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The intracellular localization of Cu/Zn- and Mn-superoxide dismutases (SOD), which catalyze the dismutation of superoxide radicals (O2−) to O2 and H2O2, was studied in the thyroid tissue of various thyroid disorders by an immunohistochemical technique. The concentrations of both SODs in those tissues were measured also by a sandwich enzyme immunoassay technique. Copper/zinc-SOD in thyroid tissues were identified by immunocytochemical staining in most cases of papillary carcinoma and in some cases of other thyroid disorders. In normal follicular cells this enzyme is localized in the perinuclear cytoplasm, whereas in thyroid tumor or hyperplastic follicular cells it exists homogenously in cytoplasm. Manganese-SOD stained strongly in papillary carcinoma and papillary-growing cells in the thyroid tissue of adenoma and Graves' disease. The concentrations of Cu/Zn- and Mn-SOD in thyroid tumor tissues and hyperplastic follicular disorders were significantly higher than those in normal thyroid tissue when they were compared as a function of protein or deoxyribonucleic acid contents. The ratio of Mn-SOD to Cu/Zn-SOD was significantly higher only in papillary carcinoma, except for other thyroid disorders, as compared with that in the normal thyroid. In conclusion. SOD seems to be related to cell proliferation and differentiation in the thyroid follicular cell because Cu/Zn-SOD changes its localization in tumor and hyperplastic follicular cells and because the Mn-SOD concentration is increased in papillary carcinoma or papillary-growing cells.

The effects of oral iodide, levothyroxine and of iodide and levothyroxine in combination were studied in three groups of 30 children, age 13–15 years, with euthyroid goitre. As endpoints of this study, we used thyroid volume reduction, thyroid hormones, thyrotropin and thyroid grey-scale histograms by computerized analysis. The three groups were well matched with respect to mean age, body weight and pretreatment thyroid volumes and thyroid hormones. Mean urinary iodide excretion before treatment was in the range of 30 μg/g creatinine, since the study was conducted in an iodine-deficient area. All three treatment regimens led to significant reductions in thyroid volume within one month. After six months on 100 μg of levothyroxine, thyroid volume had decreased from 14.1±4.2 ml to 8.3±2.6 2.6ml (mean±sd);on 150 μg of iodide, from 18.5±6.2 ml to 8.8±2.7 ml; and on 100 μg of iodide plus 50μg of levothyroxine, from 17.2±3.1 ml to 8.3±2.0 ml. When treatment was discontinued for three months, or the dosage reduced, thyroid volume increased again in the levothyroxine (to 11.3±2.5 ml) but not in the iodide group. Grey-scale values (by ultrasound, computer-aided estimation) after nine months were significantly different between the three treatment groups; no change was observed with levothyroxine, but after 150 μg of iodide as well as after combined treatment with levothyroxine and iodide there were marked decreases of grey-scale values; this is interpreted as reflecting a decrease in follicle size and colloid content of the thyroid which takes place after iodide supplementation. In conclusion, iodide treatment as well as combined treatment with levothyroxine and iodide lead to volume reduction of juvenile goitre which is quantitatively similar but qualitatively superior compared to the effects of levothyroxine alone.

A fraction of enzymatically monodispersed rat thyrocytes from untreated animals clonally proliferate into thyroid follicular units following transplantation into the subcutaneous fat pads of syngeneic recipients. During the induction of experimental goiters in rats either with 3-amino-1,2,4-triazole/iodine sufficient diet or KClO4/Remington low iodine diet, the clonogenic fractions of cells from aminotriazole goiters decreased to 1.9×10−4 and KClO4 goiters to 9.8×10−5 as compared to 5.8× 10−3 for cells from age-matched controls during the growth phase of goitrogenesis. With continued aminotriazole treatment after thyroid hyperplasia had ceased, the clonogenic fraction increased to 2.0×10−3 while continued KClO4 treatment had little further effect. The changes in the clonogenic fraction induced by both regimens were reversed during involution; goitrogenic rechallenge of involuted glands led to changes in the clonogenic fraction similar to that noted during the initial challenge. The clonogenic fractions of cells from aminotriazole goiters were greater than that of cells from KClO4 goiters at all time points examined despite similar TSH levels in situ. We conclude that the rat thyroid contains a hierarchy of cells with different proliferative capacities and that the clonogenic thyrocytes possess many of the attributes of a stem-cell.

In the rat, chronic TSH stimulation leads to self-limited thyroid hyperplasia, goitrogenesis, and TSH-responsive thyroid tumors. The current studies were aimed at clarifying the mechanism by which hormone-responsive, proliferating follicular cells arise in quiescent plateau phase rat goiters. Enzymatically monodispersed rat thyrocytes from early plateau phase and involuting goiters were analyzed for the capacity to form thyroid follicular units after transplantation into syngeneic recipients. Goiters induced with two different regimens contained substantial numbers of cells capable of proliferating into functioning thyroid follicular tissue after transplantation. The clonogenic fractions of cells from goiters induced by 3-amino-1,2,4-triazole or KClO4/Remington low iodine diet were significantly lower than that of cells from control glands. Furthermore, the clonogenic fraction of cells from the KClO4 goiters was also found to be significantly less than that of cells from aminotriazole goiters despite similar TSH levels in the cell donors. The hormone responsiveness of the clonogenic goiter cells and the histological appearance and functional capacity of the thyroid tissue which arose after grafting were indistinguishable from controls. We conclude that the capacity to clonally proliferate into follicular units is a specific trait which characterizes a unique subset of follicular cells and speculate that the hormone-responsive tumors which typically appear in the chronically stimulated rat thyroid originate from cells within this subset.

In certain regions of Switzerland, before prophylaxis, 0.5% of the inhabitants were cretins, almost 100% of schoolchildren had large goitres and up to 30% of young men were unfit for military service owing to a large goitre. Iodization of salt was introduced in 1922 at 3.75 mg I per kg and the iodine content was doubled twice, in 1962 and 1980, to the present 15 mg I per kg. In 1988, 92% of retail salt and 76% of all salt for human consumption (including food industry) was iodized, even though its use is voluntary. Urinary iodine excretion, previously between 18 and 64 μg per per day, has now risen to 150 μg per day. No new endemic cretins born after 1930 have been identified. Goitre disappeared rapidly in newborns and schoolchildren, more slowly in army recruits, and incompletely in elderly adults. In some Cantons (by constitution in charge of health matters and the salt monopoly) which allowed iodized salt only in 1952, disappearance of goitre lagged behind accordingly, proof that iodized salt was the cause of regression. The Swiss data provide evidence that isolated deafness, mental deficiency, and short stature, each without the other attributes of cretinism have also decreased. Adverse effects of iodized salt were minimal, possibly because the initial iodine content of salt was chosen very low. Iodization of salt has proved a highly cost-effective preventive measure in Switzerland.

In patients with Graves' disease, thyrostatic drug treatment may induce definitive remission without the need of more aggressive measures such as surgery or radioiodine. Following drug therapy, however, relapses often occur. In the present study, a multivariate analysis of pretreatment variables was performed, in order to identify individuals running a high risk of an unfavourable outcome of thyrostatic drug therapy. We studied 109 consecutive patients with a mean age of 38 years, range 20–70, over a mean follow-up period of 5.3 years after cessation of therapy. The analysis showed that goitre size, age, thyroid hormone levels, HLA-DR 3 haplotype, and TSH receptor antibody levels were of prognostic significance, whereas HLA-B8 haplotype, a lymphocytic infiltrate at fine needle biopsy, thyroglobulin, and microsomal antibodies had no such value. In particular, patients characterized by young age, large goitre and high hormone values were found to be associated with an unfavourable course.

In order to detect somatic and psychomotor disturbances in children and adolescents residing in areas of iodine deficiency, schoolchildren from three areas with different degrees of iodine deficiency were studied. In Randan, the prevalence of severe endemic goiter was accompanied by alteration in thyroid function, increased thyrotropin levels and retardation of both bone and psychomotor age and decreased intellectual quotient. In Tehran, where iodine deficiency is mild, visible goiter was present in 1 5% of schoolchildren but no alterations in thyroid function, serum thyrotropin, somatic or psychomotor development could be detected. In Zagoon, where the prevalence and severity of goiter was less than Randan but more than Tehran, thyroid function was normal but slightly decreased as compared to Tehran; somatic development was unaltered, but retardation in psychomotor development was evident and the mean intellectual quotient was less than that of Tehranian schoolchildren. These findings indicate the occurrence of physical and psychomotor disturbances in apparently normal schoolchildren from areas of iodine deficiency. Alteration in psychomotor development may occur in children with normal physical growth, due to iodine deficiency.

A study was conducted on the incidence of postoperative nontoxic goitre in 206 patients. The mean period of postoperative observation was 7.8 years. The recurrence rate was 30.7% in the 26 patients to whom thyroxine was administered regularly and at doses of 0.15 mg/day or more in the postoperative period, and 46.9% in the 32 patients who received thyroxine regularly at low doses (0.10 mg/day). In contrast, recurrence rate was 71.4% in the 49 patients in whom use of thyroxine was irregular and 81.8% in the 99 patients who received no thyroxine. The recurrence rate was markedly reduced in the patients who used thyroxine regularly at doses of 0.15 mg/day or more as compared with those who used it irregularly or not at all. It was concluded that in Turkey, where iodine deficiency is a major contributory factor of the prevalence of goitre, postoperative administration of thyroxine is necessary in order to reduce the postoperative recurrence rate.

In 569 unselected elderly subjects over 60 years from the general population of an iodine-deficient area, a palpation and an ultrasound investigation of the thyroid were performed. Additionally, thyroid hormone values were determined in 466 of the 569 subjects (81.9%) and urinary iodine excretion in 491 subjects (86.3%). By palpation, no thyroid enlargement was noticed in 302 subjects (54.2%), goitre Ia in 98 (17.6%), goitre lb in 94 (16.9%), goitre II in 53(9.5%), and goitre III in 10(1.8%). The thyroid volumes (medians) by ultrasound were 18.6 ml in the entire group, in women (N=489) 19.2 ml, and in men (N=80) 16.6 ml. One hundred and one subjects had a thyroid nodule (17.6%), 43 persons cystic lesions (7.6%). If, according to the literature, a goitre is defined as a thyroid enlargement of more than 18 ml in women and more than 25 ml in males, a goitre prevalence of 54.2% in females and of 22.5% in males was obtained. The goitre prevalence in the entire group was calculated as 49.7%. Thyroid hormone measurements showed in subjects with goitre a significant lower TSH value (p

Most serum TSH assays have a working sensitivity (i.e. the lowest TSH value with an inter-assay co-efficient of variation below 10%) around 0.15-0.4 mU/l, which also is the critical area for cut off for further thyroid profile testing when serum TSH is used as a "first line test". A new assay (BeriLux hTSH) based on chemiluminescence was evaluated, and demonstrated a theoretical sensitivity (mean + 2 sd of the zero standard) of 0.005 mU/l and a working sensitivity as low as 0.04 mU/l. Reference range was 0.18-2.60 mU/l (N=33). Sixty-eight percent (13/19) of hyperthyroid patients had serum TSH 4 and T3 indices but serum TSH 4 treated patients had serum TSH

Large doses of radioiodione were administered since 1969 to 15 euthyroid patients with compressive voluminous goitres. A decrease in goitre size was observed in all patients (between 15 and 63%, average 39%). Maximal effect on goitre size was attained rapidly, partially already after less than one year and was almost maximal after 24 to 30 months. No significant local adverse reactions were observed; no patient required steroid administration. Hypothyroidism followed radioiodine administration in 30% of the patients after 2 years; after 8 years, all those who had survived were hypothyroid, requiring substitution therapy. In all patients there was a marked improvement in compression symptoms. The use of radioactive iodine therapy constitutes an alternative to surgery in selected patients with large compressive goitres in whom surgery is contraindicated because of age or other medical conditions.

A receptor assay was examined for the thyroid stimulating immunoglobulin using [125I]LATS. The principle of this method is the determination of displaced [125I]LATS from thyroidal plasma membrane (PM) by test serum. LATS-IgG without thyroidal antibodies was labelled with 125I, and radioactivity (RA) bound to purified PM from human thyroid was used as [125I] LATS. In the routine receptor assay, human thyroidal PM fraction, 0.1 ml of test serum, and [125I]LATS were incubated. Then [125I]LATS bound with the PM was determined after centrifugation. LATS positive serum showed a significant displacement. However, TSH (human and bovine), hCG and cholera toxin did not displace [125I]LATS from the plasma membrane. The bound per cent in euthyroid subjects was about 29 ± 3 % (mean ± sd). The displacing activity was positive in both hyperthyroid patients and in Hashimoto's thyroiditis, while in simple goitre and in hypothyroid patients with increased serum TSH it was always negative. LATS positive sera showed strong displacing activity in 16 of 17 cases, but LATS negative sera in hyperthyroid patients were positive in only 70 %. The displacing activity was also positive in all sera with positive precipitating antibody for thyroglobulin (TG), while patients with the positive haemagglutination antibody for TG (TRC: ≦ 107)in Hashimoto's disease were positive in about 50 % of cases. The displacing activity was not affected by absorption of TG antibody. Microsomal antibody in Hashimoto's disease was suggested to have an effect on the displacing activity. Although this method is not specific for determining LATS, this assay may be useful for examining thyroid plasma membrane binding immunoglobulin.

Thyroid iodoproteins were analyzed in the glandular tissue of a euthyroid female who presented a congenital goitre with circulating iodoprotein and apparent coupling defect. Serum TSH was significantly elevated (25 μU/ml) with low serum total T4 (2 μg/100 ml) and free T4 (0.4 ng/100 ml), and slightly increased total T3 (340 ng/100 ml). BE125I amounted to 5 %. The perchlorate discharge test was negative. Peroxidase and dehalogenase activities were found to be normal in thyroid homogenate. Minimal amounts of T4 (0.162 μg/g tissue) and T3 (0.032 μg/g tissue) were measured in Pronase hydrolysate of the gland. No labelled iodothyronines could be identified by various chromatography techniques despite a DIT/ MIT ratio of 1.4 and a total iodine content of 345 μg/g tissue. The salting out extraction of thyroid proteins and radioactivity indicated the presence of large amount of iodoproteins other than thyroglobulin. The distribution of proteins and radioactivity was studied by chromatography on Sephadex G-200, sucrose gradient centrifugation and disc electrophoresis on polyacrylamide gel. Only 10 to 15 % of radioactivity and proteins was identified as thyroglobulin. The remainder was recovered in the albumin fraction, and in a low molecular weight anodic iodocompound that migrated ahead of albumin and close to the front marker in polyacrylamide gel.

Primary cell cultures of normal and adenomatous human thyroid tissues were incubated with TSH or ammonium sulphate precipited IGG fractions (1 mg/ml) of sera from patients with different thyroid diseases (Graves' disease: active n = 7 in remission n = 12; thyroid autonomy n = 39; simple euthyroid goitre n = 15) and were compared to controls (n = 26). [3H]thymidine incorporation in primary thyrocyte cultures demonstrated a typical bell shape curve after incubation with EGF and TSH with a maximal effect at 10–100 μIU/ml. This effect, however, was inconsistent and positive only in 2 of 7 primary cultures. Only TSH positive cultures were used for IgG studies. 16–28% of IGG fractions from sera of thyroid patients caused high (more than X + 5 sd of controls) stimulation of [3H]thymidine incorporation. Dose response curves of IgG fractions of 19 additional patients (Graves' disease in remission n = 15; thyroid autonomy n = 4) showed an increase in [3H]thymidine incorporation at 0.1 mg protein/ml for 10 patients and at low concentrations of 10–5 mg/ml for 5 patients. There was a good correlation (r = 0.72) (P < 0.0001) between positive findings in TSH-binding inhibition (TBII) and AC-stimulation (TSI) IGG fractions but none between stimulation of [3H]thymidine incorporation and any other thyroid specific immunoglobulin nor thyroid function nor any other available data. Immunoglobulins stimulating [3H]thymidine incorporation differ therefore from TBII and TSI. The growth effect of these immunoglobulins, however, has yet to be determined.

Five cases, 2 males and 3 females, with absence of iodide concentrating mechanism are reported. Three of the five subjects are siblings and the eldest sister has no symptom to account for the cretinism. All 5 cases have improved clinically following the administration of potassium iodide and 4 cases are still in a euthyroid state without any adverse effects during a half to more than 4 years. This study suggests that the absence of iodide concentrating mechanism might be erroneously diagnosed as athyroidal cretinism or adolescent non-toxic diffuse goitre, and may at times not show any clinical symptoms.

Antibodies were raised to various sub-cellular fractions of human thyroids, (of Graves' disease, Hashimoto's thyroiditis, and non-toxic goitre). With one exception it was found that antibodies to the Graves' thyroid fractions cross-reacted with both the non-toxic goitre and Hashimoto's thyroiditis fractions. This exception was in the antiserum to the Graves' 105 000 × g pellet (Gr4) which contained an antibody (A-1) that could not be absorbed by either the non-toxic goitre (NTG) or the Hashimoto's (H) thyroid preparations. The antibody-antigen reaction between A-1 and Gr4 could be blocked by the addition of LATS (or TSH) to the antigen, thus suggesting that A-1 might be a LATS-like immunoglobulin. These results suggest that the TSH receptor may be antigenic and that an antibody to this receptor can be produced in vivo. Production of such an antibody to the TSH receptor would permit the development for the first time of a good animal model of Graves' disease.

Among fifty consecutive patients operated on for non-toxic goitre, ten were shown to have solitary, hyperfunctioning thyroid nodules. Seven days before operation the patients were given a tracerdose of Na125I orally; all had an increased iodine discharge from the thyroid gland and elevated [125I]PBI. Chromatography of the sera revealed 125I peaks corresponding only to the T4 and T3 bands. Total 1251 concentration ratio nodular/paranodular tissue varied between 11.1 and 0.4 indicating a great variation in metabolic activity in "hot" nodules in the different goitres. The thyroid tissue was chromatographically investigated; the [125I]MIT/DIT ratio of the "hot" nodules was not negatively correlated to the 127I concentration of the tissue as is the case for "cold" adenomata. Significantly more [125I]T4 and [125I]T3 were found in the nodules compared to paranodular tissue. In contrast to simple non-toxic goitre the [125I]T3/T4 ratio in the "hot" nodules was lower than in paranodular tissue in spite of a lower 127I concentration in the former. Thus the hormone synthesis of "hot" nodules was unrelated to tissue iodine concentration.

Recently it has been suggested that a substantial number of nonendemic goitre cases can be considered as organ-specific autoimmune disorders of the thyroid. Circulating immunoglobulins, probably receptor autoantibodies, stimulating guinea pig thyroid growth in vitro (TGI) can be found in 2/3 of such patients. Defects in the regulatory balance between T-helper (Th) and T-suppressor (Ts) cells have been described in other thyroid autoimmune diseases, such as Graves' disease and Hashimoto goitre. Such defects are thought to play a role in the loss of control over thyroid autoantibody producing B cells. To investigate whether Ts cell defects can also be found in nonendemic euthyroid goitre, we studied their number and function in 15 of such patients. All patients were clinically euthyroid. Eleven were positive for TGI. Circulating T cells, Th cells and Ts/cytotoxic cells were enumerated using monoclonal antibody techniques (OKT3, Leu3a and OKT8, respectively). Suppressor cell function was assessed employing a proliferation assay in which a short-lived population of such cells was removed by a 24 h preculture. A significant difference was found between patients and controls regarding the Leu3a+/OKT8+ cell ratio: 2.74 (sd 0.94) in patients vs 1.75 (sd 0.38) in controls (P < 0.01); the disturbed ratio was mainly due to a decrease in the percentage of OKT8+ cells. The functional Ts cell assay also showed a defect of patient lymphocytes: patient removal index (SRI) was 1.5 (sd 1.0) vs an index of 2.6 (sd 1.2) for healthy controls (P

Sixteen patients with congenital goitre were submitted to a bovine TSH stimulation test (bTSH), and serum thyroid hormones (T3, T4), TSH and thyroglobulin (Tg) were measured before and after bTSH injection. In 9 patients with an organification defect basal levels of Tg were normal (19.4 ± 3.1 μg/l) rising after bTSH to a mean level ± sem of 37.3 ± 4.1 μg/l. Six patients with defective Tg synthesis or release had a mean basal level of serum Tg of 8.7 ± 1.9 μg/l (mean ± sem) and failed to raise serum Tg concentrations after bTSH (mean ± sem: 10.4 ± 2.1 μg/l). In both groups a modest although significant (P < 0.05) change in serum thyroid hormones after bTSH was noted. We conclude that the bTSH test may be used to distinguish the group with defective Tg synthesis or release from other types of congenital goitre.

The frequency of agglutinating antibodies to Yersinia enterocolitica (Y. ent.) serotype 3 and 9 has been studied in sera from patients with various thyroid diseases. No antibodies to Y. ent. serotype 9 were found. Titres (≧ 10) of Y. ent. serotype 3 antibodies were found significantly more frequently in thyroid patients than in controls. In patients with Graves' disease the frequency was 59.5 per cent compared with 16.6 and 27.7 % in the two control groups (P < 0.0005). High titres (≧ 80) were significantly increased in patients with Graves' disease and diffuse nontoxic goitre when compared with the control groups. The prevalence of Y. ent. antibodies decreased with the duration of the disease. In patients with recurrent Graves' disease high titres of Y. ent. antibodies were found in 25 per cent compared with 11 per cent in patients with the first attack of Graves' disease (P < 0.05). No correlation with age, sex, exophthalmos or the presence of antibodies to thyroid antigens was found. As the O antigen of Y. ent. serotype 3 is specific the detection of these antibodies suggest an infection with Y. ent. and possibly an association between this infection and thyroid disorders, in particular Graves' disease.

The 20 min 99mTechnetium (99mTc) pertechnetate uptake in the thyroid gland has been investigated in 144 patients and compared with the 24 h 131I-uptake. The diagnostic values in 39 patients with hyperthyroidism was found to be the same with both tests whereas the 24 h 131I-uptake gave a better discrimination between the controls and 13 hypothyroid patients than the 20 min 99mTc-uptake. There was no significant difference in the prognostic value of T3 suppression of the 20 min 99mTc-uptake and the 24 h 131I-uptake in 31 patients receiving long-term antithyroid treatment. The 20 min 99mTc-uptake offers several advantages as compared with the 131I-uptake especially a very low radiation dose and less time consumption.

Thyroid growth stimulating immunoglobulins (TGI) were assayed in IgG concentrates prepared from human plasma using a cytochemical bioassay (CBA) based on the measurement of changes in glucose-6-phosphate dehydrogenase (G6PD) activity in guinea pig thyroid follicular cells. TGI was present in all 8 patients studied who had goitrous Graves' disease, in 9 who had toxic diffuse goitres with asymmetric uptake on scintigram and/or symptomatic ophthalmopathy and in 4:8 who had toxic uninodular goitre with autonomously functioning nodules. TGI were also present in 34:54 (64%) of patients who had non-toxic goitres. In contrast, TGI were undetectable in 4 patients who had Graves' disease without palpable goitre and in all 18 euthyroid non-goitrous volunteers. Maximum increases in G6PD activity occurred at an IgG concentration of 50 μg/ml in all patients who had goitrous Graves' disease and in 5:7 who had diffuse non-toxic goitres. In contrast, IgG concentrates from 20:27 patients with nodular goitres caused maximum increases in G6PD activity at an IgG concentration of 500 μg/ml. A comparison of the prevalence of TGI with that of thyroid stimulating immunoglobulins (TSI), also measured by CBA, in 63 patients showed that although both stimulators were present in 8 patients who had goitrous Graves' disease they were only simultaneously present in 18:43 (42%) who had non-toxic goitres of various aetiologies. Thyrotrophin receptor antibodies (TRAb) were present in 11/44 (25%) of non-toxic goitrous patients but there was no significant correlation with IgG stimulators in such patients. It is concluded that the finding of IgG stimulators in a variety of thyroid disorders suggests common immunological features in their pathogenesis. The presence or absence of such stimulators and their relative potencies may play a part in determining functional or structural variations between common forms of goitre.

A kindred is presented in which 4 members in 3 generations showed absent or reduced serum concentrations of thyroxine-binding globulin (TBG). TBG was undetectable by radioimmunoassay in one male and decreased to varying extent in 3 female patients (4.0, 4.2 and 8.6 μg/ml; normal range 12.5–26.0 μg/ml). Total thyroxine serum concentrations in the affected subjects were well in the hypothyroid range without clinical evidence of hypothyroidism. The mode of transmission of the trait was consistent with X-chromosome linkage. A high incidence of non-toxic goitre was also present in most of the family members examined irrespective of TBG levels. The transmission of the goitre trait was compatible with autosomal dominant inheritance. Thus its association with transmission of TBG deficiency was interpreted as not causal but coincidental.

Documented thyrotoxicosis developed in a 12 year old girl with chronic autoimmune thyroiditis. During the following 3 years there was a spontaneous progression from hyperthyroidism to hypothyroidism and vice versa fluctuating from one metabolic state to another. The diagnosis of Hashimoto's thyroiditis was based upon thyroid function tests, elevated titres of antibodies against thyroid constituents, and upon thin-needle biopsy of the enlarged thyroid gland.

Thyroid hyperplasia was induced in C3H mice by a low iodine diet feeding supplemented with propylthiouracil. The morphological modifications associated to the development of hyperplasia were analyzed at light microscopical level and the cellular proliferation was studied by autoradiography after a pulse labelling with [3H]thymidine. The initial modification during the course of hyperplasia is the development of the vascularization. It includes the dilatation of the capillaries, which occurs before any extended modification of the follicular cells and any change of the thyroid weight, and the proliferation of endothelial cells which starts earlier than that of follicular cells.

In this paper we describe methods for the early aetiological diagnosis of congenital hypothyroidism, using beside the classical T4, T3 and TSH plasma concentrations, four additional parameters in plasma and urine. The first one is thyroglobulin (Tg). In normal children of more than one year of age and in adults, 5–35 ng/ml plasma is found, in neonates 2–3 weeks old, this level is 10–250 ng/ml. In patients with a stimulated thyroid gland, as in primary congenital hypothyroidism, plasma Tg levels increase. High Tg values are found in iodine deficiency and in organification defects. In the absence of the thyroid gland plasma Tg is undetectable. Low to normal levels are found in cases with hypoplasia of the gland. In patients with a disturbed synthesis of Tg, resulting in Tg deficiency of the gland, plasma Tg levels vary from undetectable to normal. The PBI-T4 plasma difference, which is caused by circulating abnormal iodoproteins is the second parameter. The products of thyroidal breakdown processes of the abnormal iodoproteins are excreted in the urine and used as the third parameter. We found that the excretion of this low molecular weight iodinated material (LOMWIOM) was increased only in Tg-deficient patients. If the neonate is found to be hypothyroid, thyroid hormone substitution must be given immediately. Blood and urine sampling can be done just before or even directly after starting the therapy. The measurements extended with the determination of the total iodine excretion (fourth parameter) can be carried out within 1 week. With these additional methods it appeared to be possible to distinguish between several types of congenital hypothyroidism in neonates found by screening.

Serum thyroglobulin and goitre size were followed in 22 patients with simple goitre or single thyroid nodules during 9 months of thyroxine therapy, to see whether alterations in serum thyroglobulin correlated with changes in goitre size. In the case of such a correlation serum thyroglobulin could be used to predict which goitres respond to thyroxine therapy and which require surgery. Pretreatment serum thyroglobulin was elevated in 11 patients. It normalized in one of 7 patients whose goitre did not shrink and in none of the 4 patients whose goitre shrank during thyroxine treatment. Thus no simple correlation exists between alterations in serum thyroglobulin and goitre size during short-term thyroxine therapy. Since other studies suggest that increased serum thyroglobulin indicates ongoing goitre growth, thyroxine treatment might have been unsuccessful in all patients with persistently elevated serum thyroglobulin with a longer follow-up. The presence of predominantly thyroxine responsive tissue together with some autonomously growing, thyroglobulin-releasing areas in the same goitre could explain the failure of serum thyroglobulin to normalize in patients whose goitre shrank during therapy. The study shows that after eradication of iodine deficiency, thyroxine treatment is rarely successful in the Swiss goitre population and that surgical treatment is usually required.

Eight healthy males and 8 healthy females without a family history of thyroid disease or detectable thyroid autoantibodies were given 300 mg of lithium carbonate twice a day for 28 days. Using a precise and accurate ultrasonic technique we demonstrated an increase in median thyroid volume from 18 ml on day 0 to 34 ml on day 28 (P < 0.005) in the female group, whereas the median thyroid volume was unchanged in the male group. A significant increase in basal serum TSH level and serum TSH levels 20, 60 and 90 min after 200 μg of TRH iv was found in both groups after 28 days of lithium treatment. The means of the individual TSH increments during the TRH test were not significantly different between the two sexes neither before nor after lithium treatment. After 14 and 28 days a significant fall in serum T4 levels was found in both sexes. 131I uptake (24 h) in the thyroid gland was increased in both sexes, but only in the male group was the mean PB131I (24 h) significantly reduced after 28 days of lithium treatment. In conclusion the present study suggests a difference in susceptibility of the thyroid gland to the growth stimulating effect of minute increments in serum TSH in young healthy males and females given lithium carbonate.

In 65 consecutive surgical patients with multinodular goitre and with preclinical hyperthyroidism (TRH-resistant suppression of TSH in the presence of normal circulating thyroid hormones) the individual values of the FT4-index (FT4-I) and FT3-index (FT3-I) showed a wide range form low normal to high normal with mean values not differing from those in TRH-responsive goitre patients and from controls. Thirty-five patients underwent repeated pre-operative TRH tests: 11 (group A) were TRH-unresponsive on one occasion, and TRH-responsive at another time. Fifteen (group B) were TRH-unresponsive on two occasions. Nine patients (group C) were preclinically hyperthyroid on one occasion and had supranormal individual thyroid hormone concentrations at another time. In multinodular goitre patients with preclinical hyperthyroidism a significant T3 increase was observed after oral TRH. In spite of a TRH-resistant suppressoin of TSH small amounts of TSH are thus still secreted. The degree of TSH suppression may be the result of a varying degree and pattern of continued, fluctuating or elapsed increase in thyroid hormone supply. The T3 response to oral TRH depends not only on the degree of TSH suppression, but also subtlely on the thyroidal reserve: in euthyroid TRH-TSH negative goitre patients a decrease of the TSH-regulated follicular mass by goitre resection abolished the pre-operatively significant T3 response to TRH during the post-operative phase of transient TSH deficiency.

The rare occurrence of hyperthyroidism with an autonomously functioning nodule which following 131I therapy presented as toxic diffuse goitre (Graves' disease) is described in a 60 year old male. This progression was characterised by the presence of varying concentrations of IgG thyroid stimulators, thyroid stimulating immunoglobulins and thyroid growth stimulating immunoglobulins, as measured by cytochemical bioassay. It is postulated that the presence of the nodule and its associated hypersecretion of thyroid hormones may have protected the gland from the effects of IgG stimulators by bringing about inhibitory short-loop feedback on normal thyroid cells. It is further suggested that following therapeutic ablation of the nodule, normal thyroid cells became sensitive to the thyroid stimulators with the evolution of typical features of toxic diffuse goitre.

The distribution of HLA-A, -B, and -DR antigens in 53 Southern Chinese patients with Hashimoto's thyroiditis including 33 with goitre and 20 without goitre was compared with the distribution in 100 Southern Chinese controls. There was a significantly increased prevalence of HLA Bw46 in the non-goiterous patients and of HLA DRw9 in both groups of patients, but only for HLA DRw9 in the goiterous group was the increase significant after adjustment for the number of antigens studied. Based on these findings and those in other autoimmune diseases it is considered that the haplotype Bw46, DRw9 in Chinese takes the place of B8, DR3 in Caucasians in carrying genes which predispose to the development of autoimmune disease.

Since 'Thyroid-Growth-Immunoglobulins' are implicated in the pathogenesis of some goitrous thyroid diseases, we have investigated the presence of thyroid growth modulators in the sera from patients with simple non-toxic goitre (diffuse non-toxic goitre and colloid nodular goitre). To detect growth effect, two procedures were employed, both using [3H]thymidine incorporation into DNA. In one procedure, porcine thyroid follicles in suspension were employed. Gamma-globulin (2 mg/ml) from 10/26 of patients with diffuse non-toxic goitre and 8/27 of patients with colloid nodular goitre were found to increase [3H]thymidine incorporation when compared to gamma-globulins from control group. The other procedure used sparsely plated thyroid cells isolated from normal or porcine thyroid gland and from human simple non-toxic goitre. No serum from patients with simple goitre showed greater growth stimulating activity than that of normal individuals. Moreover, using simple goitre cells as target, a lower serum activity was observed in 7/28 of patients with diffuse non-toxic goitre and in 9/30 of patients with colloid nodular goitre. Analogous results were obtained with normal porcine thyroid cells. The lower serum activity of these patients was observed in a wide range of serum concentrations (1 to 15%) and was associated with and inhibitory effect recovered in the gamma globulin fraction. By the two different procedures, we have therefore evidenced the presence of thyroid growth modulators in the sera of several patients with simple non-toxic goitre. The stimulatory effect observed with the thyroid follicles strengthens the implication of thyroid growth stimulating immunoglobulin in the pathogenesis of some simple sporadic non-toxic goitre. The negative effect detected with monolayers of sparsely plated thyroid cells needs further characterization but, at least, it points out the importance of the culture conditions in the interpretation of the results.

Beta-adrenergic receptor characteristics were investigated in peripheral blood mononuclear leukocytes taken from patients before and after partial thyroidectomy. In order to discriminate the effect of surgical stress per se from that of thyroidectomy, the analysis was also performed on patients before and after cholecystectomy. Receptor characteristics were determined by using dihydroalprenolol as ligand in direct equilibrium binding experiments. The binding affinity showed no changes either when two different surgical treatments were compared or when the same patient was analysed before and after the operation. On the contrary, a significant decrease in receptor density was found in thyroidectomized patients when compared pre- and post-operatively. This fall in receptor number seems to be linked with thyroid function since no statistically significant changes were observed in cholecystectomized patients in relation to surgical operation. This view is further supported by data on T3 serum levels, which show a significant fall after thyroidectomy but no statistically significant modifications after cholecystectomy. It is concluded that betaadrenoceptor modulation plays an important role in the relationship between thyroid and beta-adrenergic system.

Epidemiological findings from the city of Cali, Colombia, support the hypothesis that water supply and iodine intake are not the only dietary factors which influence the magnitude of the goitre endemia. Experiments were conducted in rats to determine whether casein has a counteracting effect on the goitrogenic and antithyroid activities of methimazole (MMI) and goitrogenic water extracts (GWE) from the endemic area of the Cauca Valley. Female albino rats (Charles River, DC strain) 100–110 g initial weight, receiving 12 μg of iodine daily, were divided into three groups and put on special diets: protein-free, 8% casein, or 60% casein, respectively. Each group (24 rats) was then divided into three subgroups. Subgroup one received goitrogen-free water and was used as a control. Subgroup two was administered MMI, 50 μg/day/rat. Subgroup three was given per animal a daily amount of GWE equivalent in antithyroid potency to 50 μg of MMI. At 77 days, the thyroid glands were studied for weight, 131I uptake, and 127I concentration. Animals on the protein-free diet showed significantly (P < 0.05 – < 0.01) larger thyroid glands per 100 g body weight and lower thyroidal 4 h 131I uptake and 127I-concentrations than rats on casein diets. These differences were significantly increased (P < 0.01) by the administration of MMI and GWE. All the effects were completely reversed by the 60 % casein diet showing no differences between control rats and those on MMI or GWE. Rats on 8 % casein showed intermediate values between those of animals on protein-free and 60% casein diets; differences were still present between the control as against the MMI or GWE groups. The results indicate that under these experimental conditions, a poor-protein diet impairs the thyroidal transport of iodine, decreases its concentration in the thyroid and is accompanied by an enlargement of the gland. Under these circumstances, the action of thiourea-like antithyroid agents is enhanced. The administration of protein reverses these alterations and decreases the action of such antithyroid agents. Whether the changes observed are due to a direct action of casein on the thyroid and/or to effects of malnutrition on the metabolism of antithyroid compounds remains to be determined.

In order to investigate the possibility of the simultaneous expression of two different calcitonin genes during evolution, we studied the nature of calcitonin in: eel pericardium, salamander branchial region, rat thyroid, ox thyroid, medullary carcinoma of the human thyroid and human thyrotoxic goitre. Sensitive and specific RIAs for human calcitonin (hCT) and salmon calcitonin (sCT) were used in combination with high pressure liquid chromatography (HPLC). We found that two different immunoreactive calcitonins resembling hCT and sCT exist in eels, salamanders and rats. The major form is i-sCT-like in eels and salamanders, while it is i-hCT-like in rats. Extracts of ox thyroid contained, in addition to the major artiodactyl-CT, an i-hCT-like material. The various human thyroid extracts studied, contained i-hCT but no i-sCT-like material. This study demonstrates the simultaneous expression of two different calcitonin genes in several species. Taken with the presence of molecules resembling sCT and hCT in birds, this further evidence is consistent with duplication of the calcitonin gene early in vertebrate evolution.

Thyroid volume of 1397 German and 303 Swedish adults were estimated by sonography. Thyroid size of 6–16 year old Germans (n = 619) was determined and compared with findings on palpation. Thyroid volume was more than twice as great in German (21.4 ± 15.6 ml, mean ± sd) than in Swedish adults (10.1 ± 4.9 ml). The echopattern was abnormal in 16% of the Germans and in 3.6% of the Swedes. German children have a thyroid volume ranging from 1.8 ± 0.4 ml at 6 years to 10.8 ± 6.0 ml at 16 years of age. Palpation is by comparison an unreliable method for determining thyroid size. In Germany, the iodine excretion was less in children (n = 619, 39.5 ± 30.5, 34.1 μg I/g creatinine, mean ± sd, median) than in adults (n = 1193, 83.7 ± 94.4, 62.6), (P P < 0.0001). Serum thyrotropin concentration was significantly higher (P P

Human thyroglobulin (Tg) was isolated to apparent purity from various thyroid tissue samples obtained after surgery. Iodine and iodothyronine content of Tg was determined. Isoelectric focussing (IEF) was performed on thin layer agarose gels. Tg revealed a microheterogeneity of 6 bands in the range between pH 4.2 and 4.6. The intensity of the single bands depended on the iodothyronine content of Tg. With increasing degree of iodination, the bands with a lower pI (pI 4.35, 4.40) became more prominent, whereas the bands with higher pI (pI 4.55, 4.60) diminished. This typical change in microheterogeneity pattern could be confirmed by kinetic in vitro iodination and consecutive iodothyronine formation of low iodinated Tg (0.05% iodine). After in vitro desialylation, the bands shifted to a higher pH range (pH 4.60 to pH 4.90), but no reduction of the number of bands occurred. Even in desialylated Tg microheterogeneity is still dependent on iodine content. These results suggest, that the microheterogeneity of Tg is influenced, but not caused by different iodine and NANA content. Different polypeptide composition may be responsible for the microheterogeneity of Tg. In thyroid diseases without disturbance in Tg synthesis (endemic, diffuse and nodular goitre, Graves' disease) variations in relative intensity of single bands could be related to differences in iodine content. In thyroid cyst fluid and cold nodules in addition to low iodinated Tg, further bands were found with pI-values comparable to desialylated Tg.

Myxoedematous endemic cretinism is prevalent in African goitre endemies. It has been related to a thyroid 'exhaustion' atrophy occurring near birth. It is proposed that this might result from the low resistance of a fragile tissue to enhanced H2O2 generation under intense thyroid stimulation by thyrotropin. In support of this hypothesis, low selenium and glutathione peroxidase serum levels have been found in the African endemic area of the Idjwi Island (Kivu, Zaire). Serum selenium and plasma glutathione peroxidase were lower in the area of high endemicity of goitre and cretinism (Northern part of the Island). However, only the former difference is statistically significant. These data thus suggest a role of oligoelements and oxygen toxicity in the pathogenesis of endemic cretinism.

Studies were performed in 120 patients with simple goitre, defined as relatively soft diffuse goitre. All were clinically and biochemically euthyroid and their antithyroid antibodies were negative. The TRH test was performed in 115, and a T3 suppression test was performed in 99 after the TRH test, while satisfactory biopsies of the thyroid were obtained in 37. The results showed that 28 of the 115 cases (24%) had an abnormal response to TRH; 8 (7%) were hyporesponders and 20 (17%) were hyperresponders. The T3 suppression test showed that 3 of 99 cases (3%) were non-suppressible. As determined by histological examination of the needle biopsy specimen, 17 of the 37 cases (46%) had normal follicles without lymphocytic infiltration, 10 (27%) had diffuse chronic thyroiditis, 5 (14%) had focal thyroiditis and 4 (11%) had diffuse epithelial hyperplastic change, and 1 (3%) had an adenomatous goitre. It is suggested that simple goitre defined as above includes various thyroid diseases and that the results of TRH tests, antithyroid antibody estimations and histological findings do not correlate in many patients.

The availability of iodinated salt containing 20 mg of iodine as iodate/kg salt consumed on a voluntary basis enabled us to investigate its effect on goitre prevalence and iodine excretion in urine in a longitudinal, prospective, randomized study over 4 years. With this salt, under the assumption of a consumption of 5 g salt per day and person, an additional intake of 100 μg of iodine can be achieved. The study was performed on initially 334 children (168 boys, 166 girls) at the age of 10 years living in an area of iodine deficiency. After 4 years, 286 children still participated in the study. Initially, goitre prevalence as assessed by palpation was found to be 30.5% (37.4% in girls and 23.8% in boys). Neck circumference was found to be significantly higher in children with goitre compared with those without (30.2 ± 1.4 vs 29.4 ± 1.4 cm; P < 0.001). Iodine excretion in the urine was significantly lower in children with goitre compared with those without (40.4 ± 16.7 μg/g creatinine vs 46.1 ± 24.9 μg/g creatinine; x ± sd; P < 0.05). The children were randomly assigned to two different groups: group A (N = 146) was asked to use iodinated salt, group B (N = 188) non-iodinated salt. Over the 4 years, a continuous increase in iodine excretion in urine could be demonstrated in group A. After 1 year, it was significantly higher than in the control group that used non-iodinated salt. After 4 years, the mean iodine excretion in children using iodinated salt was 60.1 ± 24.1 μg/g creatinine in contrast to 45.1 ± 18.6 μg/g in the control group (x ± sd; P< 0.0001). However, no decrease in goitre prevalence could be documented: after 4 years, 23.8% of the children belonging to the group using iodinated salt and 22.5% of those in the group taking non-iodinated salt had a goitre. From these observations we conclude: 1. The voluntary use of a commercially available iodinated salt containing 20 mg iodate/kg leads to a significant increase in iodine intake, measured by urinary iodine excretion. Even after 4 years, the value is far below the daily iodine intake recommended by the WHO. No decrease in goitre frequency could be assessed. 2. An increase in iodine ingestion can be achieved either by increasing the iodine content of the salt or by application of iodine by alternative measures. The safest way would be to use iodinated salt exclusively, i.e. also in the food industry and restaurants. An increase in the iodine content of the salt and its continuous voluntary use would lead to a large variation in iodine intake. A higher risk of adverse reaction, e.g. iodine-induced thyrotoxicosis, cannot be excluded in susceptible persons.

A case is reported of a woman of 30 where chronic autoimmune thyroiditis was diagnosed in 1970. The diagnosis was based on palpation, thyroid function tests and elevated titres of antibodies against thyroid constituents. She was initially treated with small doses of prednisone with complete clinical and biochemical remission which persisted also after therapy was withdrawn. In the following 10 years she had three new episodes of goitre and biochemical hypothyroidism, all responding fast and completely to small doses of prednisone. Between these episodes she had periodes of several months up to 3 years with no detectable thyroid disease even when not on treatment.

Ultrasonic scanning has been used to estimate changes in goitre size during and after treatment with a daily dose of either 100 μg thyroxine (T4) (n = 30), 150 μg T4 (n = 33), 200 μg T4 (n = 17) or 60 μg triiodothyronine (T3) (n = 30) for one year in patients with diffuse non-toxic goitre. The thyroid volume was measured before and every 3 months during and 3 months after withdrawal of therapy. All 4 treatments resulted in a decrease in goitre size after 3 months' therapy (P < 0.05) but only in the patients given 200 μg T4 and 60 μg T3 was the decrease long lasting during additional 9 months' therapy. The mean reduction in thyroid volume after 12 months therapy was 30 ± 26 sd and 22 ± 30 (sd)%, respectively. The free-T4-index was found significantly raised throughout the treatment with all three T4 doses, whereas the free-T3-index did not change. During treatment with 60 μg T3 no persistent rise in free-T3-index was seen while free-T4-index was decreased all 12 months. No increase in goitre size was observed 3 months after withdrawal of the T3 therapy (n = 15), whereas all goitres in the T4 treated groups had returned to the pre-treatment values at that time. No rebound phenomenon was observed. The serum T3 and T4 levels were normalized 3 months after withdrawal in all four groups. Seven out of 8 patients on 200 μg T4 daily and 20 out of 25 patients on 60 μg T3 daily had no TSH response to TRH (200 μg iv) after 3 months' therapy. Forty-three out of 61 patients in the 4 groups showed no TSH response to TRH after 3 months' therapy. Only the group of patients showing no TSH response to TRH after 3 months' treatment had a significant decrease in goitre size in contrast to the group with a positive response to TRH.