Serum free thyroid hormones in subclinical hypothyroidism

Serum free thyroxine (FT4) and free triiodothyronine (FT3) concentrations were measured in a group of 52 patients with subclinical hypothyroidism (SH) and in an equal group of age and sex-matched normal controls. SH was defined by normal total T4 (TT4) and total T3 (TT3) concentrations, normal FT4 and FT3 indices, raised TSH levels, in the absence of signs and symptoms of hypothyroidism. Serum FT4 levels averaged 6.1 +/- 1.6 pg/ml (mean +/- SD, p less than 0.001 vs controls), with values below lower normal limits in 33/52 patients; mean FT3 concentrations averaged 3.1 +/- 0.7 pg/ml (p less than 0.001 vs controls), with values below lower normal limits in 8/52 patients. The analysis of results by the Galen and Gambino predictive value model demonstrated a higher sensitivity, but a lower specificity of FT4 as compared to FT3 in the diagnosis of SH. These results indicate that FT4 should be measured in addition to TSH for the diagnosis of impending thyroid failure, thus showing that in many cases patients with so-called subclinical hypothyroidism are actually already mild hypothyroid.     

Prevalence of subclinical hypothyroidism in a population living in the Milan metropolitan area

Subclinical hypothyroidism is a condition characterized by increased levels of thyroid-stimulating hormone (TSH) associated with normal levels of free triiodothyronine (FT3) and free thyroxine (FT4). The exact prevalence of this condition in Italy is not known. The aim of this study was to assess the presence of subclinical hypothyroidism in 1001 subjects living in the Milan area (age 17-89) and apparently free from thyroid pathology. This sample which had applied to a large laboratory centre (Centro Diagnostico Italiano, Milano) for a routine check-up was seen from April to July 1996. A serum TSH assay was performed using a highly sensitive immunoenzymatic method, while an FT3 and FT4 assay was performed by means of a radioimmunologic method using commercial kits. The prevalence of subclinical hypothyroidism in the total population proved to be 4.7% (95% CI-Confidence Interval: 3.4-6.0). Sex stratification showed a prevalence of 6.1% in females and 3.4% in males. Prevalence in patients up to 65 was 4.2%. This value increased up to 8.0% in subjects over 65. By combining these variables, in females >65 prevalence increased to 11.3%. Overall, symptoms typical of overt hypothyroidism were found in 58.3% of patients suffering from subclinical hypothyroidism and in 39.9% of healthy subjects (p<0.02). The results of this study show that there is a significant presence (about 5%) of subclinical hypothyroidism in this population and that its frequency is more than doubled in women over 65. Early treatment might reduce the progression to overt hypothyroidism. The benefits of such a procedure were recently suggested by a decision making modelling approach applied to the Italian environment.     

补充甲状腺激素对亚临床甲状腺功能减退患者死亡率的影响

最新发表的一项荟萃分析入选了5项观察性研究和两项随机对照试验,共21055例成人患者。结果发现,在总人群中,甲状腺激素治疗与全因死亡或心血管死亡无关。但亚组分析显示,在年龄小于65岁的人群中,甲状腺激素治疗明显降低患者的全因死亡率(相对风险=0.50,95%可信区间:0.29~0.85,P=0.011)和心血管死亡率(相对风险=0.54,95%可信区间:0.37~0.80,P=0.002)。     

Variation in thyroid function in subclinical hypothyroidism: importance of clinical follow-up and therapy

Subclinical hypothyroidism (SCH) is a common condition that is often observed without therapy. However, no evidence-based recommendation exists with regards to how patients with untreated SCH should be monitored. Monitoring involves regular assessment of symptoms and signs of hypothyroidism (HYPO) and biochemical tests of thyroid function. An important question when repeated tests of thyroid function are performed is how large a difference in test results is needed to be confident that the change is real and not just due to chance variation. Recent data show that the least significant difference between two tests in SCH is 40% for TSH and 15% for free thyroxine and free triiodothyronine, with 90% confidence. Furthermore, monitoring has to be based on biochemical function testing because serial evaluation of symptoms and signs related to HYPO is rather insensitive in detecting worsening of thyroid insufficiency. When the presence of thyroid peroxidase auto-antibodies (TPO-Ab) in serum has been demonstrated, repeated measurements do not add much useful information in the monitoring of individual subclinical hypothyroid patients, as levels of TPO-Ab vary in parallel with TSH in these patients. Lastly, we discuss how differences in the monitoring procedure influence the diagnostic outcome, and we suggest a follow-up approach for untreated subclinical hypothyroid patients.     

Prospective study of the spontaneous course of subclinical hypothyroidism: prognostic value of thyrotropin,thyroid reserve,and thyroid antibodies

Subclinical hypothyroidism is a frequent syndrome affecting about 10 million people in the United States. The management of such patients is open to debate. In a long-term prospective study we analyzed the spontaneous course and the value of predictive factors in the development of overt thyroid failure. We studied 82 female patients with subclinical hypothyroidism prospectively over a mean observation period of 9.2 yr. TSH, thyroid hormones, thyroid reserve after TRH administration, thyroid antibodies, and clinical parameters were assessed at yearly intervals. The cumulative incidence of overt hypothyroidism was calculated using life-table analysis and Kaplan-Meier curves. According to the initial serum TSH concentrations (TSH, 4-6/>6-12/>12 mU/liter), Kaplan-Meier estimates of the incidence of overt hypothyroidism were 0%, 42.8%, and 76.9%, respectively, after 10 yr (P < 0.0001). When only patients with TSH levels greater than 6 mU/liter were analyzed, the cumulative incidence was 55.3%. The incidence of overt hypothyroidism increased in patients with impaired thyroid reserve (52.6% vs. 38.1%; P = 0.05) and positive microsomal antibodies (58.5% vs. 23.2%; P = 0.03). This prospective long-term study demonstrates that only a part of the cohort of patients with subclinical hypothyroidism develops overt hypothyroidism over time and that a major group remains in the subclinical state after 10 yr. The measurement of TSH, microsomal (thyroperoxidase) antibodies, and thyroid reserve allows initial risk stratification for the development of overt thyroid failure (risk ratio ranging from 1.0-15.6). Our study helps to recognize the spontaneous course of subclinical hypothyroidism and in the identification of patients most likely to progress to overt hypothyroidism.     

亚临床甲状腺功能减退症患者及甲状腺功能正常者甲状腺功能与血糖水平的关系

目的研究亚临床甲状腺功能减退症患者及甲状腺功能正常者甲状腺功能与血糖的关系。方法采用整群抽样法于2007年至2010年从沈阳市城市成年居民中招募2751名研究对象,行问卷调查,测量血压、身高、体重、腰围、促甲状腺激素、游离三碘甲状腺原氨酸、游离甲状腺素、空腹血糖、口服葡萄糖耐量试验2h血糖、甘油三酯、总胆固醇和高密度脂蛋白胆固醇。将受试者分为亚临床甲状腺功能减退症组（n=193）及甲状腺功能正常组（n=2146）,甲状腺功能正常组又进一步分为促甲状腺激素低水平组（n=352,促甲状腺激素／〉0．3-〈1．0mU／L）、促甲状腺激素中水平组（n=916,促甲状腺激素≥1．0-≤1．9mU／L）、促甲状腺激素高水平组（n=944,促甲状腺激素1．9〈-≤4．8mU／L）。受试者根据血糖水平进一步分为糖耐量正常组、糖调节异常组、糖尿病组,分析甲状腺功能指标与血糖的关系。采用t检验及方差分析进行数据统计。结果亚临床甲状腺功能减退症组口服葡萄糖耐量试验2h血糖明显高于甲状腺功能正常组[（8．34-4．4）vs（7．74-4．2）mmol／L,t=一2．163,P〈0．05],2组糖调节异常及糖尿病的患病率差异无统计学意义。糖尿病组游离甲状腺素水平高于糖调节异常组和糖耐量正常组[分别为（16．8±2．1）、（16．3±2．1）、（16．2±1．9μmol／L,F=10．515,P〈0．01],女性中糖尿病组[15．3％（26／188）]及糖调节异常组[15．0％（34／227）]亚临床甲状腺功能减退症的患病率明显高于糖耐量正常组[9．5％（86／903）]（）（2值分别为7．165、5．685,均P〈0．05）,女性亚临床甲状腺功能减退症的患病率明显高于男性[11．1％（146／1318）VS4．6％（47／1027）,x2=31．852,P〈0．01]。多元线性回归分析显示,校正体质指数、腰围、血压、血脂后,总体受试者空腹血糖与游离甲状腺素呈正相关（β=2．748,P〈0．01）,男性受试者空腹血糖与游离甲状腺素亦呈正相关（口=2．346,P〈0．01）,女性受试者口服葡萄糖耐量试验2h血糖与游离甲状腺素呈正相关（／3=2．748,P〈0．01）。在正常范围内,游离甲状腺素水平越高,糖尿病的患病危险越大[总体：比值比（OR）=1．142,95％可信区间（cl）1．064-1．225,P〈0．01;女性：OR=1．147,95％C11．024-1．284,P〈0．05：男性：OR：1．142,95％C11．035-1．261,P〈0．01]。促甲状腺激素及游离三碘甲状腺原氨酸与糖尿病无关。结论女性糖调节异常和糖尿病患者亚临床甲状腺功能减退症的患病率增高;游离甲状腺素与血糖水平呈正相关,游离甲状腺素越高,糖尿病的患病风险越大。     

Variation in thyroid function tests in patients with stable untreated subclinical hypothyroidism.

OBJECTIVE: Knowledge of variation in thyroid function is important for interpretation of thyroid function tests. We aimed to describe intra-individual variation in thyroid function in patients with stable, untreated subclinical hypothyroidism (SCH) compared to euthyroid individuals to assess the importance of monitoring SCH patients. DESIGN: We measured thyrotropin (TSH), free thyroxine (fT4), and free triiodothyronine (fT3) monthly for 1 year in a longitudinal study of 15 untreated SCH patients with initial TSH 5-12 mU/L, without trends in TSH, and compared findings with results from 15 euthyroid individuals. Main outcome: CV% was 17.0, 6.1, and 6.2 for TSH, fT4, and fT3, respectively. Overall CV% for TSH was lower in SCH patients than controls. Contrary to euthyroid individuals, CV% in SCH patients increased with rising mean TSH (r2 = 0.29, p = 0.04). Individual disease set points were established with 45, 6, and 6 tests for TSH, fT4, and fT3, with 95% confidence. Differences required between two test results were 40%, 15%, and 15%, respectively, with 90% confidence. Conclusion: Percent variation in TSH was lower in SCH than in euthyroid controls, but increased with higher mean TSH. The number of tests needed to establish disease set points was high. The difference required between two tests to be truly different was 40% for TSH and 15% for fT4 and fT3.     

The occurrence of permanent thyroid failure in patients with subclinical postpartum thyroiditis

OBJECTIVE: The long-term effect of the subclinical form of postpartum thyroid dysfunction (PPTD) has not been well established. This study was conducted to evaluate the outcome of permanent hypothyroidism in a large cohort of women with PPTD. DESIGN AND METHODS: Of 213 women with PPTD, 172 (81%) returned for follow-up. There were 27 (16%) with subclinical (group 1) and 145 (84%) with overt hypothyroidism (group 2). They were all treated with levothyroxine for 23 +/- 16 months and followed-up for thyroid function after thyroxine (T(4)) withdrawal. RESULTS: In group 1, the time of occurrence of PPTD was longer, serum T(4) was higher and TSH was lower than in group 2. After T(4) withdrawal, 59 and 64% of patients became hypothyroid in groups 1 and 2 respectively; however, serum TSH was increased in group 2 as compared with group 1 (29.7 +/- 8.4 vs 16.4 +/- 15.4 mU/l, P < 0.002). The duration of euthyroidism, serum free T(4) and triiodothyronine indices and thyroperoxidase antibodies were not significantly different between the two groups. CONCLUSION: It was concluded that a high percentage of patients with the subclinical form of PPTD proceed to permanent thyroid failure. The timely recognition of mild to severe cases of PPTD is important for the improvement of life for mothers and infants.     

Etiologic discussion and clinical relevance of thyroid ultrasonography in subclinical hypothyroidism. A retrospective study in 1845 patients

Background

Acquired subclinical hypothyroidism in adulthood is mainly due to autoimmune thyroiditis. In the absence of a goiter or a palpable firm thyroid, measurement of thyroid antibodies can improve the diagnosis. Whether thyroid antibodies are detected or not, what might be the clinical relevance of ultrasonography in this setting?

Methods

We studied 1845 cases of subclinical hypothyroidism in adults recruited for symptoms indicative of hypothyroidism or thyroid pathology. All patients were screened for thyroid antibodies and underwent an ultrasonographic thyroid examination.

Localisation

Multicentric retrospective study.

Results

Chronic autoimmune thyroiditis was confirmed in 70% of patients. Thyroid antibodies were undetectable in 30% of patients. In all patients, thyroid ultrasound facilitated measurement of the thyroid volume and detection of non-palpable nodules and therefore allowed biopsy. In patients negative for thyroid antibodies, ultrasonography suggested autoimmune thyroiditis in 31% of cases. Ultrasonography did not contribute to diagnosis in a large number of patients without nodules and in case of normal echostructure. The strategy of thyroid hormone replacement therapy was not influenced by ultrasonographic data. Thyroid biopsies detected smears suspected to be cancerous in 10 patients (4%). Cancer was confirmed in nine patients after surgery. Ultrasonography displayed suspicious aspects in six patients.

Conclusion

In subclinical hypothyroidism, thyroid ultrasonography is not required for the diagnosis of autoimmune thyroiditis but is useful for patients with abnormal thyroid palpation and allows detection of non-palpable thyroid nodules. For patients that were negative for thyroid antibodies, thyroid ultrasonography can improve diagnosis for some patients, allowing detection of autoimmune thyroiditis.     

Evaluation of endothelial function in subclinical hypothyroidism and subclinical hyperthyroidism.

Subclinical hypothyroidism and subclinical hyperthyroidism are two frequently occurring conditions for which exact therapeutic approaches have not yet been established. The aim of this study was to compare the endothelial function and carotid artery intimae-media thickness (IMT) of these two groups of patients to euthyroid subjects and to assess the effects of these conditions on endothelial function. Study groups comprised of 25 subclinical hypothyroid patients (mean age, 32.28 +/- 9.67 years), 13 subclinical hyperthyroid patients (mean age, 35.69 +/- 9.67 years), and 23 euthyroid subjects (mean age, 35.87 +/- 7.93 years). They were evaluated for flow-mediated dilatation (FMD), and carotid artery IMT. The groups were matched strictly for atherosclerotic risk factors. The subclinical hypothyroid group was found to have significantly lower FMD values. No significant differences were observed between the groups with respect to other vascular parameters. The only discriminative factor between the groups was the state of their thyroid function. Therefore, subclinical hypothyroidism may have adverse effects on endothelial function independent from other well-known atherosclerotic risk factors.     

Thyrotropin levels in a population with no clinical, autoantibody, or ultrasonographic evidence of thyroid disease: implications for the diagnosis of subclinical hypothyroidism

CONTEXT: The current debate regarding whether to decrease the upper limit for the TSH reference range to 2.5 microIU/ml has considerable potential impact on the diagnosis and treatment of subclinical hypothyroidism worldwide. OBJECTIVE: We report an analysis of TSH distribution in a population with no evidence of thyroid disease, including a normal thyroid ultrasound. DESIGN: A subset of the Hanford Thyroid Disease Study cohort was used to examine the TSH distribution in a population having no evidence of thyroid disease, seronegative thyroid autoantibodies, no history of thyroid medications, and a normal thyroid ultrasound. The shape of the TSH distribution was compared with the Gaussian and lognormal distributions. SETTING: This study was performed in the general community. PARTICIPANTS: Of 1861 Hanford Thyroid Disease Study participants with TSH measured by ELISA who also had thyroid peroxidase antibody measurements, 766 comprised the normal reference group 3 (NRG-3) with no evidence of thyroid disease, including no positive antibodies and normal thyroid ultrasound. MAIN OUTCOME MEASURE: TSH was measured. RESULTS: The TSH distribution in the NRG (NRG-3) was right skewed and followed an approximate lognormal distribution. The best estimates of the 97.5th percentile, the percentage above 2.5 microIU/ml, and the percentage above 3.0 microIU/ml for TSH by 3rd generation immunochemiluminometric assay are 4.1 microIU/ml, 20% and 10.2%, respectively. CONCLUSION: These results indicate that the TSH reference range should be narrowed and support a value of approximately 4.0 as the upper-reference limit.     

无甲状腺疾病临床表现、自身抗体阴性、超声检查正常人群的TSH水平:对亚临床甲状腺功能减退诊断的影响

过去数年中,学术界对TSH最佳上限的确定存在较多争议,即是否应将TSH上限从多数实验室仍在使用的4～5.5μIU/ml降至2.5μIu/ml.在总人群中亚临床甲低的发病率约为5%～10%.     

Endothelial dysfunction and low grade chronic inflammation in subclinical hypothyroidism due to autoimmune thyroiditis

The relationship between subclinical hypothyroidism (SH) and cardiovascular disease has been one of the most popular topics recently. There is still some controversy concerning its cardiovascular impact and management protocols. Our study aims to investigate the presence of the well known preceding clinical situations of atherosclerosis like endothelial dysfunction and inflammation in subclinical hypothyroidism. Thirty-seven patients with subclinical hypothyroidism (29 women, 8 men) and 23 healthy volunteers (19 women, 4 men) were recruited for the study. Endothelial dysfunction was measured by examining brachial artery responses to endothelium-dependent (flow mediated dilation, FMD) and endothelium-independent stimuli (sublingual nitroglycerin (NTG)). Serum TNF-alpha, interleukin-6, and hs-CRP were measured. The estimate of insulin resistance by HOMA score was calculated with the formula: fasting serum insulin (μIU/mL) x fasting plasma glucose (μM/L) / 22.5. There were no significant differences in age, body mass index, waist circumference, HOMA scores. There was a statistically significant difference in endothelium-dependent (FMD) and endothelium-independent vascular responses (NTG) between the patients with subclinical hypothyroidism and the normal healthy controls. The groups were well matched for baseline brachial artery diameter. The TSH and LDL, IL-6, TNF-alpha and hs-CRP levels in the patient group were significantly higher than those in control group. A positive correlation was found only between endothelium-dependent vasodilation and TNF-alpha, hs-CRP and IL-6, TSH, total cholesterol, LDL and triglycerides. Endothelium-independent vascular response was not correlated with any of the metabolic or hormonal parameters. Neither of the groups were insulin resistant and there was not any difference either in fasting insulin or in glucose levels. We found endothelial dysfunction in subclinical hypothyroidism group. Endothelium-dependent (FMD) and endothelium-independent vascular responses (NTG) were lower in patient group. Our findings suggest that there is endothelial dysfunction and low grade chronic inflammation in SH due to autoimmune thyroiditis. There are several contributing factors which can cause endothelial dysfunction in SH such as changes in lipid profile, hyperhomocysteinemia. According to our results low grade chronic inflammation may be one of these factors.