John T. Dunn

Iodine Deficiency in the World: Where Do we Stand at the Turn of the Century?

Iodine deficiency is the leading cause of preventable mental retardation. Universal salt iodization (USI), calling for all salt used in agriculture, food processing, catering and household to be iodized, is the agreed strategy for achieving iodine sufficiency. This article reviews published information on programs for the sustainable elimination of the iodine deficiency disorders and reports new data on monitoring and impact of salt iodization programs at the population level. Currently, 68% of households from areas of the world with previous iodine deficiency have access to iodized salt, compared to less than 10% a decade ago. This great achievement, a public health success unprecedented in the field of noncommunicable diseases, must be better recognized by the health sector, including thyroidologists. On the other hand, the managers and sponsors of programs of iodized salt must appreciate the continuing need for greatly improved monitoring and quality control. For example, partnership evaluation of iodine nutrition using the ThyroMobil model in 35,223 schoolchildren at 378 sites of 28 countries has shown that many previously iodine deficient parts of the world now have median urinary iodine concentrations well above 300 microg/L, which is excessive and carries the risk of adverse health consequences. The elimination of iodine deficiency is within reach but major additional efforts are required to cover the whole population at risk and to ensure quality control and sustainability.

Europe is iodine deficient

original curvature, and myopia returns. Furthermore, some corneae, even after minor surgery is done and the cornea healthy before surgery, become conical (a condition called keratoconus), which if sufficiently progressive can be repaired only by corneal transplantation. No one knows the rate of risk or the timescale of this serious complication. No warnings are carried in advertisements and almost all treatments are bilateral, so patients are unable to assess the effect of surgery on one eye, before surgery on the second is undertaken. On their website, the US Food and Drug Administration (http://www.fda. gov) note that LASIK eye surgery is an option for risk takers. The time has come to issue health warnings. William Jory

World Status of Monitoring of Iodine Deficiency Disorders Control Programs

Monitoring and evaluation are the last phases of a national iodine deficiency disorders (IDD) control program but among the most important. This paper summarizes the latest recommendations by the World Health Organization (WHO), the United Nations Childrens Fund (UNICEF), and the International Council for Control of Iodine Deficiency Disorders (ICCIDD) about indicators and their normative values for monitoring the progress of IDD elimination and illustrates the successful monitoring programs in Switzerland and in China. Salt is the usual vehicle for iodine supplementation and quality control for iodine content can be assessed quantitatively by titration and qualitatively by simple test kits that can be used in the field. The most useful indicator of iodine nutrition is the median urinary iodine concentration. Thyroid size, especially by ultrasound, and neonatal thyrotropin (TSH) are also valuable. In Switzerland, access to iodized salt on a voluntary basis started in 1922. The initial level of iodization, 1.9-3.75 ppm iodine as potassium iodide (KI), was slowly increased to 15 ppm, and recently to 20 ppm, after careful epidemiologic and biologic monitoring. Elimination of IDD has been highly successful. The program costs US dollars 0.07 per year per person. In China, a national program of iodized salt (10-30 ppm) started in 1960 under the authority of the central government and rapidly expanded. National monitoring surveys have taken place every 2 years since 1993. Median urinary iodine, initially low, increased to 165 microg/L in 1995 and to 306 microg/L in 1999, prompting a decrease in the amount of iodine added to salt. The total goiter rate decreased to 20.4% in 1995 and to 8.8% in 1999. IDD can presently be considered as eliminated in China. Review of monitoring in the 128 other major countries affected by IDD shows extremely variable achievements, with evidence of IDD elimination in at least 18 additional countries. Some countries that were severely iodine deficient in the past are now exposed to iodine excess and risk its effects. Sustainable elimination of IDD is within reach and would constitute an unprecedented global success story in the field of noncommunicable diseases, but continuing vigorous action is required to attain this goal.

Tyrosine 130 Is an Important Outer Ring Donor for Thyroxine Formation in Thyroglobulin

The thyroid couples two iodotyrosine molecules to produce thyroid hormone at the acceptor site in thyroglobulin, leaving dehydroalanine or pyruvate at the donor position. Previous work has located the acceptors but not the principal iodotyrosine donors. We incorporated [14C]tyrosine into beef thyroid slices, isolated and iodinated the [14C]thyroglobulin (Tg I), separated its N-terminal ∼22-kDa hormone-rich peptide, and digested the latter with trypsin and endoproteinase Glu-C (EC3.4.21.19). Nonlabeled thyroglobulin (Tg II) was isolated from the same glands and processed similarly, without iodination in vitro. Tg I was used to initially recognize pyruvate in peptide fractions, and Tg II was used to then identify its location in the thyroglobulin polypeptide chain. Sequencing of a tryptic peptide by mass spectrometry and Edman degradation showed a cleavage after Val129. An endoproteinase Glu-C-generated peptide had the predicted molecular mass of a fragment containing residues 130–146 with Tyr130 replaced by pyruvate; the identification of this peptide was supported by obtaining the expected shortened fragment after tryptic digestion. 14C-labeled pyruvate was identified in the same fraction as this peptide. We conclude that Tyr130 is an important donor of the outer iodothyronine ring. Its likely acceptor is Tyr5, the most important hormonogenic site of thyroglobulin, because Tyr5 and Tyr130 are proximate, because they are the most prominent early iodination sites in this part of thyroglobulin, and because the N-terminal region was previously found capable of forming T4 by itself.

Choriocarcinoma with hyperthyroidism: probable identity of the thyrotropin with human chorionic gonadotropin.

A 15-year-old girl developed severe hyperthyroidism secondary to metastatic choriocarcinoma. Her serum contained high levels of human chorionic gonadotropin (HCG) by radioimmunoassay and had a thyroid-stimulating activity different from that of pituitary thyrotropin (TSH) or of long-acting thyroid stimulator (LATS) in the McKenzie mouse bio-assay. Gradient ultracentrifugation localized this thyroid stimulator to a narrow zone midway between markers of transferrin and ovalbumin. On gel filtration it emerged just before albumin as a single peak coinciding with the peak for HCG. Her HCG was identical to an authentic sample of HCG in position to gel filtration columns and on gel electrophoresis. These results suggest that the thyrotropin of choriocarcinoma is HCG.

The importance of thyroglobulin structure for thyroid hormone biosynthesis.

Thyroglobulin (Tg) is the most important protein in the thyroid because it provides the matrix for thyroid hormone biosynthesis. Here we review experimental work, principally from our laboratory, on the relationship between Tg structure and hormonogenesis. Early work showed that Tgs most important hormonogenic site was located in a fragment of approximately 26 kDa obtained on chemical reduction. With the establishment of the cDNA sequence of Tg, this and other major sites could be localized within Tgs polypeptide chain. The four major hormonogenic sites, designated A, B, C, and D, are located respectively at tyrosyls 5, 2553, 2746, and 1290. In most species, site A accounts for about 40% of Tgs hormone, and site B for about 25%. Site C is associated with increased T3, at least in some species. Site D is prominent in guinea pigs and rabbits, and TSH favors hormonogenesis at it in these species. Sequential iodination of low iodine human Tg shows three consensus sequences associated with early iodination and with T4 formation. Recent work has identified Tyr130 in beef Tg as donor of an outer iodothyronine ring, most likely to Tyr5, the most important hormonogenic site. In addition to its biochemical importance, Tg has clinical interest in familial goiter and autoimmune thyroid disease. Further elucidation of Tg structure and its relation to thyroid hormone synthesis will contribute to thyroid physiology and to its clinical application.

Iodine nutrition and the risk from radioactive iodine: a workshop report in the chernobyl long-term follow-up study.

The major fallout of radionuclides from the nuclear power station accident at Chernobyl on 26 April, 1986, occurred in regions of Ukraine and Belarus that are believed to be moderately deficient in dietary iodine. On 17 November, 2000, in conjunction with the Ukraine-Belarus-USA study of developing thyroid disease in a cohort of individuals exposed as children, a workshop was held to review what is known about iodine nutrition in the region, how this might influence the risk of thyroid tumor formation from radioiodine, and whether and how iodine nutrition should be monitored in this long-term project. This report is a summary of the workshop proceedings. Although no precise information about iodine intake in 1986 was found, the prevalence of mild goiter in the regions children suggested iodine deficiency and urinary iodine measurements begun in 1990 indicated that mild to moderate deficiency existed. Increased thyroid iodine uptake and increased thyroid size in 1986 resulting from iodine deficiency would have had counteracting influence on the thyroid radiation dose and knowledge of these parameters is required for dose reconstruction. More problematic is the possible role of iodine deficiency in the years following the accident. Theoretically, the resulting increase in thyroid cellular activity might increase the risk of tumorigenesis but experimental or clinical evidence supporting this hypothesis is meager or absent. Despite this limitation it was considered important to monitor iodine nutrition in the cohort subjects in relation to their place of residence and over time. Methods to accomplish this were discussed.

Epidemiology of iodine deficiency.

Iodine deficiency (ID) causes goiter, cretinism, neonatal hypothyroidism, irreversible mental retardation, and child and infant death. Over one billion people are at risk, most of them in developing countries. While ID is the primordial factor in these conditions, other environmental and host factors significantly modify the magnitude and clinical presentation of iodine deficiency disorders. The interactions and mechanisms by which these factors operate are complex and mostly unknown, requiring more investigation.

Iodine supplementation and the prevention of cretinism.

Normal development of the CNS requires adequate thyroid hormone exposure. Since iodine is an essential component of the thyroid hormone molecule, its deficiency during fetal development can cause hypothyroidism and irreversible mental retardation. The full-blown syndrome, called cretinism, includes deaf-mutism, short stature, spasticity, and profound mental retardation. The clinical spectrum can vary in degree and combination of these features. Screening programs in iodine-deficient countries show that up to 10% of neonates have elevated serum TSH levels, putting them at theoretical risk for permanent brain damage. About one billion people worldwide risk the consequences of iodine deficiency, all of which can be prevented by adequate maternal and infant iodine nutrition. Iodized salt is usually the preferred prophylactic vehicle, but iodized vegetable oil, iodized water, and iodine tablets are also occasionally used. The United Nations and the heads of state of most countries have pledged the virtual elimination of iodine deficiency by the year 2000. This goal is technically feasible if pursued with sufficient vigor and resources.

Fast Colorimetric Method for Measuring Urinary Iodine

International groups recommend the following median urinary iodine concentration as the best single indicator of iodine nutrition in populations: severe deficiency, 0–0.15 μmol/L (0–19 μg/L); moderate deficiency, 0.16–0.38 μmol/L (20–49 μg/L); mild deficiency, 0.40–0.78 μmol/L (50–99 μg/L); optimal iodine nutrition, 0.79–1.56 μmol/L (100–199 μg/L); more than adequate iodine intake, 1.57–2.36 μmol/L (200–299 μg/L); and excessive iodine intake, ≥2.37 μmol/L (≥300 μg/L) (1). The range in which the median falls is more important than the precise number (2)(3). Many methods for assessing urinary iodine exist (3)(4)(5)(6)(7)(8), most based on the Sandell–Kolthoff reaction (9), in which iodide catalyzes the reduction of ceric ammonium sulfate (yellow) to the colorless cerous form in the presence of arsenious acid. Although iodide is the chemical form for both the catalytic reaction and in urine, some preliminary treatment is needed to rid urine of impurities, most commonly by acid digestion (3)(5). We have extended previous approaches (5)(6)(10) with improved conditions and here present a new method (“Fast B”) that is rapid, inexpensive, reliable, and flexible. The equipment required for the Fast B method includes a heating block, Pyrex test tubes (13 × 100 mm), two fixed-volume pipettes (0.5 mL and 1.0 mL), one adjustable pipette (0–200 μL), and a multipet (Eppendorf) for quick reagent volume additions of 0.125 and 0.1 mL. The basic chemicals used are potassium iodate, arsenic trioxide, ammonium persulfate, ammonium cerium(IV) sulfate dihydrate, sodium chloride, ferroine, and sulfuric acid. The solutions used in the assay are as follows: