Radioiodine treatment with 30 mCi after recombinant human thyrotropin stimulation in thyroid cancer: effectiveness for postsurgical remnants ablation and possible role of iodine content in L-thyroxine in the outcome of ablation

The main steps in the management of differentiated thyroid cancer are thyroidectomy, treatment with iodine-131 ((131)I), and follow-up with whole-body scanning (WBS) and serum thyroglobulin (Tg) determination. Both (131)I treatment and follow-up require maximum stimulation of normal or pathological thyroid remnants by TSH. The use of recombinant human TSH (rhTSH) has been shown to be useful for follow-up, whereas previous reports are not univocal regarding the use of (131)I postsurgical ablation of thyroid remnants, at least when low doses (30 mCi) of (131)I are administered. A possible explanation for the diminished effectiveness of (131)I treatment after rhTSH may be the interference of iodine content of L-thyroxine (L-T4) therapy during the protocol of administration of rhTSH. We have evaluated the effectiveness of stimulation by rhTSH for radioiodine ablation of postsurgical remnants, stopping L-T4 the day before the first injection of rhTSH and restarting L-T4 the day after (131)I. The study included two groups of patients: group 1 included 16 patients with differentiated thyroid cancer (15 papillary cancers and 1 follicular cancer, stages I and II), who were treated with 30 mCi (131)I with the aid of rhTSH, using the standard protocol but stopping L-T4 as stated previously; and group 2 included 24 patients with the same features (histology and stage) of disease treated with 30 mCi in the hypothyroid state after L-T4 withdrawal. In both groups, serum TSH reached a very good stimulation level [76-210 U/liter (mean, 112 +/- 11 SE) and 38-82 U/liter (mean, 51 +/- 3 SE), respectively]. At the first WBS (after (131)I treatment), all patients showed thyroid remnants. Furthermore, two patients of the first group and three patients of the second group showed lymph node metastases. After 1 yr, all patients were studied again and underwent WBS with a tracer dose of (131)I and serum Tg measurement using rhTSH with the same protocol in both groups. The percentage of ablation (undetectable Tg and a negative WBS) was higher, although not reaching statistical significance, in patients treated with rhTSH: 81.2% in patients treated by rhTSH withdrawal and 75.0% in patients treated by L-T4 withdrawal, respectively. No patient experienced symptoms of hypothyroidism during the 4 d of L-T4 interruption, and serum T4 remained in the normal range. Urinary iodine was analyzed in both groups and compared with a control group of patients who received, for diagnostic purposes, rhTSH without stopping L-T4. In the first group, urinary iodine was 47.2 +/- 4.0 microg/liter (mean +/- SE; P = 0.21 vs. the second group, P = 0.019 vs. control group). In the second group, urinary iodine was 38.6 +/- 4.0 microg/liter (mean +/- SE; P < 0.001 vs. control group); urinary iodine in the control group was 76.4 +/- 9.3 microg/liter (mean +/- SE). Our data show that rhTSH, as administered in the protocol stated previously, allows at least the same rate of ablation of thyroid remnants when low doses (30 mCi) of (131)I are used. The possible role of interference of iodine content in L-T4 is not surprising if we consider that the amount of iodine in 30 mCi is negligible (5 microg) compared with the amount of iodine content in a daily dose of T(4) ( approximately 50 microg). The cost of rhTSH seems modest compared with the high cost of complex therapeutic regimens in other areas of oncology and in consideration of the well-being of patients and of the high level of effectiveness of the treatment.     

Acute changes in clinical parameters and thyroid function peripheral markers following L-T4 withdrawal in patients totally thyroidectomized for thyroid cancer

After total thyroidectomy, differentiated thyroid cancer (DTC) patients have to undergo L-T4 withdrawal for measuring serum thyroglobulin and 131I whole-body scan (131I WBS) to evaluate residual/recurrent malignant disease. The aim of the present work was to study in these patients the effects of acute thyroid hormone deficiency on various target organs and tissues. Clinical parameters and thyroid function peripheral markers were evaluated in 20 DTC patients, both before and after L-T4 withdrawal. A 24-h urine collection, a fasting blood sample for laboratory examinations, a clinical score for hypothyroidism and cardiovascular, neurological and neuropsychological evaluations were carried out. After L-T4 withdrawal, the clinical score significantly increased, as well as total cholesterol, triglycerides, creatine kinase, lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase, whereas SHBG, osteocalcin and urine hydroxyproline levels significantly decreased. The acute thyroid hormone deficiency caused a systolic dysfunction of the left ventricle associated with an increase in systemic vascular resistance without cardiac contractility alterations. A significant increase in the left ventricular mass and thickness was also observed. Carpal tunnel syndrome appeared in 30% of patients and a significant reduction in the immediate auditive memorization and in attentive performance was also detected. These observations indicate that acute hypothyroidism causes significant clinical alterations of peripheral tissue function. In the follow-up of DTC patients, therefore, L-T4 withdrawal procedure should be restricted to cases where the cost/benefit ratio is favorable. Alternative procedures, such as the use of recombinant human TSH, should be used whenever possible.     

Is excessive weight gain after ablative treatment of hyperthyroidism due to inadequate thyroid hormone therapy?

There is controversy about the correct dose and form of thyroid hormone therapy for patients with hypothyroidism. Despite restoration of serum thyrotropin (TSH) concentrations to normal, many patients complain of excessive weight gain. We have compared weight at diagnosis of hyperthyroidism with that when euthyroid, evidenced by a stable, normal serum TSH concentration, with or without thyroxine (T4) replacement therapy, in patients treated with an 18-month course of antithyroid drugs (43 patients), surgery (56 patients), or 13I (34 patients) for Graves' disease. In addition, weights were recorded before and after treatment of 25 patients with differentiated thyroid carcinoma by total thyroidectomy, 131I, and long-term T4 suppressive therapy, resulting in undetectable serum TSH concentrations. Mean weight gain in patients with Graves' disease who required T4 replacement therapy following surgery was significantly greater than in those of the same age, sex, and severity of hyperthyroidism rendered euthyroid by surgery (3.9 kg) (p < 0.001) or at the end of a course of antithyroid drugs (4.1 kg) (p < 0.001). Weight gain was similar in those requiring T4 replacement following surgery or 131T therapy (10.4 versus 10.1 kg). In contrast, ablative therapy combined with suppression of TSH secretion by T4 in patients with differentiated thyroid carcinoma did not result in weight gain. The excessive weight gain in patients becoming hypothyroid after destructive therapy for Graves' disease suggests that restoration of serum TSH to the reference range by T4 alone may constitute inadequate hormone replacement.     

Acute effects of corticosteroids on thyroid activity in Graves' disease.

We studied the effects of administration of dexamethasone, 2 mg orally every 6 hr for 4 doses, on circulating thyroid hormone levels in hyperthyroid Graves' disease patients and in normal subjects. Serum triiodothyronine (T3), thyroxine (T4) and thyroglobulin (Tg) fell significantly below baseline values within 24 to 48 h after the first dose of dexamethasone in hyperthyroid patients; the values returned to or toward baseline levels in the subsequent 5 to 6 days. Serum T3 fell transiently in normals but to a much smaller degree than in hyperthyroid patients; T4 and Tg showed no significant change. Dexamethasone had ni inhibitory effect on the thyroid response to exogenous TSH in the hyperthyroid patients. Studies in vitro demonstrated lack of any appreciable effect by dexamethasone or hydrocortisone on stimulation of human thyroid adenyl cyclase by TSH or immunoglobulin G(IgG) from patient with Graves' disease. The fall in serum T3 without a change in serum T4 in normals suggested an effect of dexamethasone on peripheral conversion of T4 to T3. However, the markedly greater, more persistent drop in T3 in the hyperthyroid patients, as well as the associated drop in T4 and Tg, suggested an additional effect of dexamethasone administration on thyroid secretion in these patients. Preservation of thyroidal response to TSH during dexamethasone administration both in vivo and in vitro indicated that dexamethasone had not impaired thyroidal cellular processes per se. The data were consistent with an effect of dexamethasone on thyroid stimulator. The putative stimulator does not appear to be normal pituitary thyrotropin (TSH), since TSH was not detected in serum of anyof the patients studied. Additionally, the changes observed were too rapid to be explained by a steroid-induced fall in the level of a circulating IgG thyroid stimulator. The data are consistent with the possibility that there may be a non-TSH non-IgG thyroid stimulator in Graves' disease.     

Defective thyroidal iodine concentration in protein-calorie malnutrition

Although protein-calorie malnutrition (PCM) is known to result in various abnormalities of thyroid function, the exact relationship between the two is not clearly understood. Therefore, the thyroid function of 10 men, 13-55 yr of age, with severe PCM was studied in a clinical research ward before and 3-4 months after protein-calorie repletion. Before repletion, all subjects had low serum T4 (mean +/- SEM, 5.1 +/- 0.5 micrograms/dl) and T3 (74 +/- 6 ng/dl) concentrations. Eight subjects were chemically euthyroid, and their free T4 (1.5 +/- 0.1 ng/dl) and serum TSH (2.9 +/- 1.4 microU/ml) values were normal. Two subjects were chemically hypothyroid, with low free T4 values and high serum TSH values. After repletion, the 8 euthyroid subjects had significant increases in serum T4 (P less than 0.01) and T3 (P less than 0.005), but TSH did not change. Serum T4 and T3 were still lower (P less than 0.05-0.001) and TSH higher (P less than 0.01) than in 28 normal men of comparable age coming from the same area. After repletion, values remained unchanged in the 2 hypothyroid subjects, except for moderate increases in serum T3 and slight decreases in TSH. In all PCM subjects, values of thyroidal exchangeable iodine (23.1 +/- 7 vs. 42.9 +/- 8 mg; P less than 0.02), estimated thyroidal I per g wet wt (1.05 +/- 0.3 vs. 1.99 +/- 0.36 mg; P less than 0.02), and thyroidal iodide clearance (13.8 +/- 1.6 vs. 19.4 +/- 1.3 ml/min; P less than 0.002) were lower before repletion than after; the protein-bound 131I level (72 h; 0.27% vs. 0.08 dose/liter; P less than 0.05) was higher, but thyroid hormone secretion rates (200 +/- 49 vs. 153 +/- 25 micrograms/day) were not significantly different. Thyroid iodide clearance was lower even though plasma inorganic iodine (6.3 +/- vs. 12.5 +/- 3 micrograms/liter; P less than 0.05) and daily urinary iodine excretion (158 +/- 43 vs. 395 +/- 62 micrograms; P less than 0.01) were lower before than after repletion. In 2 PCM euthyroid subjects, baseline thyroid 131I uptake was lower before than after repletion, and the magnitude of the increase after TSH (10 U, im) stimulation was greater when the malnourished state improved. TSH increased concentrations of serum T4 and T3 both before and after protein repletion. After repletion, one hypothyroid patient failed to respond to TSH; the other had a small increase in 131I uptake but not in serum T4 or T3. The results indicate defective thyroid iodine concentration in human PCM, but adequate hormone secretion. This situation leads to depletion of thyroid iodine stores. This alteration, if extreme, might result in hypothyroidism. Adequate protein-calorie intake tends to reverse these abnormalities.     

Serum concentrations of osteocalcin in patients with hyperthyroidism, hypothyroidism and subacute thyroiditis.

Serum concentration of osteocalcin (OC) was measured in sera from untreated patients with Graves' disease, hypothyroidism due to Hashimoto's thyroiditis, and subacute thyroiditis. Serum concentration of OC in Graves' disease and hypothyroidism were 14.1 +/- 5.6 micrograms/L and 3.8 +/- 2.7 micrograms/L, respectively which were significantly different from that of healthy subjects (Graves' disease, p less than 0.001, hypothyroidism, p less than 0.01). Serum concentration of OC in patients with subacute thyroiditis was 8.0 +/- 3.5 micrograms/L which was not statistically different from age-matched normal controls. Serial measurement of serum OC for 24 mo in 15 patients with Graves' disease after initiation of antithyroid drugs disclosed that the decline of serum OC was obtained only 24 mo after antithyroid drug therapy. On the other hand, in hypothyroid patients, increased serum OC was observed after 1-2 months treatment of L-T4. Correlation coefficients between serum concentrations of OC and T3, T4, FT3 or FT4 in all the patients with thyroid disorders were 0.66, 0.51, 0.50 and 0.54, respectively, which were statistically significant (all, p less than 0.001). These results suggest that osteoblastic activity is enhanced in hyperthyroidism and suppressed in hypothyroidism. In hyperthyroid patients, despite of normalization of FT4 concentration in relatively short period (within 3-4 mo), it took 24 mo after initiation of antithyroid drugs for OC to normalize, suggesting not only thyroid hormone per se but also some unknown factor(s) participates in serum OC secretion. In contrast to thyrotoxic patients, rapid increase in serum OC after initiation of supplemental L-T4 treatment in hypothyroidism was observed, suggesting a direct effect of thyroid hormone on the osteoblasts in patients with hypothyroidism.     

SERUM THYROGLOBULIN AFTER MANTLE IRRADIATION FOR HODGKIN''S DISEASE

Thyroid function and serum thyroglobulin levels were studied in 66 subjects whose Hodgkin's disease had been previously treated by cervical, mediastinal and axillary lymph node (mantle) irradiation. Three patients were already undergoing treatment for thyroid disorders (one for primary hypothyroidism, two for Graves' disease) and a fourth was found to have euthyroid Graves' disease. 36 (Group I) of the remaining 62 patients had normal free thyroxine indices, normal basal thyrotrophin (TSH) levels and normal TSH response to thyrotrophin releasing factor (TRH). In 20 patients (Group II) free thyroxine indices were normal but either basal TSH levels were raised or normal basal TSH levels were associated with an exaggerated response to TRH. In 6 patients (Group III) free thyroxine indices were subnormal. Although results of thyroid function tests in group I lay within the normal range, the mean free thyroxine index was significantly lower and mean basal and peak TSH levels were significantly higher than those of a group of 35 normal subjects, indicating mild thyroid hypofunction. Elevated thyroglobulin levels were demonstrated in 11 irradiated subjects (18%). Mean thyroglobulin levels were significantly raised in each of the three groups of irradiated subjects. Significant positive correlations were found between log serum thyroglobulin and log basal TSH (r = 0.453, P less than 0.001) and log peak TSH (r = 0.515, P less than 0.001) levels. Mild thyroid hypofunction is common after mantle irradiation for Hodgkin's disease and raised serum thyroglobulin levels are a sensitive indicator of TSH stimulation of the damaged thyroid gland.     

Studies on the radioreceptor assay of TSH: the properties of TSH-binding inhibitor immunoglobulins (TBII) in patients with Graves' disease (author's transl)]

In the radioreceptor assay system for TSH, serum immunoglobulin G (IgG) from some patients with Graves' disease has been shown to inhibit the binding of labelled TSH to its receptor sites. In order to clarify the properties of these TSH-binding inhibitor immunoglobulins (TBII) in patients with Graves' disease, TBII were measured in sera from 31 untreated and 51 131I-treated patients, and their relation to clinical and laboratory findings was studied. TBII were detected in 18 (60%) out of 31 patients with untreated Graves' disease. TBII levels in these patients correlated well with thyroidal 99mTc uptake at 30 min and also with the grade of epithelial hyperplasia of thyroid follicles. There was no significant correlation between TBII and serum T3, serum T4, free T4 index, antibody titers against thyroglobulin and microsomes, or association of exophthalmos. There were many patients with Graves' disease whose sera contained high TBII levels but no detectable bioassayable thyroid-stimulating activity (LATS), and in these patients a close correlation was observed between serum levels of TBII and bioassayable LATS-protector activity. In patients with Graves' disease who had been treated by 131I from 5 to 17 years before, the incidence of TBII was very low at 20% (10/51). All except two cases having TBII were found to be still thyrotoxic. Thus, TBII were detected in 8 out of 10 thyrotoxic patients and in only 2 out of 18 euthyroid and none of 23 hypothyroid patients. These findings suggest that TBII in patients with Graves' disease were in close association with human thyroid stimulating activity, and that TBII might be useful as an indicator for checking the effectiveness of the treatment.     

乳头状甲状腺癌术后131I治疗后短期内TSH和甲状腺激素水平变化及临床意义

目的 探讨乳头状甲状腺癌(PTC)患者首次131I治疗清除残余甲状腺组织(清甲治疗)后第5天血清甲状腺功能指标的变化及临床意义.方法 PTC术后患者74例,首次131I清甲治疗剂量3.7 GBq,分别于131I治疗前1 d及治疗后第5天监测PTC患者血清FT3、FT4、TSH.以治疗前TSH水平分A、B两组:A组TSH＜30 mIU/L 22例,B组TSH≥30 mIU/L 52例.统计分析采用配对资料的符号秩和检验及相关性分析.结果 A组在131I治疗后第5天TSH下降87%,FT4升高88%,FT3升高87%,3项指标前后变化均有统计学意义(均P＜0.05),其中45%(10/22)患者达一过性甲状腺毒症水平.B组治疗后第5天三指标变化个体差异大,TSH小幅上升6%(P＞0.05);而FT4下降13%,FT3下降14%,前后变化有统计学差异(均P＜0.05).结论 针对PTC患者首次清甲治疗后短期内,部分患者甲状腺功能指标会升高甚至出现一过性甲状腺毒症,而另一些患者甲状腺激素只轻微下降,个体变化差异大.所以针对清甲治疗后的甲状腺激素替代和抑制治疗宜根据血清甲状腺功能指标监测结果制定个性化治疗计划.     

Use of adjunctive potassium iodide after radioactive iodine (131I) treatment of Graves' hyperthyroidism

One hundred and nineteen patients with Graves' hyperthyroidism who were treated with 131I alone or 131I followed by potassium iodide (131I + KI) were studied retrospectively. Patients in both groups who required only a single dose of 131I for successful treatment of hyperthyroidism had similar age, gland size, 24-h radioactive iodine uptake, pretreatment serum T4 concentrations, and radioactive iodine treatment dose. Seven weeks after 131I, mean serum T4 concentrations were 12.3 +/- 6.1 micrograms/dl (mean +/- SD) in patients who received 131I alone and 8.0 +/- 3.9 micrograms/dl in patients who received 131I + KI (p less than 0.001). Sixty percent of the patients who received 131I + KI and remained euthyroid 1 yr after 131I treatment developed documented transient hypothyroidism while receiving KI (serum T4, 1.4 +/- 0.9 micrograms/dl). Patients with transient hypothyroidism receiving KI had larger estimated thyroid gland weights when hypothyroid than patients whose hypothyroidism was permanent (32 +/- 6 vs. 16 +/- 11 g; P less than 0.001). The overall incidence of hypothyroidism 1 yr after treatment with 131I was 58% in each of the two groups. Sixteen percent of each group were not successfully treated by a single dose of 131I and required further therapy. Adjunctive KI effectively treated thyrotoxicosis more rapidly than 131I alone without adversely affecting outcome at 1 yr; however, patients taking KI more often develop transient hypothyroidism.     

Reappraisal of the 3,5,3'-triiodothyronine-suppression test in the prediction of long term outcome of antithyroid drug therapy in patients with hyperthyroid Graves' disease

Thyroidal suppressibility by exogenous T3 in terms of both radioiodine uptake (RAIU) and serum T4 was evaluated in 115 hyperthyroid patients treated with methimazole for 2 yr and followed for an additional 2 yr to study the rate of recurrence. Various other serum parameters including serum thyroglobulin concentrations, thyroid autoantibody, and TSH receptor antibody titers, and thyroidal responses to TRH-induced TSH elevation were also determined. After 2 yr of methimazole therapy, thyroidal RAIU was not suppressible (RAIU less than 12%/4 h was defined as suppressible) in 50 of 115 patients (group I). Of 65 patients with suppressible thyroid RAIU, serum T4 was significantly reduced (less than 60% of pre-T3 level) by T3 administration in only 43 patients (group III) but not in the remainder (group II). Antithyroid drug therapy was discontinued in the group II and III patients, and 7 of the patients had recurrence of hyperthyroidism within 2 yr of follow-up. All of them were from group II. The thyroidal response to TSH was greater in group III patients than in group II patients. During antithyroid drug therapy, decrease of microsomal antibody titer was more likely to occur in group III patients than in those of group II. Serum thyroglobulin concentrations were uniformly normal in treated patients irrespective of T3 suppressibility. TSH receptor antibody was positive in all 13 untreated patients with Graves' disease but was negative in treated patients regardless of their T3 suppressibility. Measurement of both thyroidal RAIU and serum T4 after administration of T3 improves the reliability of T3-suppression testing as a predictor of the remission of Graves' disease.     

Congenital goitrous hypothyroidism: discordant systolic time intervals, pituitary and peripheral responses to high daily doses of T4 or T3 therapy

Left ventricular performance was studied by a noninvasive technique through the measurement of the systolic time intervals (total eletromechanical systole, left ventricular ejection (LVET) time, preejection period (PEP) and PEP/LVET ratio (Systolic Quotient) in 8 young adults with congenital goitrous hypothyroidism. All subjects showed lengthening of PEP, shortening of LVET and an increased PEP/LVET ratio associated with low serum T3 and T4, an exaggerated TSH response to TRH, high levels of serum cholesterol, triglycerides and carotene. They were treated with increasing L-T4 at monthly intervals (100, 200 and 400 micrograms daily), followed by L-T3 (50 and 200 micrograms daily) after stopping medication for another month. Systolic time intervals and the systolic quotient promptly reversed to the normal range with physiologic L-T4 (100 micrograms) or L-T3 (50 micrograms) replacement, but the TSH peak response to TRH was still present and exaggerated. Further reductions of the systolic quotient occurred with 200 micrograms L-T4, but not with supraphysiological doses (400 micrograms L-T4 or 200 micrograms L-T3) of thyroid hormones. The highest dose of L-T3 (200 micrograms/day) induced a significantly lower mean systolic quotient than 400 micrograms L-T4 daily, while 5 patients still had a significant TSH response to TRH. This was interpreted as discordant pituitary and cardiac response to L-T3 and L-T4 therapy. Serum cholesterol and triglycerides were considered as very sensitive index of thyroid hormone peripheral action. These had a significant positive correlation with changes in the left ventricular performance. Serum carotene, although decreasing significantly with L-T4 or L-T3 treatment, had no significant correlation with the systolic quotient.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in thyroid volume during antithyroid drug therapy for Graves' disease and its relationship to TSH receptor antibodies, TSH and thyroglobulin

Changes in thyroid volume during antithyroid drug therapy for Graves' disease compared with circulating thyroid parameters were evaluated. One hundred and forty-four patients with Graves' disease were treated with methimazole. Thyroid volume was measured by ultrasonography (thyroid volume = pi abc/6, where a is length, b width, and c depth). Serum TSH, TSH-binding inhibitory immunoglobulins, thyroid-stimulating antibodies, thyroglobulin, antimicrosomal antibodies, and antithyroglobulin antibodies were also measured. In the whole group of patients, thyroid volume correlated significantly with thyroglobulin (p less than 0.01) and TSH-binding inhibitory immunoglobulins (p less than 0.01), but not with TSH, antimicrosomal antibodies, and antithyroglobulin antibodies. Furthermore, a positive correlation was found between thyroglobulin and TSH-binding inhibitory immunoglobulins (p less than 0.01). In 11 patients the mean thyroid volume decreased significantly after one year of therapy (p less than 0.01), associated with decreasing levels of serum TSH-binding inhibitory immunoglobulins. Ten patients experienced transient hypothyroidism with an overdose of methimazole, and the mean thyroid volume increased significantly (p less than 0.01) with increasing serum TSH levels. In conclusion, it is suggested that TSH receptor antibodies may have a thyroid growth-stimulating effect. In addition, circulating thyroglobulin levels reflect thyroid volume in Graves' disease.     

Radioiodine treatment of metastatic differentiated thyroid cancer in patients on L-thyroxine, using recombinant human TSH

OBJECTIVE: This study tested the hypothesis that administration of human recombinant thyroid-stimulating hormone (rhTSH: Thyrogen, thyrotropin alpha) could promote iodine-131 ((131)I) uptake in the therapy for metastatic or locally invasive differentiated thyroid cancer (DTC), obviating L-thyroxine suppressive therapy (L-T4) withdrawal and hypothyroidism in patients with advanced disease. METHODS: Twelve totally (or almost completely) thyroidectomized adults, nine of whom had received earlier therapy after L-T4 withdrawal, underwent (131)I treatment while euthyroid on L-T4, after rhTSH administration. Nine underwent diagnostic whole-body scanning (WBS) after two consecutive daily i.m. injections (0.9 mg) of rhTSH. They then received an identical second course of rhTSH to promote therapeutic (131)I uptake. Post-therapy WBS was performed one week later. Three patients received only rhTSH (131)I therapy. RESULTS: Administration of rhTSH promoted (131)I uptake in all patients, as demonstrated by post-therapy WBS. Administration of rhTSH also promoted a significant increase in serum thyroglobulin (Tg) concentrations. According to the most recent measurements, 3-12 months after therapy, serum Tg levels fell in four, and stabilized in two out of eleven patients. Upon additional rhTSH-WBS 8 months post-study, a reduction in one metastatic site was noted in one patient. The rhTSH was well tolerated, with mild, transient fever and/or nausea occurring in only a minority of patients. Individuals with bone metastases experienced degrees of peritumoral pain and swelling that were similar (though more short-lived) to those seen in the same or other patients after L-T4 withdrawal. CONCLUSIONS: Administration of rhTSH is a safe, successful tool for inducing (131)I uptake in local and metastatic DTC lesions, and avoids L-T4 withdrawal, preserving metabolic homeostasis and preventing the debilitating effects of hypothyroidism.     

Follow-up of differentiated thyroid carcinoma

Thyroid cancer is the most common endocrine malignancy. More than 90% of primary thyroid cancers are differentiated papillary or follicular types. The treatment of differentiated thyroid carcinoma (DTC) consists of total thyroidectomy and radioactive iodine ablation therapy, followed by L-thyroxine therapy. The extent of initial surgery, the indication for radioiodine ablation therapy and the degree of TSH-suppression are all issues that are still being debated cancers are in relation to the risk of recurrence. Total thyroidectomy reduces the risk of recurrence and facilitates (131)I ablation of thyroid remnants. The aim of radioiodine ablation is to destroy any normal or neoplastic residuals of thyroid tissue. These procedures also improve the sensitivity of thyroglobulin (Tg) as a marker of disease, and increase the sensitivity of (131)I total body scan (TBS) for the detection of persistent or recurrent disease. The aim of TSH-suppressive therapy is to restore euthyroidism and to decrease serum TSH levels, in order to reduce the growth and progression of thyroid cancer. After initial treatment, the objectives of the follow-up of DTC is to maintain adequate thyroxine therapy and to detect persistent or recurrent disease through the combined use of neck ultrasound (US) and serum Tg and (131)I TBS after TSH stimulation. The follow-up protocol should be adapted to the risk of recurrence. Recent advances in the follow-up of DTC are related to the use of recombinant human TSH (rhTSH) in order to stimulate Tg production and the ultrasensitive methods for Tg measurement. Undetectable serum Tg during TSH suppressive therapy with L-T4 does not exclude persistent disease, therefore serum Tg should be measured after TSH stimulation. The results of rhTSH administration and L-thyroxine therapy withdrawal are equivalent in detecting recurrent thyroid cancer, but the use of rhTSH helps to avoid the onset of hypothyroid symptoms and the negative effects of acute hypothyroidism on cardiovascular, hepatic, renal and neurological function. In low-risk DTC patients serum Tg after TSH stimulation, together with ultrasound of the neck, should be used to monitor persistent disease, avoiding diagnostic TBS which has a poor sensitivity. These recommendations do not apply when Tg antibodies are present in the serum, in patients with persistent or recurrent disease or limited thyroid surgery. Low-risk patients may be considered to be in remission when undetectable Tg after TSH stimulation and negative US evaluation of the neck are present. On the contrary, detectable Tg after TSH stimulation is an indicator in selecting patients who are candidates for further diagnostic procedures.     

Evaluation of the nocturnal serum thyrotropin (TSH) surge, as assessed by TSH ultrasensitive assay, in patients receiving long term L-thyroxine suppression therapy and in patients with various thyroid disorders

Circadian variations of serum TSH concentrations have been reported, with higher values occurring in the late evening or early morning. In patients receiving long term L-T4 suppression therapy, it may be important to achieve suppression of TSH secretion throughout the day. To investigate whether undetectable serum TSH values in the morning are associated with undetectable serum TSH levels at night, serum TSH concentrations were measured by an ultrasensitive immunoradiometric assay in 16 normal subjects, 20 hyperthyroid patients, 10 patients with primary hypothyroidism (either untreated or inadequately treated with L-T4), 1 patient with central hypothyroidism, 10 patients with nontoxic nodular goiter, 5 patients with functioning thyroid adenoma, 20 patients receiving L-T4 replacement therapy, and 30 patients receiving L-T4 suppression. In 6 subjects blood was drawn at hourly intervals for 24 h; in 2 normal subjects a major TSH surge occurred between 2300-0100 h, with other minor peaks, and the same pattern was found in two patients receiving L-T4 replacement, whereas in 2 patients receiving L-T4 suppression, serum TSH was constantly below the limit of detection of the assay (i.e. less than 0.07 mU/L). In the remaining patients blood was drawn at hourly intervals between 2300-0200 h and on the next morning before (0830-0900 h) and 30 min after iv TRH administration. In normal subjects, in patients receiving L-T4 replacement therapy, and in hypothyroid patients, serum TSH values at night were higher than in the morning, with normal responses to TRH in the first 2 groups and exaggerated responses in the latter. The patient with central hypothyroidism had no nocturnal TSH surge and no TSH response to TRH. In all hyperthyroid patients, serum TSH was undetectable both at night and during the day, and none had a serum TSH response to TRH. Among patients with nontoxic goiter, 7 had detectable serum TSH in the morning, with higher values at night, and a normal response to TRH; the remainder had undetectable serum TSH both at night and in the morning, and subnormal or absent TSH responses to TRH. All 5 patients with a functioning thyroid adenoma had undetectable serum TSH levels in the morning and during the night, and subnormal or absent TSH responses to TRH. Of the 30 patients receiving long term (greater than 6 months) L-T4 suppression therapy, 28 had undetectable serum TSH both during the night and in the morning and unresponsiveness to TRH.(ABSTRACT TRUNCATED AT 400 WORDS)     

Decreased thyroidal response to thyrotropin in diabetic mice

The effect of diabetes mellitus on the synthesis and secretion of thyroid hormone ws investigated in mice with streptozotocin-induced diabetes. Thyroid glands were labeled in vivo with 131I for 2 h. In control animals, TSH stimulated the synthesis of PB127I and 131I-labeled iodothyronines and simultaneously decreased the proportion of 131I-. These effects of TSH were not observed in diabetic animals but were demonstrable in diabetic animals treated with insulin. For studies of hormone secretion, labeled thyroid glands were cultured in vitro in medium containing 1 mM mononitrotyrosine. The rate of the hydrolysis of labeled thyroglobulin was measured as the proportion of 131I-labeled iodotyrosines and 131I-labeled iodothyronines recovered at the end of culture and was used as an index of thyroid secretion. TSH in vivo stimulated the rate of thyroglobulin hydrolysis for 6 h, with a peak occurring after 2 h. The diabetic mice had a diminished response to TSH, which improved on treatment with insulin. The addition of TSH and insulin to the culture medium significantly increased the rate of thyroglobulin hydrolysis in glands of diabetic mice over that resulting from the addition of dibutyryl cAMP alone. The generation of thyroidal cAMP in response to TSH was higher in diabetic mice than in controls. The rise in plasma T4 and T3 2 h after the administration of TSH was less in diabetic mice than in control mice or diabetic mice treated with insulin. Our studies, therefore, indicate that the thyroidal response to TSH is decreased in diabetes mellitus. The defect appears to be at a step beyond the generation of cAMP.     

Thyroid hormone formation in ectopic thyroid gland. A case study

Several steps of thyroid hormogenesis were studied on a subhyoid ectopic thyroid tissue in a case of compensated hypothyroidism with simultaneous sublingual and subhyoid ectopic thyroid. The patient, a 19-year-old girl, had normal values for serum T4, T3U and T3, and an elevated serum TSH level. The thyroidal 131I uptake was elevated both at 3 h and 24 h after oral 131I intake. No significant discharge of radioiodine was observed after perchlorate load. On the thyroid biopsy specimen, peroxidase activity was shown to be normal by both assays of guaiacol oxidizing and iodinating activity. Thyroglobulin was 19S and was normally iodinated in vitro with peroxidase. Iodine content of thyroglobulin was within the normal range. The mean percentage distribution of 131I administered 7 days prior to the biopsy showed no significant difference from the normal pattern. From these studies, no specific defects in thyroid hormogenesis could be detected in this case. It is suggested that abnormalities in thyroid function in this case are mainly due to insufficient functioning mass in the ectopic thyroid.     

甲氧氯普胺在分化型甲状腺癌患者随访中的应用

对分化型甲状腺癌（DTC）患者随访时，需停用左旋甲状腺素（L-T4）4—6周，检测血清甲状腺球蛋白及^131I-全身显像，以利于早期发现DTC病灶复发和转移。本研究将甲氧氯普胺（MCP，胃复安）用于随访的DTC患者，结果显示MCP没有明显升高TSH，其临床应用有待于进一步研究。     

Detection and properties of TSH-binding inhibitor immunoglobulins in patients with Graves' disease and Hashimoto's thyroiditis.

TSH-binding inhibitor immunoglobulins (TBII) have been detected in patients with Graves' disease and Hashimoto's thyroiditis by using the radioreceptor assay of TSH. In untreated Graves' patients, TBII levels correlated well with thyroidal 99mTc uptake at 30 min and the grade of epithelial hyperplasia of thyroid follicles. There were many Graves' patients whose sera contained high TBII levels but no detectable bioassayable thyroid-stimulating activity (LATS), and in these patients, close correlation was observed between serum levels of TBII and bioassayable LATS-protector activity. TBII were detectable in 2 (10%) of 20 patients with Hashimoto's thyroiditis, both of whom were clinically hypothyroid. The serum or IgG fraction from one of them, however, did not contain any significant LATS, LATS-protector, or human thyroid adenylate cyclase-stimulating activity and caused inhibition of adenylate cyclase stimulation by TSH. In that patient, TBII may be acting to block TSH binding to TSH receptors, thus causing TSH unresponsiveness and hypothyroidism.