Complete Inhibition of rhTSH-, Graves’ Disease IgG-, and M22-Induced cAMP Production in Differentiated Orbital Fibroblasts by a Low-Molecular-Weight TSHR Antagonist.
van Zeijl CJ, van Koppen CJ, Surovtseva OV, de Gooyer ME, Plate R, Conti P, Karstens WJ, Timmers M, Saeed P, Wiersinga WM, Miltenburg AM, Fliers E, Boelen A.  JCEM 2012 May;97(5):E781-5. Epub 2012 Mar 14.
The TSH receptor (TSHR) on orbital fibroblasts (OF) is a proposed target of the autoimmune attack in Graves’ ophthalmopathy. In the present study, we tested whether the novel low-molecular-weight (LMW) TSHR antagonist Org-274179-0 inhibits cAMP production induced by rhTSH, Graves’ disease IgG (GD-IgG), or M22 (a potent human monoclonal TSHR stimulating antibody) in cultured and differentiated OF from Graves’ ophthalmopathy patients. cAMP production significantly increased after incubation either with 10 mU/ml rhTSH (3-fold; P ≤ 0.05), 1 mg/ml GD-IgG (2-fold; P ≤ 0.05), or 500 ng/ml M22 (5-fold; P ≤ 0.05). Incubation with the LMW TSHR antagonist dose dependently inhibited rhTSH, GD-IgG as well as the M22-induced cAMP production at nanomolar concentrations; complete blockade was affected at 10(-6) m. Our results suggest that GD-IgG- and M22-induced cAMP production in differentiated OF is exclusively mediated via the TSHR because it can be completely blocked by the LMW TSHR antagonist.
COMMENT-That cAMP  production caused by Graves’ IgG can be completely blocked in a TSH receptor antagonist, fits with a single-function antibody in the IgG, but does not rule out other possible antibodies, or other stimulatory pathways.  However this study raises hope for cliically useful low molecular weight TSHR antagonists that could be safe and effective in GD and GO.

ABSTRACT-Medullary thyroid carcinoma (MTC) is a calcitonin (CT)-producing C-cell tumor. In hereditary cases, a germline RET mutation is found in 98% of families. Because MTC is cured only if intrathyroidal, prophylactic thyroidectomy is recommended in the gene carrier (GC). Aims: The aim was to determine whether thyroidectomy performed when stimulated CT becomes detectable is as safe as prophylactic thyroidectomy and to identify the serum CT cutoff able to distinguish intrathyroidal from extrathyroidal MTC. Eighty-four GC were prospectively enrolled; 53 of the 84 underwent total thyroidectomy, one refused surgery, and 30 with normal basal and stimulated CT were under surveillance. The follow-up ranged from 2 to 18 yr. Results: GC operated on for elevated stimulated CT included 27 GC with a positive peak CT at the screening and four cases who became positive after 4 yr. All of them had intrathyroidal MTC and no node metastases; all were cured after a mean follow-up of 7.5 yr. Among those operated on for detectable basal CT, intrathyroidal tumors were found when CT was below 60 pg/ml, whereas either node metastases or larger tumors were observed when CT was above 60 pg/ml. No correlation among serum CT, age, and type of RET mutation was observed. Thirty GC were still biochemically negative at the annual control.
Conclusions: The time of thyroidectomy in GC with negative CT could be personalized and safely planned when stimulated CT becomes positive, independent of the type of RET mutation and patient’s age. In this series, a basal CT below 60 pg/ml was always associated to an intrathyroidal localization of MTC.
COMMENT-The authors argue that timing of thyroidectomy for mutation carriers should not depend entirely on the type of mutation. Rather, they show that it is safe to follow patients with repeated basal and/or PG-stimulate CT levels. Above 10 (based on their local assay results), operation is indicated, and if below 60pg/ml, the tumor seems always to be intrathyroidal and susceptible to eradication.  L De Groot, MD

AbstractThyroid hormones exert their effects through alpha (TRα1) and beta (TRβ1 and TRβ2) receptors. Here we describe a child with classic features of hypothyroidism (growth retardation, developmental retardation, skeletal dysplasia, and severe constipation) but only borderline-abnormal thyroid hormone levels. Using whole-exome sequencing, we identified a de novo heterozygous nonsense mutation in a gene encoding thyroid hormone receptor alpha (THRA) and generating a mutant protein that inhibits wild-type receptor action in a dominant negative manner. Our observations are consistent with defective human TRα-mediated thyroid hormone resistance and substantiate the concept of hormone action through distinct receptor subtypes in different target tissues. Comment- This is a report of the first person identified with a mutation in the TRα gene, that appeared to cause clear hypothyroidism, but was not readily reversed by T4 treatment. T4 was 3.3 ug/dl, T3 155 ng/dl, TSH 1.04 mU/l,  normal TBG, IGF-1 low at 59 ng/ml,  BP82/51, and BMR 3.49M/day (nl=4.06). Sequencing identified one heterozygous mutation (c1207 G>T  in TRα), present in multiple tissues but not in 200 control alleles,  that could explain the phenotype. The abnormal receptor did not bind T3, did not activate a control gene, mediated suppression of basal promoter activity, and was a “dominate negative”. Treatment with T4 suppressed TSH, but failed to normalize growth or sluggish bowel function. The biochemical findings have many similarities to those seen in mice with dominant negative TRα mutations, but interestingly TRα null mice do not have abnormalities similar to the patient. A combination of hypothyroid features, near normal T4 with slightly elevated T3, and low rT3 may characterize the syndrome. Effective treatment is unclear at present

Title: Iodine Content of U.S. Prenatal Multivitamins

Authors: Leung AM, Braverman LE, Pino S, He X, & Pearce EN.

Reference: Thyroid 18 (Suppl. 1) S-45, 2008 Abstract of a poster presented at the 79th Annual Meeting of the American Thyroid Association (Chicago, October 2008)

Summary

Background

Adequate maternal iodine intake during pregnancy and lactation is essential for thyroid hormone production in the fetus and neonate. The Institute of Medicine recommends a daily iodine intake of 220 µg in pregnancy and 290 µg in lactation. The American Thyroid Association (ATA) recommends vitamin supplements containing 150 µg of iodine daily during pregnancy and lactation, yet the iodine content of U.S. prenatal multivitamins is not mandated.

Methods

Using the Internet, the authors found 127 non-prescription and 96 prescription prenatal multivitamins marketed in the United States.

Results

Sixty-nine percent (N=87) of non-prescription and 28% (N=27) of prescription brands listed iodine as a constituent. Of 114 iodine-containing prenatal multivitamins, 101 (89%) listed ≥150 µg/serving [kelp, n=42; KI, n=67; other, n=5]. Since 150 µg KI contains only 76% (114 µg) iodine, current labelling is misleading. The iodine content of 60 iodine-containing brands was measured. Measured iodine content per serving in 35 KI-containing vitamins was 119 (mean) ± 14 (SE) µg, which was similar to 120 ± 7 µg of iodine, calculated as 76% of the labelled KI. The measured iodine-containing brands prepared from kelp contained 33-610 µg/serving. Fourteen of 25 had iodine levels that were ≥50% discordant with listed values (including 10 that were lower by ≥50%), likely due to variation in kelp iodine content.

Conclusions

Only 69% of non-prescription and 28% of prescription U.S. prenatal multivitamins contain iodine. Multivitamins containing iodine as kelp have variable iodine content. Although more consistent, multivitamins from KI also are misleading, since the iodine content is only 76% of the labelled KI. Prenatal multivitamin manufacturers should be encouraged to use only KI, to maintain consistency in labelling, and to include ≥197 µg KI/serving to ensure 150 µg of supplemental daily iodine, as recommended by the ATA.

Commentary

Iodine deficiency during pregnancy and childhood has serious consequences. Severe iodine deficiency during pregnancy results in miscarriage and cretinism, while inadequate iodine intake during a child’s development can lead to goiter and learning disabilities. Adequate iodine supplementation can eradicate these deleterious outcomes. Theoretically, iodine deficiency can be eliminated through a combination of universal salt iodination and mandatory inclusion of iodine in prenatal vitamins. Yet, despite international efforts, spanning several decades, the World Health Organization estimates that worldwide iodine deficiency still occurs today in 2 billion people ( NEJM , 354:2819, 2006). Adequate iodine intake is particularly critical during pregnancy as the iodine needs are increased due to a 50% rise in thyroid hormone production and increased renal iodine losses.

Iodine status in the United States has been periodically assessed since the early 1970s through the National Health and Nutrition Examination Surveys (NHANES). A decrease in median urinary iodine concentration (UIC) was observed between NHANES I (1970s) and NHANES III (1988-1994). Specifically, the median UIC decreased from 320 µg/L to 145 µg/L. Of particular concern in NHANES III, was that 14.9% of women between the ages of 15-44 years, and 6.9% of pregnant women, had median UIC of ≤50 µg/L (Public Health Nutrition, 10:1532, 2007). Iodine deficiency is defined as a median UIC of less than 100 µg/L ijn a given population. These data raise the question as to whether or not a segment of pregnant women in the United States may suffer from iodine deficiency.

The abstract presented by Leung and colleagues at the annual meeting of the American Thyroid Association in 2008 provides an analysis of the iodine content in prenatal vitamins (PNVs) in the United States. The compelling data from their abstract are as follows:

1. there is a minimum of 221 PNVs available in the US (96 of them available by prescription only);
2. only 69% of non-prescription PNVs and 28% of prescription PNVs contain iodine;
3. kelp was the source of iodine in 42 of the 101 iodine-containing PNVs; and
4. the iodine content measured in kelp-containing PNVs was markedly discordant with the labelling, while the iodine content of KI containing PNVs was more accurately reflected in the label.

In summary, the multitude of PNVs in the United States, the lack of iodine in the majority of prescription brand PNVs and a third of non-prescription PNVs, and the variable content of iodine measured in kelp containing PNVs, leads one to conclude that whether or not a pregnant woman receives an iodine containing PNV (or if she does what the iodine content is) is simply a chance occurrence. The study of Leung and colleagues, in conjunction with the recent NHANES III data, should serve as a call to action to prevent iodine deficiency during pregnancy in the US. It is time for medical organizations to work together to mandate that all PNVs contain a minimum of 150 µg of KI. Editorial written by Alex Stagnaro-Green (Related to Chapters 14 & 20 of TDM)

J Clin Endocrinol Metab. 2011 Jan;96(1):E109-13. Epub 2010 Oct 13.

The prevalence of occult medullary thyroid carcinoma (MTC) in the general population is unknown but may be important when considering strategies to diagnose clinically relevant MTC in nodular goiter or other populations. The authors conducted a systematic review of autopsy series from 1970 to present using a PubMed search. The patients came from 21 countries, ages ranged from 6-95 yr, both genders were represented, and none had clinical evidence of thyroid disease before autopsy. An average prevalence of 0.14 and 7.6% for occult MTC and papillary thyroid carcinoma, respectively, was found among 7897 autopsies from 24 published series. Greater than 75% of patients with MTC were more than 60 yr old, and male to female ratio was comparable. Tumor size was virtually all subcentimeter, and there was no lymph node spread, extrathyroidal extension, or distant metastases reported. A small number of people in the general population, who do not have known thyroid disease, have occult MTC and die of other causes. This finding of untreated occult MTC without morbidity or mortality should be considered in population prevalence studies, when strategies to detect thyroid neoplasia are considered (e.g. serum calcitonin or ultrasound), and included in cost-effectiveness models of routine serum calcitonin screening for nodular thyroid disease.