The Effects Of Chronic Iodine Excess On Thyroid Function And Structure

ObjectiveIodine is essential for biosynthesis of thyroid hormones and causes changes on thyroidal health as an important environmental factor. Iodine deficiency disorders lead to severe brain damage and thyroid goiter. Generalizing of iodized salt has made great progress to eliminate iodine deficiency. However, experts noted that with iodine prophylaxis and overtaking thyroid dysfunctions appeared, such as hyperthyroidism, hypothyroidism, autoimmune thyroid disease and thyroid cancer. Much attention about iodine excess was arosed allover endocrine society. In 2001 WHO, UNICEF and ICCIDD reedited the standard of iodine intake, defining 100 - 199μg/L of median urinary iodine as iodine adequate, 200 -300μg/L as iodine sufficient and over 300μg/L as iodine excess. The universal salt iodination has been carried out in our country since 1996. After that it past a 5 - year period of iodine excess through 1996 to 2001, and then nearly 4 - year of iodine sufficient since 2002. Whether the sufficient to excess iodine intake is safe or not is still unknown. In the first part of the present study, Wist-ar rats with different iodine intake were determined on their thyroid hormones, i-odine uptake, iodine organization and morphology of thyroid gland, in order to confirm the safe spectrum of iodine nutrition.Our previous epidemiological studies found that overt and subclinical hypothyroidism were evidently increased in iodine sufficient and excess regions. 77% of overt hypothyroid patients were affected by autoimmune thyroiditis, and thyroid autoantibodies appeared more frequently in subclinical patients than normal controls. Those suggested that enriched iodine might induce and aggravate immune confusion in thyroid gland. Thyroid stimulation blocking antibody ( TS-BAb) is one of the antibodies against thyrotropin receptor, and blocks the activity of thyrotropin. It was considered recently TSBAb associated with overt hypo-thyroid occurrence. So far no report was about correlations of TSBAb and sub-clinical hypothyroidism or iodine nutrition. In the present research, we derter-mined 39 overt hypothyroid patients and 118 subclinical ones from three communities with varies iodine intake by China hamster ovary cells transferred with re-combinant human thyrotropin receptor, aiming to reveal the relation of TSBAb to thyroid function, iodine intake and prognosis of diseases.Methods1. The Effects of Chronic Iodine Excess on Thyroid Function and Structure in Wistar RatsSix hundred Wistar rats were fed by ordinary feed and distilled water with i-odine concentration of 0, 100, 400 or 1000(xg/L, which represents adequate, sufficient, three times excess and six times excess of iodine respectively. Thirty rats in each group were killed on 0, 1, 2, 4 or 8 months after iodine feeding. U-rine was collected within 24 hours before sacrifice. Then the rats were anaesthetized, their blood and thyroids were collected. Iodine concentration was determined in urine and thyroid tissue homogenate by arsenic cerium catalytic spec-trophotometry method ( WS/T107 -1999). Radioimmunoassay was used to examine TSH, FT4, FT3, TT4and TT3 in rats serum, then TT4and TT3 in thyroid homogenate. 'Hiyroid peroxidase activity was assayed by Guaiacol and KI respectively. 0.6|xCi of Na131I was injected ip 24 hours before sacrifice, thyroid homogenate was tested to calculate I31I uptake in vivo. Flowcytometry was used to analyze expression of NIS on thyroid cell chorion. After fixed with paraformal-dehyde and embedded in parafiEin thyroid was sliced up and stained with HE then observed morphometrically. NIS was marked on paraffin sections to calculate positive rate and measure optical density and integrated optical density. Ultra-thin sections were cut and examined with electron microscope. All data analysis was completed in SPSS 11.5 software.2. Thyroid Stimulation Blocking Antibody in Overt and Subclinical Hypo-thyroid Patients and Its Relation to Iodine Intake or PrognosisEpidemiological study was performed on 16 287 adult inhabitants in iodine deficient, iodine sufficient and iodine excess areas in 1999, 3 761 individuals were sampled, among which 39 overt hypothyroid patients ( female 38, male 1) and 118 subclinical hypothyoid ones (female 92, male 26) were diagnosed, and reinvestigated two years later by 78%. Additionally, 143 normal controls (female 119, male 24) were chosen from 2 503 normal persons based on similar area, gender and age as patients. Serum TSBAb was determined by rhTSHR -CHO cells bioassay: IgG extraction from serum was redissolved in Hanks buffer containing lmU/ml bTSH, then reacted with rhTSHR -CHO cells in 37X. and 5% CO2 for two hours. The cAMP production was measured in supernatant and was used to calculate the activity of TSBAb. Statistical processes were performed in SPSS 11.5 software.Results1. The Effects of Chronic Iodine Excess on Thyroid Function and Structure in Wistar RatsAverage median urinary iodine was 147jxg/L in control group. The urinary iodine level of each iodine group was about 1.5 times, 3 times or 6 times to that of control. Rats'weight and thyroids'weight had no apparent differences between iodine groups and control group. There was no marked difference in serum FT4, FT3, TT4 or TT3 level between iodine group I and normal control. But FT4 and TT3 decreased, while TT4 tended to increase in iodine group II. In iodine group III, serum FT4, FT3 and TT4 all lifted up on the first month, TT3 severely increased after eight months. The serum TSH levels were generally lower in all iodine groups. With increasing of iodine dose, contents of TT4, TT3 and iodine in thyroid tissue evidently fortified and positively correlated with iodine intake levels ( r = 0.59 - 0.967 ). Thyroid peroxidase activities were mainly suppressed in iodine group II and III. Radioiodine uptake rate in iodine group I was 56% of control level on the eighth month, which was even lower in group II and III. NIS expression rate on chorion was 32 ~44% in control group, which was decreasedin each iodine group. But two months later, the positive rate resumed in iodine group I. Those in group II and III were severely low after eight months. Paraffin slices showed that NIS expression transfered from chorion to cytoplast.in all iodine groups in different period. There appeared inverse correlations between tissue iodine content and peroxidase activity, iodine uptake rate or NIS expression (r = -0. 556 ~ -0. 878). Structure morphological study showed that follicle cavities augmented in early period of iodine group I, and more severe in group II and III. Hypofunction follicles increased in group II and III after four months, and exhibited extreme dilatation of rough endoplasmic reticulum, markedly swollen and disrupted of mitochondria, evident accumulation of secondary lysosomes and nuclear degeneration.2. Thyroid Stimulation Blocking Antibody in Overt and Subclinical Hypo-thyroid Patients and Its Relation to Iodine Intake or PrognosisThe positive rate of TSBAb was 15.4% in overt hypothyroid patients and 11.0% in subclinical ones. The activity of TSBAb in overt hypothyroidim was significantly higher than that of subclinical group, but the TSBAb activities were higher in patients than in normal controls. TSBAb showed positive correlation with serum TSH level (r =0.345) , it was higher in those with TSH >4mU/L. TSBAb was negatively correlated with FT4 in all patients ( r = - 0.321). As iodine intake level rising, activity and positive rate of TSBAb gradually increased. In objects with TSH >4. 8mU/L, the prevalence rate of TSBAb was 0% (0/ 11), 8.2% (5/61) and 16.5% (14/85 ) in each community. Those with urinary iodine >300 ~900^g/L had more positive TSBAb than ones under 300|xg/L (9.4% vs 3.2% ). TPOAb positively correlated with TSBAb(r =0.231). TSBAb appeared in 20. 0% patients with autoimmune hypothyroid disease, in which there were 22.2% and 19.0% in AT and HT respectively. But no positive TSBAb showed in normal controls and nonautoimmune thyroid patients. 40. 7% of subclinical hypothyroid patients had positive autoantibodies of anyone of TSBAb, TPOAb and TgAb. Ones with positive TSBAb had smaller thyroid volume in those with normal volume values. During follow -up study, 13 of overt hypothyroid patients still maintained the disease, and their TPOAb higher than others, and TSBAb was (50.4 ±26. 3)% in first study and (50.2 ± 13.6)%during follow - up. Those with initial TPOAb > 35IU/ml ~ 500IU/ml gained a better release of TSH and FT4 compared with those > 500IU/ml, TSBAb decreased in the same time. 63.4% of subclinical hypothyroid ones spontaneously resumed to normal thyroid function. Several factors displayed advanced effects in prognosis, they were TSH < 8mU/L( OR 0.21), TSBAb dereasing with TPOAb < 100IU/ml(OR 0.29)and male gender(0R 0.25).ConclusionsChronic iodine sufficiency leads to subclinical abnormalities of thyroids in Wistar rats.Chronic iodine excess of three or six times cannot induce thyroid goiter in Wistar rats. While thyroid hormones tend to increase in serum and evidently stored up in thyroid gland.The restriction on iodine uptake and organization in rats with chronic iodine excess seems to be one of the non - autoimmune mechanisms for iodine induced hypothyroidism.In rats with chronic iodine excess thyroid follicles distend and contain plentiful colloid. It also appears small follicular hyperplasia, cytoplast vesicles and markedly abnormal of ultrastructure, which all relate to hypofunction of epithelial cells.Its improper to take chronic sufficient iodine, and insecure to have excessive iodine.TSBAb is one of the markers in autoimmune thyroiditis, and correlates with occurrence and degrees of hypothyroid functions.In iodine sufficient and iodine excess areas, high prevalence of overt and subclinical hypothyroidism correlates with enhancement of TSBAb activity.TSBAb induces growth retardation and atrophy of thyroid gland.It is destruction degree of thyroid cells the main factor in hypothyroid prognosis. If impairment is mild, thyroid function resumed with TSBAb decreasing.The progressive factors in subclinical hypothyroid prognosis are TSH < 8mU/L, TSBAb dereasing with TPOAb < lOOIU/ml and male gender.