Serum thyrotropin concentration as a novel predictor of malignancy in thyroid nodules investigated by fine-needle aspiration

CONTEXT: Thyroid nodules and goiter are common, and fine-needle aspiration biopsy (FNAB) is the first investigation of choice in distinguishing benign from malignant disease. OBJECTIVE: The objective of the study was to assess whether simple clinical and biochemical parameters can predict the likelihood of thyroid malignancy in subjects undergoing FNAB. DESIGN: The design was a prospective cohort. SETTING: The study was conducted at a single secondary/tertiary care clinic. PARTICIPANTS: One thousand five hundred consecutive patients without overt thyroid dysfunction (1304 females and 196 males, mean age 47.8 yr) presenting with palpable thyroid enlargement between 1984 and 2002 were evaluated by FNAB of the thyroid. INTERVENTION(S): There were no interventions. MAIN OUTCOME MEASURES: Goiter type was assessed clinically and classified as diffuse in 183, multinodular in 456, or solitary nodule in 861 cases. Serum TSH concentration at presentation was measured in a sensitive assay in patients presenting after 1988 (n = 1183). The final cytological or histological diagnosis was determined after surgery (n = 553) or a minimum 2-yr clinical follow-up period (mean 9.5 yr, range 2-18 yr). RESULTS: The overall sensitivity and specificity of FNAB in predicting malignancy were 88 and 84%, respectively. The risk of diagnosis of malignancy rose in parallel with the serum TSH at presentation, with significant increases evident in patients with serum TSH greater than 0.9 mU/liter, compared with those with lower TSH. Binary logistic regression analysis revealed significantly increased adjusted odds ratios (AORs) for the diagnosis of malignancy in subjects with serum TSH 1.0-1.7 mU/liter, compared with TSH less than 0.4 mU/liter [AOR 2.72, 95% confidence interval (CI) 1.02-7.27, P = 0.046], with further increases evident in those with TSH 1.8-5.5 mU/liter (AOR 3.88, 95% CI 1.48-10.19, P = 0.006, compared with TSH < 0.4 mU/liter) and greater than 5.5 mU/liter (AOR 11.18, 95% CI 3.23-8.63, P < 0.001, compared with TSH < 0.4 mU/liter). Males (AOR 1.8, 95% CI 1.04-3.1, P = 0.04), younger patients (AOR 1.1, 95% CI 1.01-1.15, P = 0.025), and those with clinically solitary nodules (AOR 2.53, 95% CI 1.5-4.28, P = 0.001) were also at increased risk. Based on these findings, a formula to predict the risk of the diagnosis of thyroid malignancy in individual patients, taking into account their gender, age, goiter type determined clinically, and serum TSH, was calculated. CONCLUSIONS: The risk of malignancy in a thyroid nodule increases with serum TSH concentrations within the normal range. In addition to patient's gender, age, and goiter type, the serum TSH concentration at presentation is an independent predictor of the presence of thyroid malignancy. We propose that these simple clinical and biochemical factors can serve as an adjunct to FNAB in predicting risk of malignancy.     

Higher serum thyroid stimulating hormone level in thyroid nodule patients is associated with greater risks of differentiated thyroid cancer and advanced tumor stage

CONTEXT: TSH is a known thyroid growth factor, but the pathogenic role of TSH in thyroid oncogenesis is unclear. OBJECTIVE: The aim was to examine the relationship between preoperative TSH and differentiated thyroid cancer (DTC). DESIGN: The design was a retrospective cohort. SETTING, PARTICIPANTS: Between May 1994 and January 2007, 1198 patients underwent thyroid surgery at a single hospital. Data from the 843 patients with preoperative serum TSH concentration were recorded. MAIN OUTCOME MEASURES: Serum TSH concentration was measured with a sensitive assay. Diagnoses of DTC vs. benign thyroid disease were based on surgical pathology reports. RESULTS: Twenty-nine percent of patients (241 of 843) had DTC on final pathology. On both univariate and multivariable analyses, risk of malignancy correlated with higher TSH level (P=0.007). The likelihood of malignancy was 16% (nine of 55) when TSH was less than 0.06 mIU/liter vs. 52% (15 of 29) when 5.00 mIU/liter or greater (P=0.001). When TSH was between 0.40 and 1.39 mIU/liter, the likelihood of malignancy was 25% (85 of 347) vs. 35% (109 of 308) when TSH was between 1.40 and 4.99 mIU/liter (P=0.002). The mean TSH was 4.9+/-1.5 mIU/liter in patients with stage III/IV disease vs. 2.1+/-0.2 mIU/liter in patients with stage I/II disease (P=0.002). CONCLUSIONS: The likelihood of thyroid cancer increases with higher serum TSH concentration. Even within normal TSH ranges, a TSH level above the population mean is associated with significantly greater likelihood of thyroid cancer than a TSH below the mean. Shown for the first time, higher TSH level is associated with advanced stage DTC.     

甲状腺自身抗体阳性妇女孕期干预对婴儿甲状腺功能的影响

目的 探讨甲状腺自身抗体阳性妇女孕期甲状腺功能干预对婴儿甲状腺功能的影响.方法选择产前检查发现的甲状腺过氧化物酶抗体(TPOAb)和(或)甲状腺球蛋白抗体(TgAb)阳性妊娠妇女55例.随机分为干预组(子代为A)36例和非干预组(子代为B)19例,设同期自身抗体阴性对照组(子代为N)30例.选择左旋甲状腺素片作为干预制剂.采用化学发光酶免疫分析法测定3组入选后和分娩前空腹血清TPOAb、TgAb、TSH、TT3、TT4、FT3、FT4水平,同时测定母体尿碘含量.新生儿出生后测定脐血、出生后3～4周及8～10周静脉血TSH、TT3、TT4、FT3、FT4水平.结果干预组、非干预组母体基线血清TSH水平显著高于对照组(P＜0.05).分娩前非干预组与另两组比较,血清TSH增高和TT3、TT4、FT4降低具有统计学差异(P＜0.05或P＜0.01).胎儿出生后脐血TSH水平在B组(7.06±1.31)mIU/L和A组(6.23±1.26)mIU/L均显著高于N组(5.48±1.17)mIU/L(P＜0.01或P＜0.05).出生3～4周新生儿B组血清TSH(3.21±0.70)mIU/L高于N组[(2.72±0.51)mIU/L]和A组[(2.78±0.42)mIU/L,均P＜0.05].出生8～10周婴儿B组血清TSH[(2.99±0.57)mIU/L]高于N组[(2.48±0.68)mIU/L,P＜0.05].多元逐步回归分析,母体TSH、TPOAb及尿碘含量与婴儿TSH独立相关.结论不同甲状腺功能状态的妊娠妇女,其子代出生后的甲状腺功能存在差异.胎儿出生后甲状腺功能与母亲甲状腺自身抗体及孕期甲状腺功能状态有关.     

Association between thyroid function and gallstone disease

AIM: To investigate those associations using data of the population-based Study of Health in Pomerania. METHODS: A study population of 3 749 residents aged 20-79 years without previously diagnosed thyroid disease was available for analyses. Serum TSH was used to assess thyroid function. Cholelithiasis was defined by either a prior history of cholecystectomy or the presence of gallstones on ultrasound. Logistic regression was performed to analyze independent associations between thyroid function and cholelithiasis. RESULTS: There were 385 persons (10.3%) with low (<0.3 mIU/L), 3 321 persons (88.6%) with normal and 43 persons (1.2%) with high serum TSH levels (>3 mlU/L). The proportion of cholelithiasis among males and females was 14.4% and 25.3%, respectively. Among males, there was an independent relation between high serum TSH and cholelithiasis (OR 3.77; 95%-CI 1.06-13.41; P＜0.05). Also among males, there was a tendency towards an elevated risk of cholelithiasis in persons with low serum TSH (OR 1.40; 95%-CI 0.96-2.02; P=0.07). In the female population, no such relation was identified. CONCLUSION: There is an association between thyroid and gallstone disease with a gender-specific relation between hypothyroidism and cholelithiasis.     

术前血清促甲状腺素水平与甲状腺结节良恶性关系的研究

]调查了1 870例甲状腺手术患者的术前血清TSH、手术记录、术后组织病理报告等.发现分化型甲状腺癌患者的术前血清TSH明显高于良性甲状腺结节患者[(1.95±1.69对1.40±1.98)mIU/L,P＜0.01].在分化型甲状腺癌患者中,有淋巴结转移或肿瘤直径大于10 mm的患者较无淋巴结转移或肿瘤直径小于10 mm的患者术前血清TSH水平升高(均P＜0.01).提示术前血清TSH水平是预测分化型甲状腺癌风险的一个指标.     

In vivo and in vitro regulation of thyroid leukemia inhibitory factor (LIF): marker of hypothyroidism.

Several cytokines regulate thyroid function and may be involved in the pathogenesis of thyroid disorders, including euthyroid sick syndrome. Leukemia inhibitory factor (LIF), a neuroimmune pleiotropic cytokine, was measured to assess its role in hypothalamic-pituitary-thyroid function. Mean circulating serum LIF levels in 10 hypothyroid patients [TSH, 23+/-0.5 mIU/L (mean+/-SEM); free T4, 0.77+/-0.1 ng/dL] was 0.29+/-0.04 ng/mL, 145% higher (P < 0.04) than in 20 normal subjects (LIF, 0.20+/-0.02 ng/mL; TSH, 2.23+/-0.21 mIU/L; free T4, 1.23+/-0.04 ng/dL) but was not different from those in 10 hyperthyroid patients (LIF, 0.21+/-0.03 ng/mL; TSH, 0.01+/-0.00 mIU/L; free T4, 3.63+/-0.51 ng/dL). Serum LIF concentrations linearly correlated with serum TSH in the 40 samples (r = 0.58, P < 0.001). When T4 (1-8 microg/kg x day) was administered to cynomolgus monkeys with methimazole-induced hypothyroidism, serum T4 and T3 levels increased appropriately, and TSH and LIF concentrations decreased. When methimazole was given alone, both serum TSH (146+/-30 mIU/L) and LIF (8.84+/-0.49 ng/mL) were markedly induced. When methimazole together with T4 (>2 microg/kg x day) was administered, both serum TSH (7.5+/-1.2 mIU/L) and LIF (6.22+/-0.31 ng/mL) were lowered (P < 0.01). Monkey serum LIF levels and log TSH levels also correlated (r = 0.72, P < 0.01). Cultured thyroid carcinoma cells produced LIF (9.2 ng/10(6) cells/48 h). TSH (100 mIU/mL) and interleukin (IL)-6 (10 nmol/L) stimulated in vitro LIF secretion from the cells by 170+/-12% (P < 0.05) and 261+/-8% (P < 0.05), respectively. Dexamethasone (1 micromol/L) inhibited basal LIF concentration by 83% (P < 0.05), whereas TSH and IL-6 stimulated LIF by 52% (P = 0.04) and 42% (P = 0.03), respectively. However, using Northern blot analysis, we could not observe induction of LIF mRNA by TSH, suggesting that LIF regulation by TSH may be due to stimulation of secretion. The results show that the thyroid gland is a source of LIF production; TSH, IL-6, and glucocorticoid influence thyroid cell LIF expression. The correlation between TSH and LIF suggests that LIF may participate in the physiologic regulation of hypothalamic-pituitary-thyroid function.     

The Colorado thyroid disease prevalence study

CONTEXT: The prevalence of abnormal thyroid function in the United States and the significance of thyroid dysfunction remain controversial. Systemic effects of abnormal thyroid function have not been fully delineated, particularly in cases of mild thyroid failure. Also, the relationship between traditional hypothyroid symptoms and biochemical thyroid function is unclear. OBJECTIVE: To determine the prevalence of abnormal thyroid function and the relationship between (1) abnormal thyroid function and lipid levels and (2) abnormal thyroid function and symptoms using modern and sensitive thyroid tests. DESIGN: Cross-sectional study. PARTICIPANTS: Participants in a statewide health fair in Colorado, 1995 (N = 25 862). MAIN OUTCOME MEASURES: Serum thyrotropin (thyroid-stimulating hormone [TSH]) and total thyroxine (T4) concentrations, serum lipid levels, and responses to a hypothyroid symptoms questionnaire. RESULTS: The prevalence of elevated TSH levels (normal range, 0.3-5.1 mIU/L) in this population was 9.5%, and the prevalence of decreased TSH levels was 2.2%. Forty percent of patients taking thyroid medications had abnormal TSH levels. Lipid levels increased in a graded fashion as thyroid function declined. Also, the mean total cholesterol and low-density lipoprotein cholesterol levels of subjects with TSH values between 5.1 and 10 mIU/L were significantly greater than the corresponding mean lipid levels in euthyroid subjects. Symptoms were reported more often in hypothyroid vs euthyroid individuals, but individual symptom sensitivities were low. CONCLUSIONS: The prevalence of abnormal biochemical thyroid function reported here is substantial and confirms previous reports in smaller populations. Among patients taking thyroid medication, only 60% were within the normal range of TSH. Modest elevations of TSH corresponded to changes in lipid levels that may affect cardiovascular health. Individual symptoms were not very sensitive, but patients who report multiple thyroid symptoms warrant serum thyroid testing. These results confirm that thyroid dysfunction is common, may often go undetected, and may be associated with adverse health outcomes that can be avoided by serum TSH measurement.     

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.     

Is there a relationship between thyroid function and serum osteocalcin in women with multinodular goitre? A preliminary report

The relationship between thyroid function and serum osteocalcin was studied in a population of 27 women with multinodular goitre and normal serum concentrations of thyroid hormones. Seven patients were found to have suppressed TSH levels (less than 0.1 mU/l) as measured by an immunoradiometric assay. Osteocalcin was statistically significantly correlated with serum free thyroxine (FT4), both in the total population and in the subpopulation of patients with TSH greater than or equal to 0.1 mU/l (r = 0.61; P less than 0.001, resp. r = 0.51; P less than 0.05). Mean (+/- SEM) serum osteocalcin and FT4 were higher in the patients with suppressed TSH than in those with TSH greater than or equal to 0.1 mU/l (10.6 +/- 1.9 vs. 7.1 +/- 0.6 micrograms/l; P less than 0.05, resp. 16.3 +/- 1.4 vs. 13.3 +/- 0.5 pmol/l; P less than 0.02). This study suggests that women with multinodular goitre who proceed to autonomous function are at risk of developing osteoporosis even when thyroid hormone concentrations are in the normal range.     

A population study of the association between thyroid autoantibodies in serum and abnormalities in thyroid function and structure

OBJECTIVE: Patients with autoimmune overt hypothyroidism may present with goitrous Hashimoto's disease or autoimmune atrophic thyroiditis. Little is known about the prevalence of subclinical autoimmune hypothyroidism. The aims of this study were to evaluate the association between thyroid autoantibodies in serum and abnormalities in thyroid function and structure, and to study the thyroid volume in subjects with subclinical autoimmune hypothyroidism. DESIGN: A population study including 4649 randomly selected subjects. MEASUREMENTS: Blood tests were used to analyse for thyroid peroxidase autoantibodies (TPO-Ab), thyroglobulin autoantibodies (Tg-Ab), TSH, fT3 and fT4. RESULTS: Thyroid volume was categorized as small (< 6.6 ml) in 4.7%, normal (6.6-14.9 ml) in 60.4% and large (> 14.9 ml) in 34.9% of participants. Thyroid nodules were found in 29.7%. Serum TSH was low (< 0.4 mIU/l) in 4.7%, normal (0.4-3.6) in 91.0% and high (> 3.6) in 4.3%. The prevalence rate of subclinical goitrous Hashimoto's disease was 0.62% and of subclinical autoimmune atrophic thyroiditis 0.24%. There was a strong association between large volume and autoantibodies, but only in subjects with elevated TSH (P < 0.001). An association between thyroid nodules and TPO-Ab in univariate analyses (P < 0.001) was due to confounding by sex and age (multivariate model, P = 0.23). CONCLUSION: We identified a subgroup of the population with subclinical goitrous Hashimoto's disease and a smaller subgroup with subclinical autoimmune atrophic thyroiditis. This relationship between small and large thyroid volume in subclinical disease is opposite to that in overt disease, which may suggest that the period between development of a small volume with circulating autoantibodies and overt hypothyroidism is relatively short.     

Preoperative serum thyroid stimulating hormone levels in well-differentiated thyroid carcinoma is a predictive factor for lateral lymph node metastasis as well as extrathyroidal extension in Korean patients: a single-center experience

It has been known that thyroid stimulating hormone (TSH) stimulates the growth or development of thyroid malignancy and higher serum TSH has association with both thyroid cancer incidence and advanced tumor stage. However, the role of TSH in high-risk features of well-differentiated thyroid cancer was not fully evaluated especially in Asian population. The purpose of our study is to evaluate the association of preoperative serum TSH levels with the advance of differentiated thyroid cancer and its high-risk clinicopathological features in Korean patients. We evaluated 554 patients retrospectively who underwent thyroidectomy and diagnosed as differentiated thyroid cancer during a 3-year period at Pusan National University Hospital. The preoperative TSH levels were significantly higher in the patients with extrathyroidal extension (P = 0.002) and those with lateral lymph node metastasis (P = 0.007). As the increase of the serum TSH concentration, there were significant rising trends in the prevalence of extrathyroidal extension (P = 0.009). In the patients with TSH ≥ 2.5 mIU/L, the prevalences of extrathyroidal extension (P = 0.006) and lateral lymph node metastasis (P = 0.024) were also significantly higher. Using multiple logistic regression, preoperative TSH level was a predictive factor for the presence of extrathyroidal extension (P = 0.008) and lateral lymph node metastasis (P = 0.025). Hashimoto's thyroiditis itself was not associated with the status of extrathyroidal extension and lateral lymph node metastasis. In conclusion, preoperative TSH levels were associated with lateral lymph node matastasis, a novel finding, and extrathyroidal extension in well differentiated thyroid cancer and might be useful as a preoperative supplementary marker for determining the optimal extent of differentiated thyroid cancer surgery in Korean patients.     

初诊2型糖尿病患者正常范围甲状腺功能状态的临床分析

目的了解正常范围甲状腺功能状态与2型糖尿病的关系。方法选取甲状腺功能正常的初诊2型糖尿病患者156例,检测空腹血糖、糖化血红蛋白、胆固醇、甘油三酯、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、空腹胰岛素浓度,计算稳态模型胰岛素抵抗指数、体重指数,分析血清促甲状腺激素（TSH）、FT3、FT4与上述指标的相关性。将测得TSH值,按四分位法分为低水平组和高水平组,比较组间各指标的差异。结果正常范围内血清TSH水平与体重指数显著正相关,与胰岛素抵抗指数、糖化血红蛋白、甘油三酯呈正相关。TSH高水平组（TSH3．5—4．6mIU／L）患者的体重指数、空腹胰岛素、胰岛素抵抗指数、糖化血红蛋白及甘油三酯均较TSH低水平组（TSH0．3～1．4mIU／L）明显增高（P〈0．05）。结论2型糖尿病患者正常范围的甲状腺功能状态下,高水平的TSH对糖脂代谢紊乱、体重增加及胰岛素抵抗有一定影响,临床不容忽视。     

Maternal thyroid function during gestation is related to breech presentation at term

Objective To study the relationship between suboptimal maternal thyroid function during gestation and breech presentation at term. Design Prospective follow‐up study during three trimesters of gestation. Patients A total of 1058 Dutch Caucasian healthy pregnant women were prospectively followed from 12 weeks gestation until term (≥37 weeks) delivery. Measurements Maternal thyroid parameters [TSH, free T4 (FT4) and auto‐antibodies to thyroid peroxidase] were assessed at 12, 24 and 36 weeks gestation as well as foetal presentation at term. Results At term, 58 women (5·5%) presented in breech. Compared with women with foetuses in the cephalic position, those women who presented in breech at term had significantly higher TSH concentrations, but only at 36 weeks gestation (P = 0·007). No between group differences were obtained for FT4 level at any assessment. The prevalence of breech presentation in the subgroup of women with TSH ≥ 2·5 mIU/l (90th percentile) at 36 weeks gestation was 11%, compared with 4·8% in the women with TSH < 2·50 mIU/l (P = 0·006). Women with TSH below the 5th percentile had no breech presentations. Breech position was significantly and independently related to high maternal TSH concentration (≥2·5 mIU/l) at 36 weeks gestation (O.R.: 2·23, 95% CI: 1·14–4·39), but not at 12 and 24 weeks gestation. Conclusions Women with TSH levels above 2·5 mIU/l during end gestation are at risk for breech presentation, and as such for obstetric complications.     

碘充足地区血清TSH正常值范围及其影响因素的流行病学研究

目的 分析血清TSH测定的影响因素,参考美国国家临床生化协会(NACB)指南,建立中国辽宁碘充足地区血清TSH的正常参考范围.方法 2007年,来自辽宁省3个碘充足地区的5 348人参加了甲状腺疾病的社区调查,进行了TSH、甲状腺自身抗体[甲状腺过氧化物酶抗体(TPOAb)和甲状腺球蛋白抗体(TgAb)]的测定,并作了甲状腺超声检查和问卷调查.结果 正常人群的TSH分布向右偏斜,接近于对数正态分布.年龄在12～19岁血清TSH水平明显高于其他年龄段(P＜0.01),而其他年龄段之间无统计学差异.血清TSH水平女性[(1.68±1.90)mIU/L]明显高于男性[(1.45±1.92)mIU/L,P＜0.01].因此,年龄大于20岁的健康男性TSH的分布范围是0.43～4.74 mIU/L,健康女性TSH的分布范围是0.48～5.39 mIU/L.甲状腺疾病家族史、甲状腺超声异常、甲状腺抗体阳性均影响TSH的测定水平,非甲状腺疾病对TSH参考范围没有显著影响.结论建立了碘充足地区血清TSH参考范围.

Abstract：

Objective To verify the criteria proposed by National Academy of Clinical Biochemistry(NACB)guidelines in investigating the factors that affect serum TSH determination, and to determine the reference range of serum TSH in iodine-sufficient areas of China. Methods In 2007, 5 348 inhabitants were enrolled from 3 iodine-sufficient areas of Liaoning Province, and were asked to fulfill the questionnaire. Serum TSH, thyroid peroxidase antibody(TPOAb), and thyroglobulin antibody(TgAb)were determined, and thyroid ultrasonography was carried out. Results The distribution of TSH levels was skewed in healthy people and closely fit the curve of Gaussian distribution after logarithmic transformation. The levels of TSH in subjects of 12-19 years of age were significantly higher than those of other age groups(P＜0.01), and no significant difference was found among the latter groups. TSH level in females [(1.68±1.90)mIU/L] was higher than in males[(1.45±1.92)mIU/L, P＜0.01]. The reference range of TSH was 0.43-4.74 mIU/L in males, and 0.48-5.39 mIU/L in females. Family history of thyroid disease, abnormal thyroid ultrasonography, and positive thyroid antibodies were the factors that influenced TSH level. Conclusion The reference range of serum TSH in iodine-sufficient areas of China is established.     

Low basal thyrotropin with normal thyroid function in primary hyperparathyroidism

TSH serum levels and thyroid function in 32 patients with primary hyperparathyroidism and hypercalcemia were compared to those of 30 age and sex-matched normal subjects. Serum T3 and T4 concentrations in hyperparathyroidism were not different from normal. However, basal serum TSH concentrations measured with an ultrasensitive immunoradiometric assay were significantly lower than normal (1.09 +/- 0.49 vs 2.06 +/- 0.85 mU/l, p less than 0.001). In hyperparathyroidism, TSH, but not T4 or T3, was negatively correlated with serum calcium, not with iPTH. The increase in TSH (delta TSH) 30 min after the iv injection of TRH was also significantly blunted in patients with primary hyperparathyroidism; delta TSH was highly correlated with basal TSH in hypercalcemic patients. The basal TSH concentration was higher and no longer different from normal (1.70 +/- 1.2 mU/l) 2 to 12 months after removal of the parathyroid adenoma, when serum calcium was normalized, whereas T3 and T4 did not change. A low basal TSH with normal T4 and low T3 was found in 13 patients with hypercalcemia of malignancy. In these patients, TSH increased after treatment of hypercalcemia with 3-amino-l,hydroxypropylidene-1, 1-bisphosphonate, whereas T4 did not change. The results suggest that the set point of pituitary thyroid feedback control could be decreased in chronic hypercalcemia and that hypercalcemia could render the thyroid more sensitive to TSH.     

Increased deoxyribonucleic acid synthesis of autonomously functioning thyroid adenomas: independent of but further stimulable by thyrotropin

The percentage of cells in the S/G2M fraction and the cytosol deoxythymidine kinase activity (TKA) were measured in autonomously functioning thyroid adenomas (AFTA) and paranodular tissue (PNT), with special regard to the impact of the patient's serum TSH concentration on DNA synthesis. The S/G2M fraction was determined by means of DNA flow cytometry, and TKA was determined by radioenzyme assay. The S/G2M fraction of AFTA (n = 15, median; 7.1%; range, 3.2-9.2%) exceeded the S/G2M fraction of normal thyroid tissue (n = 8; median, 2.8%; range, 2.3-4.0%; P = 0.008) and in 12 of 13 AFTA was 1.2- to 2.3-fold higher than the S/G2M fraction in the corresponding PNT (median, 4.0%; range, 2.5-6.7%; P = 0.0022). TKA of AFTA (n = 15; median, 681 microIU/mg; range, 432-854 microIU/mg) exceeded TKA of normal thyroid tissue (n = 8; median, 356 microIU/mg; range, 194-426 microIU/mg; P = 0.0001) and was 1.1- to 4.2-fold increased compared with TKA activity in the corresponding PNT (median, 430 microIU/mg; range, 162-570 microIU/mg; P = 0.001). In the absence of measurable serum TSH there was a constant increase in the S/G2M fractions and the TKA in AFTA vs. those in PNT. In patients treated with methimazole with serum TSH concentrations of 0.5 mIU/L or more, the S/G2M fraction and TKA in both AFTA and PNT were significantly higher than those in untreated patients with serum TSH concentrations of 0.5 mIU/L or less. In the majority of AFTA, functional autonomy and increased DNA synthesis are concomitant phenomena. Although TSH may stimulate DNA synthesis in both AFTA and PNT, measurable serum TSH concentrations are apparently not essential for DNA synthesis.     

Serum thyrotropin measurements in the community: five-year follow-up in a large network of primary care physicians

BACKGROUND: Subclinical thyroid disease is common; however, screening recommendations using serum thyrotropin (TSH) level determinations are controversial. METHODS: To study the use of serum TSH by primary care physicians and define populations at risk for having an abnormal TSH level at follow-up, based on initial TSH levels, we conducted an observational study of a large health care database in the setting of a health management organization. All outpatients without thyroid disease or pregnancy or taking medication that may alter thyroid function in whom the TSH level was measured in 2002 and during 5-year follow-up were included in this study. Repeated TSH level determinations were compared with the initial TSH level values. RESULTS: In 422 242 patients included, 95% of the initial serum TSH concentrations were within normal limits (0.35-5.5 mIU/L), 1.2% were decreased (<0.35 mIU/L), 3.0% were elevated (>5.5 to 10 mIU/L). In 346 549 patients without thyroid-specific medications, the TSH levels became normal in 27.2%, 62.1%, and 51.2%, whose initial serum TSH level was highly elevated, elevated, and decreased, respectively, and remain normal in 98% of the patients with normal initial TSH levels. When the initial serum TSH level was elevated, patients in the highest quintile of this group, who had a shorter interval between the first and second measurements, had a higher probability of a second highly elevated TSH concentration (P < .001). CONCLUSIONS: When the serum TSH level is normal, the likelihood of an abnormal level within 5 years is low (2%). More than 50% of patients with elevated or decreased serum TSH levels have normal levels in repeated measurements.     

Effect of low- and high-dose levothyroxine on thyroid nodule volume: a crossover placebo-controlled trial

OBJECTIVE: The efficacy and the effective dose of levothyroxine suppressive therapy in the treatment of benign thyroid nodules are controversial. In this study, we aimed to determine the response of solitary thyroid nodules to low- or high-level TSH suppression in a placebo-controlled, randomized crossover trial. DESIGN: Forty-nine patients with solitary thyroid nodules on palpation were randomized to high-level and low-level TSH suppression groups. In each group, patients were further randomized to placebo and active levothyroxine subgroups. Patients in each subgroup were crossed over to placebo or active levothyroxine at the end of the first year and were then followed up for an additional year. METHODS: TSH levels were suppressed to 0.4-0.6 mIU/ml and < or = 0.01 mIU/ml in the low-level and high-level TSH suppression groups, respectively. Nodule volumes were measured at baseline and every 6 months after the desired level of TSH was reached if the patients were in the active levothyroxine treatment group or every 6 months if they were in the placebo group. RESULTS: In high-level TSH suppression groups, nodule volume decreased significantly at the end of the active treatment periods (4.99 +/- 2.02 ml vs. 3.20 +/- 1.50 ml, P < 0.01, in Group 1; and 3.72 +/- 1.79 ml to 2.05 +/- 0.64 ml, P < 0.001, in Group 2). In the low-level TSH suppression groups, nodule volume also decreased significantly at the end of the active treatment periods (4.43 +/- 1.76 ml vs. 3.04 +/- 1.32, P < 0.05, in Group 3; and 3.59 +/- 0.89 ml to 2.22 +/- 0.59 ml, P < 0.01, in Group 4). Nodule volumes regained their original volumes during the placebo treatment periods. The percentage decline in clinically relevant nodule volume reduction (> or = 50%) was similar in the low-level and high-level TSH suppression groups. CONCLUSION: Low- and high-level TSH suppression were equally effective in reducing nodule volume and thus, considering the complications of high-level TSH suppression, low-level TSH suppression should be used if one considers levothyroxine suppressive therapy to reduce thyroid nodule size.     

Preparation for radioactive iodine administration in differentiated thyroid cancer patients

OBJECTIVE: Because in recent years the practice of TSH suppression has changed, and thyroxine doses have been reduced significantly in the treatment of patients with low-risk differentiated thyroid cancer, the goal of this study was to determine the time needed to attain a target TSH level (of 30 mIU/l) following levothyroxine withdrawal in patients treated with thyroxine according to current guidelines, in anticipation of radioactive iodine (RAI) administration. DESIGN: Observational study. PATIENTS: Thirteen consecutive patients with differentiated thyroid cancer on suppressive doses of levothyroxine planned for RAI administration. Five of the patients received cholestyramine in an attempt to facilitate TSH recovery. MEASUREMENTS: Serum TSH, free-T3 and free-T4, at 3-4-day intervals. RESULTS: In 13 patients on suppressive doses of thyroxine, on 15 separate occasions, baseline TSH levels were between 0.01 and 0.4 mIU/l. The mean interval required to reach the target TSH concentration of at least 30 mIU/l was 17 days (95% CI 15-19; range 11-28 days). Cholestyramine had no effect on the rate of TSH recovery. Once TSH concentration became detectable, it increased exponentially; and once it reached the upper limit of normal, it rarely took more than 10 days to attain target level. CONCLUSIONS: Attaining target TSH level before radioactive iodine administration requires a considerably shorter time than is currently recommended. Reducing preparation time might improve patients' acceptance of the procedure.     

Serum thyrotropin (TSH) levels after recombinant human TSH injections in children and teenagers with papillary thyroid cancer

CONTEXT: In preparation for whole body radioactive iodine scanning, recombinant human TSH (rhTSH) is usually administered as 0.9-mg i.m. injections on 2 consecutive days without regard to age, body size, or other comorbid conditions. OBJECTIVE: Our objective was to determine whether the usual adult rhTSH dosing regimen would result in excessive elevations of serum TSH in children and teenagers with thyroid cancer. DESIGN/SETTING/PATIENTS/INTERVENTIONS: A retrospective review identified 53 children and teenagers with thyroid cancer who underwent whole body radioactive iodine (RAI) scanning over a 12-yr period at two major medical centers (34 after thyroid hormone withdrawal and 19 after rhTSH treatment). MAIN OUTCOME MEASURES: The dynamic time course of changes in serum TSH after rhTSH administration and/or hypothyroid withdrawal was examined. Peak TSH levels were correlated with age, weight, and body surface area. RESULTS: The mean serum TSH at the time of RAI administration was similar in patients undergoing hypothyroid preparation (188 +/- 118 mIU/liter; range, 110-452 mIU/liter) and those treated with rhTSH (134 +/- 75 mIU/liter; range, 32-290 mIU/liter; P = 0.07). Serial determinations after rhTSH injections revealed a mean serum TSH of 268 +/- 76 mU/liter (range, 87-628) at 6 h and 130 +/- 58 mU/liter (range, 67-250) at 24 h after the initial injection, and 361 +/- 78 mU/liter (range 161-524) at 6 h and 134 +/- 44 mU/liter (range, 32-290) at 24 h after the second injection. CONCLUSIONS: The mean TSH levels achieved in children after rhTSH injections are remarkably similar to values previously reported in adults despite marked differences in clinical characteristics between children and adults. These data suggest that dose adjustments are not generally required in children and teenagers undergoing rhTSH stimulation for RAI scanning or serum-stimulated thyroglobulin determinations.