia;" "insulin for severe gestational hypertriglyceridemia;" and "heparin for treatment of severe hypertriglyceridemia." We then reviewed the literature.Results: Given the risks to the mother and fetus of severe hypertriglyceridemia, aggressive therapy should be initiated within a multidisciplinary team. There are multiple treatment modalities, including restrictive diet, various medications such as niacin, fibrates, intravenous heparin, insulin, and apheresis. Choice of treatment will depend on the patient's comorbidities, clinical status, and if there are any associated complications.Conclusion: Treatment for severe gestational hypertriglyceridemia should be initiated immediately and aggressively to avoid risk to the mother and infant, including pancreatitis, hyperviscosity syndrome, preeclampsia, fetal death, and preterm labor. (AACE Clinical Case Rep. 2019;5:e99-e103) Abbreviations: HDL = high-density lipoprotein; LPL = lipoprotein lipase; TG = triglyceride; VLDL = very-low-density lipoprotein METHODS Search StrategyWe conducted a search in PubMed for the following terms: "severe hypertriglyceridemia in pregnancy;" "pathophysiology of gestational hypertriglyceridemia;" "management of hypertriglyceridemia in pregnancy;" "apheresis for severe gestational hypertriglyceridemia;" Abbreviations: LPL = lipoprotein lipase; TG = triglyceride; VLDL = very-low-density lipoprotein. a Table adapted from references (1,3,4).