A patient-specific model of the negative-feedback control of the hypothalamus-pituitary-thyroid (HPT) axis in autoimmune (Hashimoto's) thyroiditis.

The purpose of modelling the negative-feedback control mechanism of the hypothalamus-pituitary-thyroid (HPT) axis in autoimmune (Hashimoto's) thyroiditis is to describe the clinical course of euthyroidism, subclinical hypothyroidism and overt hypothyroidism for patients. Thyroid hormone thyroxine (T4) and triiodothyronine (T3) levels are controlled by negative-feedback control through thyroid-stimulating hormone (TSH). T4, like other hormones, can be bound or unbound; the unbound T4 (FT4) is used as a marker for hypothyroidism. Autoimmune thyroiditis is a disease in which the thyroid-infiltrating lymphocytes attack autoantigens in follicle cells, destroying them over a long time. To describe the operation of the feedback control, we developed a mathematical model involving four clinical variables: TSH, FT4, anti-thyroid peroxidase antibodies and the thyroid gland's functional size. The first three variables are regularly measured while the last variable is determined through relationships between the other three variables. The problem of two different time scales for circulating hormones and thyroid damage is addressed using singular perturbation theory. Analysis of the mathematical model establishes stability and conditions under which the diseased state can maintain the slow movement toward diseased state equilibrium. Although we have used four variables in modelling the feedback control through the HPT axis, the predicted clinical course given any set of parameters is shown to depend on the steady-state levels of TSH and FT4. This observation makes possible the development of the clinical charts based only on the levels of TSH, time and potential steady-state values. To validate the model predictions, a dataset obtained from a Sicilian adult population has been employed.

Low-level laser therapy in chronic autoimmune thyroiditis: a pilot study.

BACKGROUND AND OBJECTIVES: Chronic autoimmune thyroiditis (CAT) remains the most common cause of acquired hypothyroidism. There is currently no therapy that is capable of regenerating CAT-damaged thyroid tissue. The objective of this study was to gauge the value of applying low-level laser therapy (LLLT) in CAT patients based on both ultrasound studies (USs) and evaluations of thyroid function and thyroid autoantibodies. STUDY DESIGN/MATERIALS AND METHODS: Fifteen patients who had hypothyroidism caused by CAT and were undergoing levothyroxine (LT4) treatment were selected to participate in the study. Patients received 10 applications of LLLT (830 nm, output power 50 mW) in continuous mode, twice a week, using either the punctual technique (8 patients) or the sweep technique (7 patients), with fluence in the range of 38-108 J/cm(2). USs were performed prior to and 30 days after LLLT. USs included a quantitative analysis of echogenicity through a gray-scale computerized histogram index (EI). Following the second ultrasound (30 days after LLLT), LT4 was discontinued in all patients and, if required, reintroduced. Triiodothyronine, thyroxine (T4), free T4, thyrotropin, thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) antibodies levels were assessed before LLLT and then 1, 2, 3, 6, and 9 months after LT4 withdrawal. RESULTS: We noted all patients' reduced LT4 dosage needs, including 7 (47%) who did not require any LT4 through the 9-month follow-up. The LT4 dosage used pre-LLLT (96 +/- 22 microg/day) decreased in the 9th month of follow-up (38 +/- 23 microg/day; P < 0.0001). TPOAb levels also decreased (pre-LLLT = 982 +/- 530 U/ml, post-LLLT = 579 +/- 454 U/ml; P = 0.016). TgAb levels were not reduced, though we did observe a post-LLLT increase in the EI (pre-LLLT = 0.99 +/- 0.09, post-LLLT = 1.21 +/- 0.19; P = 0.001). CONCLUSION: The preliminary results indicate that LLLT promotes the improvement of thyroid function, as patients experienced a decreased need for LT4, a reduction in TPOAb levels, and an increase in parenchymal echogenicity.

Studies on experimental iodine allergy: 1. Antigen recognition of guinea pig anti-iodine antibody.

It has generally been thought that iodine allergy is cross-sensitive to various iodine-containing chemicals. However, this concept seems to deviate from the immunological principle that immune recognition is specific. To solve this contradiction, we hypothesize that iodine allergy is an immunological reaction to iodinated autologous proteins produced in vivo by iodination reaction from various iodine-containing chemicals. Antisera to iodine were obtained from guinea pigs immunized subcutaneously with iodine-potassium iodide solution emulsified in complete Freund's adjuvant (CFA). The specificity of guinea pig anti-iodine antiserum was determined by enzyme-linked immunosorbent assay (ELISA) inhibition experiments using microplates coated with iodinated guinea pig serum albumin (I-GSA). Antibody activities were inhibited by I-GSA, diiodo-L-tyrosine, and thyroxine, but not by potassium iodide, monoiodo-L-tyrosine, 3,5,3'-triiodothyronine, monoiodo-L-histidine, or diiodo-L-histidine, or by ionic or non-ionic iodinated contrast media. The results that antigen recognition of anti-iodine antibody is specific to iodinated protein support our hypothesis. While protein iodination usually takes place both at histidine residues as well as at tyrosine residues, only iodinated tyrosine acted as an antigenic determinant and no antibody activities to iodinated histidine were detected in our experimental iodine allergy model.

Iodine content of rat thyroglobulin affects its antigenicity in inducing lymphocytic thyroiditis in the BB/Wor rat.

The BB/Wor rat develops spontaneous insulin dependent diabetes mellitus (DM) and lymphocytic thyroiditis (LT). We have recently demonstrated that immunization of BB/Wor rats with allogeneic thyroglobulin (Tg) induces LT at an early age. The incidence of spontaneous and Tg induced LT is extremely variable among different BB/Wor sublines. It has been shown that high iodine diet significantly increases the incidence of spontaneous lymphocytic thyroiditis (LT) and low iodine diet significantly decreases the incidence of LT in genetically predisposed BB/Wor rats. Recent studies on thyroglobulin (Tg) induced LT in chicken and mouse have shown that iodine rich Tg is far more antigenic than Tg with a low iodine content, suggesting that a high iodine diet increases the immunogenicity of Tg molecule. In order to determine whether the extent of Tg iodination would affect its immunogenicity in the BB/Wor rats, the current study was carried out. Normal iodine Tg (NTg) or low iodine Tg (LTg) was obtained from thyroids of rats that were placed on regular diet or regular diet plus 0.5% methimazole, respectively. 120 rats from the NB (highly susceptible) and BB (low susceptible) sublines were randomized in three groups. Immunization was carried out with a 1:1 emulsion of complete Freund's adjuvant (CFA) and LTg, NTg (0.6 mg/rat) or saline at 30 and 37 days of age. Since spontaneous LT rarely occurs before age 75 days, rats were sacrificed at age 65 days to specifically study Tg induced LT. Immunization with NTg induced LT in 31% of the NB rats, but not in the BB subline. LTg did not induce LT in either subline.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-bovine thyrotropin autoantibodies in patients with Hashimoto's thyroiditis, subacute thyroiditis, and systemic lupus erythematosus.

We report four cases found to have anti-bovine thyrotropin (bTSH) antibodies, two with Hashimoto's thyroiditis and the other two, each with subacute thyroiditis and systemic lupus erythematosus (SLE). The unusually high negative titers of anti-TSH receptor antibodies (Case no. 1, -43.1%; Case no. 2, -34.9%; Case no. 3, -55.2%; Case no. 4, -59.9%) led to the incidental finding of the presence of anti-bovine (bTSH) antibodies in each patient. Case no. 1 was diagnosed to have Hashimoto's thyroiditis and was treated with L-thyroxine (L-T4). With the treatment, serum free T4 (FT4)normalized with a decline in the serum TSH concentration. The other patient diagnosed to have Hashimoto's thyroiditis (Case no. 2) remained euthyroid even without supplemental thyroid hormone therapy and the serum concentrations of FT4 and TSH stayed within the normal range. The third is a case of subacute thyroiditis (Case no. 3) with a typical clinical course of the disease. She had the anti-bTSH antibodies on her first outpatient visit. Serial examination of her sera disclosed the antibody titers to be on the same range over the 28 months after the onset of the symptoms. The fourth is a patient with SLE who had been treated with steroid (alternative day therapy of 40 mg/day prednisolone). Titers of the anti-bTSH antibodies spontaneously declined to the negative level 5 months later. None of the four cases had antibodies against human TSH alpha-subunit of bovine LH and alpha-subunit of bovine FSH.(ABSTRACT TRUNCATED AT 250 WORDS)

Production and evaluation of high-quality thyroxine antisera for use in radioimmunoassay.

High-quality thyroxine (T4) antisera were raised in rabbits. Conjugates of protein and T4 or T4 methyl ester were given intracutaneously in Freund's complete adjuvant at one or two sites on the back at 1/2- to 3-month intervals. Eleven of 16 immunized rabbits produced antiserum with titers higher than 2 commercial antisera and 4 antisera from other laboratories. All 16 antisera had equilibrium constants (K) higher than the 6 reference sera. The highest titer observed was 130,000 with 88 fmol labeled T4 per ml incubate. A drastic increase in K from about 4 X 10(8) to 5.8 X 10(10) 1/mol was observed as the immunization proceeded. Cross-reactivity with triiodothyronine (T3) varied but was generally low. Suppression of the T4 synthesis was attempted by giving 30 nmol (20 mug) T3 per os once a day. Antiserum from rabbits given T3 suppression contained less iodine than antiserum from nonsuppressed control rabbits. The possible reasons for the successful production of the high-quality antisera are discussed.

The significance of partial suppressibility of serum thyroxine by triidothyronine administration in euthyroid man.

Recent evidence indicates that triiodothyronine (T3) administration may not completely inhibit normal thyroid secretion. To further corroborate this observation, measurement of serum T4-RIA concentrations was performed on 15 normal controls (10 men, 5 women; ages 20-42) who were placed on 100 mug of T3 daily for a 5-week period. Decrements of 53%, 36%, and 28% from the baseline T4-RIA were noted at weeks 1, 2, and 3 respectively. At 3 weeks a nadir T4-RIA of 2.5 mug/100 ml was reached which did not significantly differ from the 4th (2.9 mug/100 ml) and 5th weeks (2.6 mug/100 ml). Further, seven euthyroid patients who had received replacement thyroid hormone for 1-16 were switched to T3 (75-100 mug/day) for 28 days. At the end of this period, their mean T4-RIA was 2.6 mug/100 ml. Similar T3 treatment studies were performed on 20 primary hypothyroid patients. After 4 weeks of T3 all 20 patients displayed a T4-RIA below the limits of assay detectability (less than 0.625 mug/100 ml) while all euthyroid subjects had values greater than 1.2 mug/100 ml. Suppression of T4-RIA with T3 was also noted in 4 patients with pituitary and 2 patients with hypothalamic hypothyroidism. Three days after cessation of T3 treatment in normal subjects, no significant rise in mean T4-RIA was seen (2.3 mug/100 ml). Subsequently, T4-RIA rose to 4.5 mug/100 ml on day 7 and 6.7 mug/100 ml on day 10 (74% of the presuppression value) in normals. A similar rise to 7.9 mug/100 ml 10 days after withdrawal from T3 was noted in the euthyroid subjects who had received long-term thyroid hormone replacement. In contrast, all primary hypothyroid patients had either a minimal or nondetectable elevation in T4-RIA while demonstrating a marked rise in TSH 10 days after T3 withdrawal. An absent or impaired rise in T4-RIA after T3 withdrawal was also noted in patients with pituitary and hypothalamic hypothyroidism. These observations indicated: 1) There is continued thyroidal T4 secretion in euthyroid subjects receiving 100 mug of T3 daily. 2) The hypothesis is advanced that an intact hypothalamic-pituitary-tyhroid axis may be required for continued T4 secretion while on T3. 3) The duration of prior suppression with thyroid hormone medication does not appear to influence this phenomenon.

Changes in plasma thyroxine, triiodothyronine, and TSH during adaptation to iodine deficiency in the rat.

We have measured plasma thyroxine (T4), triiodothyronine (T3), and TSH with specific radioimmunoassays in rats during adaptation to severe iodine deficiency after they had previously received regimens supplying various quantities of iodine. Rats were maintained on a high-iodine diet (HID) containing 3 mg iodine/kg or a low-iodine diet (LID) containing 30 mug iodine/kg supplemented with 0.1, 0.2, or 0.4 mug iodine/ml of drinking water before swtiching to KID alone. Frequent serial blood samples were obtained up to 3 months, using 6 or more animals for each time interval. In animals originally fed HID, T4 remained at 4-6 mug/100 ml unitl the tenth day of LID, then rapidly decreased to a value of less than 0.4 mug/100 ml at 1 month. TSH was initially 50 muU/ml and increased linearly to 165 muU/ml on day 16. Thence there was a much more rapid rate of rise to 640 muU/ml at 38 days. The rats changed to LID alone after having been fed LID with iodine supplementation underwent similar qualitative hormonal changes. However, the decrease in plasma T4 and the increase in plasma TSH occurred sooner in the rats which had drunk water containing only 0.1 or 0.2 mug iodine/ml than in the previous experiment. Rats which had received 0.4 mug iodine/ml showed a pattern essentially identical to that of the animals which had been fed HID. plasma T3 did not change significantly in any of the experiments, remaining at 60-90 ng/100 ml, although there was a tendency for the values to be somewhat lower after several weeks of LID. There was a highly significant negative correlation of plasma T4 with plasma TSH. There was no significant correlation of plasma T3 with either plasma T4 or plasma TSH. It is concluded that the combined physiologic effect of plasma T4 and T3 concentration is more important in determining TSH secretion through negative feedback effects on the hypothalamus and/or pituitary than is the concentration of plasma T3.