Incidence of Thyroid Diseases and Variation of Neonatal TSH Values -
Influence of Iodine Content Correction?

Nebojša Paunković, Jane Paunković
Nuclear Medicine, Medical Centre Zajecar

INTRODUCTION

Authors have reported the significant increase of incidence of autoimmune hyperthyroidism (Graves’ disease) in Region of East Serbia (Timok Region) for the period 1994-1996 (1,2). The increase was authentic, documented by correct diagnostic methodology (3). Feasible factors influencing the increase in incidence were summarized: psychological stress inflicted upon the population by the war in former Yugoslavia; increased iodine consumption and Chernobyl accident.
The aim of this report is to supplement contemporary findings (four years later), and further exploit the possibility of iodine influence in induction of autoimmune hyperthyroidism. We have delineated iodine for several reasons: a) Region of East Serbia was not iodine deficient, (previously existent mild iodine deficiency was corrected by salt iodization (10 mg/ kg of NaCl) implemented in 1953)(4,5);: b) new regulation of iodine supplementation (20 mg KJ/kg NaCl) was introduced in 1993(6) ; c) reports from 1953-1963 (the first introduction of iodine prophylaxis in Serbia), indicated transitory increase in incidence in hyperthyroidism including Graves’ disease (7).

METHODS

Registration of patients with Graves’ disease
Methods and registration technique for patients with Graves’ disease is discussed in details in previous report (1). In summary, only patients with clinically manifested Graves’ disease were registered. Diagnosis was based on contemporary endocrinological, functional and immmunological criterion (“free” thyroid hormones, "ultra sensitive" TSH, TSH receptor antibodies, ¹³¹I and ^99mTc uptake, thyroid scintigraphy). All diagnostic and clinical investigations were performed in a single institution , and only permanent residents of the Timok Region (before 1985), were included in this study.

1. Investigation of parameters indicative of iodine status:
   a) Thyroid morbidity: cumulative incidence of thyroid diseases from Thyroid Disease Register. Continuous registration of thyroid diseases (both autoimmune and non autoimmune was introduced in 1970 for the patients from Timok Region (population of approximately 315,000 people)
   b) Annual systematic examination of school children, (average number of children per year was 2341
   c) 131I uptake tests in healthy persons, performed on 411 of healthy persons referred to thyroid service in a period form 1963-1973. Euthyroid status was confirmed by clinical examination, T3 suppression test, PB¹³¹I until 1970, and total T4 since 1970.
   d) Neonatal TSH (1987-1999)(8) was performed as a part of Screening for congenital hypothyroidism (Neonatal hTSH, DELFIA, WALLAC). Samples from only one county (Zajecar) were included. Total number of investigated samples was N= 5338. Cases of congenital hypothyroidism were excluded from this study.
2. Investigation of incidence of thyroid disease (autoimmune and non autoimmune) and comparison with historical reports on increased incidence of hyperthyroidism following iodine prophylaxis in Yugoslavia (1953-1963).

RESULTS

Parameters indicative of iodine status

a) Thyroid morbidity
Cumulative incidence of thyroid diseases (both autoimmune and non immune) in Timok Region for the period 1970-1993 is presented in Table1.

c) 131I Uptake tests for healthy persons
Value of ¹³¹I Uptake after 3 hours was 7-20% ( MV+ 3SD) and
Value of ¹³¹I Uptake after 24 hours was 20-45% ( MV+ 3SD).

e) Neonatal TSH
MV+ SD for the entire investigated period (1987-1998) was 2.17+ 1.98 mU/l . Upper normal level was calculated as MV+ 2SD = 6.13 mU/l. Total number of registered cases of TSH>6 mU/l for the entire period was 137 (2.93%); for period 1987-1993 total number was TSH>6 mU/l was 96 (3.1%) and for period 1984-1998 total number was TSH>6 mU/l was 41 (2.5%) .

Increased incidence of hyperthyroidism was reported subsequent to implementation of the iodine prophylaxis in 1953. Honouring the memory of Professor Kicic we supplement the results of his report (7) on Graph 6 for comparison with our contemporary findings on Graph 4 and Graph 5 .


Graph 4. Incidence of autoimmune and non-immune thyroid diseases (1978-2000)


Graph 5. Comparative standardized incidence of Graves’ disease
for the Timok region and central county (Zajecar)

DISCUSSION

Studies and reports on interrelation of thyroid morbidity and iodine status are numerous (9-12). Data from experimental (13,14) and epidemiological surveys (15-18) is available. Discussions on the subject generally become substantial in a course of a decision-making about iodine supplementation or correction (19-23).



Graph 6. Incidence of hyperthyroidism following the first implementation
of iodine prophylaxis (adopted from Kicic report (7))

Correction of severe iodine deficiency in addition to elimination of endemic thyroid dystrophy (goiter and cretinism) was reported to induce hyperthyroidism, (generally regional thyroid autonomy -Plummer’s disease) in cases of existent euthyroid polynodular goiter (24-26). Increase in incidence of Graves’ disease is less frequently well documented (27-30).
Evidently, there are open questions about the effect of mild iodine deficiency correction on thyroid morbidity, especially induction of hyperthyroidism, and ultimately about the impact of iodine content increase in a population, in area that is not iodine deficient.
The first question has been adequately addressed by Austrian investigators, recently. They observed the implementation of increase in KJ content in consume salt (from 10 to 20mg KJ/kg NaCl) and reported increase in incidence of Graves’ disease (27). Analogous observation was reported from Lebanon (28). A historical report from 1964, by Kicic (reported only in Serbian Journal) indicated a transitory increase in incidence of Graves’ disease in areas without endemic goitre (7).
We have observed multiple increase in incidence of Graves’ disease in Timok Region (East Serbia) with maximum in 1996 (152 patients registered compared with regular incidence of 35-40 patients from 1980 to 1994). Appreciating the complexity of pathogenetic factors of Graves’ disease, this report is just an attempt to presume the capacity of iodine in observed increase of incidence of the Graves’ disease.
Summarizing the approving factors of the potential influence of iodine correction:
Iodine prophylaxis implemented in 1953 (10 mg KI per kg of salt, and since 1963 per kg of salt for human consumption) successfully corrected existent mild iodine deficiency in Timok Region. This statement is documented by:
- Low prevalence of euthyroid goitre in school children (around 2 %);
Average 131I tests in healthy persons adequate for areas without iodine deficiency;
Low incidence of elevated Neonatal TSH values (around 3%).
Two years after the implementation of the second iodine content correction (from 10 to 20mg KI/kg NaCl in 1993) we have registered the increase in incidence of Graves’ disease, which attained the maximum in 1996. Increase in incidence of Graves’ disease was transitory and by 2000 numbers of registered cases relapsed to values from 1992. These findings are analogues to report following iodine prophylaxis in 1953 (7).
Statistically significant decrease in mean values of Neonatal TSH was registered for the period 1994-1999 compared with period 1988-1993, with the evident minimum in 1995.There was no significant alteration in frequency of distribution of normal values between investigated periods.
Benefits of iodine supplementation programs have been extensively reviewed (31,32,33) and are undisputable. There is a general agreement that development of Graves’ disease depends on complex interaction between genetic and environmental factors (including iodine intake), but more studies are required to elucidate the exact mechanism. In spite of maxima ""Post hoc" is not necessarily "Propter hoc"", authors believe that it is synonymous in this observation and that every potential environmental change requires cautious consideration.

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