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ObjectiveThe objective of this study was to re-evaluate the adult CT reference values determined by five different immunoassays and by introducing criteria for selecting control subjects.DesignA prospective multicenter study.PatientsThree hundred and seventy-five clinically euthyroid subjects.MethodsWe used five different CT immunoassays. Sera were assayed for the concentration of TSH, gastrin, procalcitonin, urea, calcium, and anti-thyroperoxidase antibodies.ResultsScreening for the various potential causes of hypercalcitoninemia led to the exclusion of 23% of the sera. Our reference value analysis dealt with 287 subjects (142 men and 145 women). The proportion of samples in which no CT was detected varied from 56% (for assay D) to 88% (for assay C). We observed significant correlations (whose magnitude depended on the assay used) between CT levels and age or body mass index (BMI) (primarily in men). The distribution of CT levels showed that 4.7, 9.8, 2.5, 6.5, and 8.0% of the values were over 10 pg/ml respectively. These values corresponded essentially to samples from 11 male subjects (median age: 55 years), most of whom were smokers. The highest CT values were around twice as high in men than women, and were higher in smokers than non-smokers.ConclusionIn clinical practice (and after having excluded the usual causes of raised CT levels), the interpretation of CT assay results must take into account i) the method used; ii) the patient's gender, age, and weight; and iii) the potential influence of cigarette smoking.

Familial medullary thyroid carcinoma only is related to germline mutations in the protooncogene RET, mainly in exons 10, whereas noncysteine mutations (exons 13-15) are considered infrequent. We analyzed 148 patients from 47 familial medullary thyroid carcinoma only families, and we found noncysteine RET mutations in 59.5% of these families. Of the index cases with noncysteine mutations, 43.4% presented with a multinodular goiter and high basal calcitonin; they were older at diagnosis than those with mutation in exon 10 and had more multifocal medullary thyroid carcinoma, but no difference in size, bilaterality, presence of C cell hyperplasia, or nodal metastases was found. Gene carriers with noncysteine RET mutations had a lower incidence of medullary thyroid carcinoma (78.2% vs. 94.1%) than those with mutation in exon 10; 20.2% had C cell hyperplasia only, although thyroidectomized at an older age. In conclusion, familial medullary thyroid carcinoma with noncysteine RET mutations are not infrequent and are overrepresented in presumed sporadic medullary thyroid carcinoma, suggesting that RET analysis should routinely be extended to exons 13, 14, and 15. The phenotype is characterized by a late onset of the disease, suggesting a delayed appearance of C cell disease rather than a less aggressive form. In familial medullary thyroid carcinoma gene carriers, the optimal timing for thyroidectomy remains controversial. Based on these data, we propose that surgery should be performed before elevation of the basal calcitonin level, potentially as soon as the pentagastrin test becomes abnormal.

In an attempt to explore the natural variable heavy and light chain (VH/VL) pairing of autoantibodies involved in Graves’ disease, we constructed a phage-displayed Ab library obtained by in-cell PCR of thyroid-infiltrating cells. We report here the molecular cloning and characterization of human single-chain fragment variable regions (scFv) specific for thyroid peroxidase (TPO) generated from this library. On the basis of the nucleotide sequences, three different scFvs were obtained (ICA1, ICB7, and ICA5). All were encoded by genes derived from the VH1 and Vλ1 gene families. Using BIACORE for epitope mapping and kinetic analysis, we showed that these scFvs exhibited high affinity (Kd = 1 nM) for TPO and recognized three different epitopes. The biological relevance of these scFvs as compared with serum anti-TPO autoantibodies was assessed by competition studies. Sera from all the 29 Graves’ disease patients tested were able to strongly inhibit (60–100%) the binding of the 3 scFvs to TPO. These data demonstrate that the in-cell PCR library generated human anti-TPO scFvs that retained the VH/VL pairing found in vivo and that the different epitope specificities defined by these scFvs overlapped with those found in the sera of patients with autoimmune thyroid disease.

THE ASSOCIATION of Graves' disease and hypothyroidism with chronic lymphocytic thyroiditis has long been recognized. In some cases, hypothyroidism seems to be the final outcome of Graves' thyrotoxicosis. 1 Many reports are not completely substantiated, however, and none, to our knowledge, reports on the histological appearance of the thyroid gland at both stages of the disease in the same patient. Report of a Case A 39-year-old woman (height, 159 cm; weight, 55 kg) was seen in 1972 with thyrotoxicosis, unilateral exophthalmos, and a large, smooth goiter. The six-hour sodium iodide uptake was raised at 68% (normal, 25% to 35% dose), and the scan was homogenous. The patient was euthyroid during antithyroid drug therapy (carbimazole, 30 mg/day), as confirmed at repeated checkups during 1972 and 1973. Treatment was discontinued voluntarily by the patient from 1973 to January 1977. At that time, the patient was again found to be thyrotoxic with a