Journal of Regional Section of Serbian Medical Association in Zajecar

Year 2004     Volumen 29     Number 3
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UDK: 616.441-008.61-084:546.15(497.11) ISSN 0350-2899, 29(2004) 3 p.144-149
Original paper

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

Nebojša Paunković, Jane Paunković
Nuclear Medicine, Medical Centre Zajecar



Iodine prophylaxis implemented at the territory of former Yugoslavia in 1953, has successfully corrected previously existent mild iodine deficiency in East Serbia. Clinical findings (incidence of goiter in school children, ratio of diffuse to focal toxic goiters, uptake of 131I in healthy persons) in subsequent decades were adequate for the areas with corrected iodine deficiency. Iodine content in consume salt was increased from 10mg KI/ kg to 20 mg KI/kg, for the entire territory of Serbia, by federal legislation, in 1993. This report is presenting an occasional investigation of variation in thyroid morbidity and neonatal TSH, in the area of corrected iodine deficiency, in conditions of increasing iodine consumption. Investigated parameters included: neonatal TSH, incidence of autoimmune thyroid diseases (Graves'-Basedow disease, Hashimoto's thyroiditis, primary hypothyroidism), and autonomous thyrotoxicosis (Plummer's disease), incidence of goiter in school children, uptake of 131I in healthy persons, in the period 1978 - 2000. Results have demonstrated that two years following the implementation of increased iodization, findings of neonatal TSH decreased for average 40% and incidence of autoimmune hyperthyroidism increased over 250%. In subsequent two years, both parameters have recovered. Incidence of Hashimoto's thyroiditis, primary hypothyroidism, and autonomous thyrotoxicos (Plummer's disease) incidence of goiter in school children, was unchanged. There is a considerable probability that modification of thyroid morbidity was initiated by increased iodine consumption in the region with previously corrected iodine deficiency, although other factors could not be excluded.

Key words: iodine content correction, thyroid disease, neonatal TSH

Napomena: sažetak na srpskom jeziku
Note: summary in Serbian


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).



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).


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.

Disease Number of patients
Graves’ disease 758
Plummer’s disease 169
Hashimoto’s thyroiditis 75
Hypothyroidism 135
Nodular goiter 1312
Diffuse goiter 152
Thyroid cancer 84
Table 1.
Cumulative incidence
of thyroid disease in Timok Region (1970-1993)
  b) Prevalence of goitre in school children for the period from 1970-1993
In the course of obligatory systematic examination of school children special attention to goitre palpation was applied. Qualified Thyroidologist trained all doctors involved in systematic examination of children in period 1970-1975. Every year, around 2% of the children were referred to Thyroid service and registered with the goitre. That percentage remained unaltered for the entire investigated period (1978-2000).

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%) .

Graph 1
. Neonatal TSH (MV+ SD) for investigated period (1987-1998)

Comparative results of calculated mean values of neonatal TSH for the period 1987-1993 and 1994-1998 are presented on Graph 2 and comparative profiles of the Neonatal TSH values between two investigated periods on Graph 3.

Graph 2. Mean values (MV+SD) of Neonatal TSH for period from
1987-1993 compared to mean values (MV+SD) for period from 1994-1998

Graph 3. Comparison of frequency distribution between
Neonatal TSH values for two investigated periods
  2. Comparative analysis of increase incidence of hyperthyroidism following the implementation of iodine prophylaxis 1953-1963 and 1993-2000

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)



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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  Corresponding Address:
Jane Paunković
Javorska 5, 19000 Zaječar
e-mail: mcza@sezampro.yu
  Paper received: 12. 08. 2004.
Paper accepted: 02. 09. 2004.
Published online: 18. 09. 2004.
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