Biomedical subjects
Publications and source records attributed to A Shiroozu.
A 70 year-old-Japanese man underwent gastrectomy for early gastric cancer with preoperative hypocellular marrow. Three weeks later, acute myelomonocytic leukemia developed with tetrasomy for chromosome 8 (48,XY,+8,+8). The patient died of leukemia on the 33rd postoperative day. Whether or not the operation triggered the leukemia remains unknown.
In a 68-year-old Japanese woman, who had a right supraclavicular cyst containing thyroglobulin-rich fluid, metastatic adenocarcinoma was demonstrated in the cyst. A subsequent total thyroidectomy showed a papillary carcinoma measuring 11 mm in the ipsilateral lobe of the thyroid. A high thyroglobulin level in a cervical cyst may facilitate the detection of hidden primary cancer in the thyroid.
Two patients with post-traumatic diabetes insipidus (DI) are reported. One had suffered a fatal injury and the other a mild contusion without amnesia before DI developed. These two instances exemplify the wide spectrum of post-traumatic DI and, hence, the importance of ruling out DI even afer a mild closed-head injury.
Serum levels of thyroglobulin (Tg) were measured using immunoradiometric assay in 18 patients with primary hypothyroidism, whose serum levels of thyroid stimulating hormone (TSH) were higher than 40 mU/l and anti-Tg antibodies were negative. In 12 patients, serum Tg levels were extremely elevated above the upper limit of normal (30 ng/ml) and the levels were more than 800 ng/ml in 10 of them. In all of these 12 patients, thyroid function recovered spontaneously with only iodide restriction and the serum Tg levels declined concomitantly with the decrease in serum TSH concentrations, events suggesting the TSH dependency of this Tg elevation. In the other 6 patients without elevated Tg levels, thyroid function did not recover and replacement therapy with L-thyroxine had to be given. Data from our study show that the TSH dependent Tg secretion is observed in reversible type primary hypothyroidism and that it may proceed vigorously even though thyroid hormone production is subnormal. Measurement of serum Tg may be valuable for predicting the prognosis of primary hypothyroidism.
The lysosomal acid protease is thought to be a main enzyme in hydrolysis of thyroglobulin. The protease activity of lysosome-rich fractions of various diseased thyroid glands were assayed by the sensitive and reproducible method developed in our laboratory. They included 78 diseased thyroid glands; 37 thyrotoxic goitres, five irradiated thyroids, five Hashimoto's thyroiditis, one granulomatous thyroiditis, six multinodular goitres, 14 'cold' adenomas, four 'hot' adenomas with three paranodular tissues, and six carcinomas. Fifteen paranodular tissues of cold and solitary thyroid nodules were served as controls. The protease activities were significantly increased in thyroid tissues of thyrotoxic goitres, Hashimoto's thyroiditis, adenomas and adenocarcinomas. In thyrotoxic goitres, the protease activity correlated well with the mean area size of colloid follicles. The 'hot' adenomas had higher protease activity than 'cold' ones. The protease activity of multinodular goitres was nearly normal. Only the irradiated thyroid glands had low protease activities. Therefore the high protease activities in hyperfunctioning goitres seem to reflect hormone secretory activities. On the other hand, cold neoplastic goitres seem to have lysosomal protease activities which are not associated with thyroidal secretory process. The assay of acid protease activity will be useful to understand the pathophysiology of lysosomal system in diseased thyroid glands.
The effects of methylmercaptoimidazole (MMI) and propylthiouracil (PTU) were compared in patients with Graves' hyperthyroidism. Firstly, the duration of action of the drugs was studied by the perchlorate discharge test, which was performed 2, 12, or 24 h after administering a single dose of 15 mg MMI or 300 mg PTU. After 2 h, the 9 MMI-treated patients who were tested had marked discharge (mean +/- SD, 65.0 +/- 15.8%), as did the 6 patients treated with PTU (57.6 +/- 26.6%). The mean values for the percent discharge 12 and 24 h after drug administration were 34.9 +/- 31.9% (4 patients) and 36.5 +/- 26.9% (69 patients), respectively, in the MMI group and 19.1 +/- 11.7% (11 patients) and 8.6 +/- 10.5% (7 patients) in the PTU group, indicating that the effect of MMI lasted longer. Secondly, the clinical effects of long term administration of the drugs were compared in a different group of patients with Graves' hyperthyroidism. Within 5 weeks after the onset of treatment, 34 (52%) of 66 patients treated with MMI (10 mg, 3 times daily) were euthyroid, while only 1 of 17 patients treated with PTU (100 mg, 3 times daily) was euthyroid. The average time required to achieve euthyroidism, namely normal serum T3 and T4 levels, was significantly shorter in the MMI group [6.7 +/- 4.6 (+/-SD) weeks] than in the PTU group (16.8 +/- 13.7). In spite of the well known effect of PTU on the extrathyroidal conversion of iodothyronines, the serum T3 level normalized much faster with MMI than with PTU. These results indicate that in our patient population 15 mg MMI had a longer inhibitory effect on the organification of iodide than did 300 mg PTU, and that MMI was more rapidly effective in the treatment of Graves' hyperthyroidism.
The duration of action of methimazole (MMI) was studied in patients with hyperthyroidism due to Graves' disease. Perchlorate discharge tests performed 24 h after MMI administration revealed greater than 10% discharge in 77% of 53 patients who received a single dose of 15 mg MMI and in 74% of 23 patients who received 30 mg. The mean percent discharges were 41.5 +/- 26.4% (+/- SD) and 35.4 +/- 28.0, respectively. Based on these results, hyperthyroidism was treated with a single daily dose (SDD) of 15 mg in 43 patients and with 30 mg in 32 patients, and the results were compared with retrospective analysis of 50 patients who were treated with divided doses of MMI (10 mg, 3 times daily). Within 12 weeks, 93% of the patients treated with 15 mg SDD, 91% treated with 30 mg SDD, and 86% treated with divided doses were euthyroid. The mean times to achieve euthyroidism in these patients were 5.3 +/- 3.6 (+/- SD), 5.3 +/- 3.1, and 5.6 +/- 3.0 weeks, respectively. Side-effects occurred in 2 patients treated with 15 mg SDD and in 6 treated with 30 mg SDD. We conclude that a single daily dose of 15 mg MMI is not only effective in most patients with Graves' hyperthyroidism, but also less frequently causes adverse effects.
The value of predictive tests in bromocriptine therapy and the effects of long-term bromocriptine therapy were investigated in acromegalic patients. In 72 acromegalic patients, there was a tendency for patients with a plasma GH response to TRH or with an elevated basal plasma PRL level, but without a plasma GH response to LHRH, to have a plasma GH response to bromocriptine, though statistical analysis did not reveal a significant difference. Acute and chronic effects of bromocriptine were significantly interrelated, while the chronic effect of bromocriptine and abnormal plasma GH response to TRH or elevated plasma PRL levels were not, in 18 acromegalic patients. These results suggest that the acute bromocriptine test is a better predictor than the TRH test and plasma PRL levels for evaluating the effects of chronic bromocriptine therapy. To maintain the low plasma GH levels, increasing doses of bromocriptine were needed in most patients, and failure to control the elevated GH level despite increasing doses was observed in 2 of 18 patients.
A 47-year-old housewife was admitted to our hospital because of general fatigue and constipation suggesting hypothyroidism. For 3 years before admission, general fatigue, arrhythmia, dry skin, drowsiness, cold intolerance and hypermenorrhea occurred insidiously. She had habitually taken considerable amounts of seaweed every day, e.g. more than 50 g of " Kombu " for more than 5 years and at least 1 g of " Wakame " for 6 months. On admission, serum thyroxine (T4) was 1.3 micrograms/dl, serum triiodothyronine (T3) was 47 ng/dl, TSH was 132 microunits/ml, and 123I thyroidal uptake was 60% at 3 hr. and 75% at 24 hr. Anti-thyroglobulin hemagglutination antibodies and anti-thyroid microsomal hemagglutination antibodies were both negative. When seaweed was omitted from her diet, T4 rose to 6.3 micrograms/dl and T3 rose to 113 ng/dl, whereas TSH lowered to 11 microunits/ml in 2 weeks. The seaweed-free diet was continued and 4 months later, when she had become euthyroid, an open biopsy of the thyroid gland was carried out. Histological examination of the specimen revealed a marked colloid deposition without characteristic features of Hashimoto's disease. Five months after admission, with the daily administration of 100 mg potassium iodide (KI), the effects of inorganic iodide on thyroid function had begun to be seen. On the 16th day of the KI regimen, palpitation and tachycardia (pulse rate 160/min.) with multifocal ventricular premature beat appeared, and T4 on the 11th day was 5.9 micrograms/dl, which was clearly lower than the pretreatment level of 8.4 micrograms/dl. KI was discontinued on the 16th day, and one week after the withdrawal, T4, T3 and TSH all returned to the pretreatment level. For more than 3 years on a seaweed-free diet, she remained euthyroid without any thyroid regimen. To see the effects of inorganic iodide on thyroid function after this long period on a seaweed-free diet, KI was again administered. One hundred mg/day KI for 14 days followed by 200 mg/day for 21 days had virtually no effect on T4, T3 and free T4 and she remained well. None of the perchlorate discharge tests performed on 3 occasions during the 6 month period after the initiation of the seaweed-free diet showed a discharge.(ABSTRACT TRUNCATED AT 400 WORDS)
Twenty seven hypothyroid patients with a serum concentration of thyroid stimulating hormone (TSH) of over 40 mU/1 were followed up for three to 20 weeks without replacement therapy. The serum thyroid hormone concentrations increased with a dramatic decrease in serum TSH values in 14 patients (reversible group) but there was no significant change in the other 13 (irreversible group). Fourteen out of 19 patients with goitre but none of the eight patients without goitre belonged to the reversible group. All of the 11 patients with a high uptake of iodide by the thyroid, three of the six with a normal uptake, and none of the 10 with a low uptake belonged to the reversible group. These observations indicate that patients with goitrous hypothyroidism with a preserved thyroid uptake of iodide are likely to become euthyroid spontaneously without replacement therapy.
Although the activity of lysosomal protease in Graves' thyroid is considered to be increased, there has been no quantitative method to estimate the protease activity in the thyroid tissue due to the contamination of thyroglobulin (Tg) which varies in susceptibility to the protease. In the present study, the proteolytic activity (PA) of thyroid lysosomal protease preparation (P25) separated from Tg was assayed using 125I labeled rat Tg. More than 95% of 125I-Tg was hydrolyzed at pH 4.0 without deiodination, and the pattern of liberated iodoamino acids resembled that of pronase digest except for a higher T3/T4 ratio. Thirty-seven Graves' thyroids and 15 paranodular thyroid tissues were assayed. PA, the specific PA (SPA; calculated as PA per mg P25 protein) and PA per DNA content in Graves' thyroids were significantly higher than those in controls. There were good correlations among PA, SPA and PA per DNA content of the thyroid tissue. PA and SPA in the thyroid from 29 patients with Graves' disease treated with propylthiouracil or methimazole did not correlate with serum thyroid hormone level immediately before surgery. In 8 patients treated with KI, PA from 5 patients whose serum thyroid hormone levels had been normalized were significantly lower than those from 3 patients who were still thyrotoxic.(ABSTRACT TRUNCATED AT 250 WORDS)
We have previously shown that the thioureylene antithyroid drugs 6-propyl-2-thiouracil (PTU) and 1-methyl-2-mercaptoimidazole (MMI) can inactivate thyroid peroxidase (TPO) in a model iodination system containing relatively high concentrations of iodide. The purpose of the present study was to determine whether these drugs may also inactivate TPO in vivo in rats. Assays for total TPO activity after injection of PTU or MMI did not prove to be a valid approach. As TPO inactivation might be expected to result in a relatively prolonged inhibition of enzyme activity, most of our experiments involved measurement of the duration of the inhibitory effect of a single injection of drug. Young rats were injected with low doses of PTU or MMI, and the effect on thyroidal organic iodine formation was determined at intervals after injection, either by 1-h pulse labeling with 131I- in vivo or by incubation of excised thyroid lobes in a medium containing 131I-. Results of both types of experiment demonstrated that the inhibitory effect of a small dose of PTU (1 mumol/100 g BW) was still very marked 17-18 h after injection. Moreover, an inhibitory effect of this small dose of PTU on the metabolism of [35S]MMI could also be demonstrated. Administration of MMI to rats, on the other hand, did not show the prolonged inhibitory effect observed with PTU. This is most likely attributable to the much lower thyroidal uptake of MMI than of PTU in rats. Intrathyroidal metabolism of [35S]PTU and [35S]MMI was also investigated. In contrast to the rapid disappearance of 35S from plasma, both drugs showed accumulation and retention of 35S in the thyroid. However, we obtained no evidence that thyroidal accumulation of PTU or one of its metabolites could explain the prolonged inhibitory effect of this drug. It seemed more likely that this was attributable to TPO inactivation. The clinical implications of our findings are discussed with relation to the dosage schedule commonly employed in the treatment of Graves' disease with antithyroid drugs.
The aims of the present study were to investigate the incidence of adverse effects of thioureylene antithyroid drugs and to see if there were any factors related to the development of the adverse effects. Methimazole or propylthiouracil was administered to 151 patients with Graves disease; 76 untreated cases and 75 treated cases. The overall incidence was 22.4% among the 76 untreated cases. The incidences were 26.7% (13/45 cases) for methimazole and 16.1% (5/31 cases) for propylthiouracil, respectively, which were significantly higher than those previously reported. Fourteen out of 17 cases with the adverse effects were given the other thioureylene. The successive incidence of the adverse effects was 28.6% (4 cases), which was not significantly different from that under the drug of first choice. The result suggests that methimazole and propylthiouracil may not have cross-reaction each other. On the other hand, antinuclear antibody and anti-DNA antibody became positive in 2 out of the 4 cases. It would be a significant phenomenon, since antinuclear antibody was positive in only 3% of cases before the drug treatment. Thus, an immunological mechanism seemed to be involved in the problems, although there was no correlation between antithyroid autoantibodies and the development of the adverse effects. The adverse effects were observed within 2 months of administration of less than 250 tablets in total in most of the cases. The results imply that allergic mechanism rather than accumulating or toxic effect may concern the development of adverse effects of the thioureylenes.
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Eleven thyroid follicular adenomas, cold on scintigram were analysed to determine whether defect in iodide organification or iodide transport causes low iodide uptake in cold nodules of the thyroid. The results were compared with perinodular tissue samples used as controls. In eight of eleven adenomas incubated in medium with 0.1 microM of iodide, newly organified iodide was 85.6 +/- 8.6% of total trapped iodide, which was significantly higher than 52.3 +/- 12.8% in controls. The remaining three adenomas showed a value as low as 4.0 +/- 2.7%. These data suggest that follicular adenomas are of two different groups; one with high organic iodinating activity and the other with none. These two groups were defined as FA-1 and FA-2. Thyroid:medium ratios of iodide of both groups were significantly depressed, indicating that the essential alteration in the thyroid follicular adenoma is a disturbance of iodide transport. In contrast to controls of organification of iodide was not inhibited by the addition of 100 microM iodide to the medium in FA-1 adenomas. In both FA-1 and FA-2, the degree of iodination of thyroglobulin (Tg) in equilibrium was significantly lower than that in controls. Therefore, in most cases with the follicular adenoma, the principal cause of decreased iodination of Tg was considered to be a depressed iodide transport, but not an impairment of organic iodination.
The unique inhibitory effect of cycloheximide (CH) on the coupling of iodotyrosines was examined in vitro. Rat thyroid lobes were incubated for 8 h under our improved condition. In the presence of 10(-4) - 10(-3) M CH, the per cent uptake of 131I decreased, proportionate synthesis of [131I]MIT increased slightly, and that of [131I]T4 or [131I]T3 decreased markedly. The incorporation of medium 127I into T4 or T3 during the 8 h incubation period decreased markedly, but was fairly constant into MIT and only slightly decreased into DIT. Thus the inhibitory effect of CH seemed more prominent on iodothyronine formation than on iodotyrosine formation in this in vitro system. Inhibition of formation of newly labelled iodothyronines seemed to occur almost in parallel with the inhibition of [3H]amino acid incorporation into the thyroidal soluble protein. However, the coupling of iodotyrosines prelabelled in the absence of CH did not seem to be affected by CH. The presence of 10(-4) M CH induced the Wolff-Chaikoff effect at a lower iodide concentration than that which occurred in the absence of CH, suggesting that CH sensitized the Wolff-Chaikoff effect. However, the organification of 127I and T4 synthesis were markedly reduced in the presence of CH even before the apparent Wolff-Chaikoff effect was initiated. These results give further support to out contention that prethyroglobulin is more important for organification of iodide than pre-existing thyroglobulin. We conclude that CH reduces coupling efficiency indirectly, probably by inhibiting the formation of prethyroglobulin with a favourable structure for coupling.
In order to study the prognosis of Graves' disease, 236 patients, who had been diagnosed as having had Graves' disease more than 10 years before, were examined. Although one patient had died of leukemia and 2 patients had been operated on for breast cancer after 131I therapy, and another 6 patients had died between the ages of 20 and 50, the patients were doing quite well. Generally, the prognosis of Graves' disease is not considered to be serious if the thyroid function is controlled. Among the 72 patients who had been treated with 131I therapy, 15 patients (21%) showed low serum levels of both T3 and T4 and were considered to be suffering from late-onset hypothyroidism. About 67% of the 131I-treated patients were considered to be almost euthyroid, but serum TSH levels were high in half of them, suggesting latent hypothyroidism. The incidence of hypertension seemed to be significantly higher in the TSH-elevated euthyroid group compared with the TSH-nonelevated patients. An excessive reaction of the hypothalamus and/or pituitary gland might have an unfavorable effect not only on the apparent hypothyroidism, but also on the latent hypothyroidism after the therapy for Graves' disease.
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