Natural history of subclinical hyperthyroidism in elderly patients with TSH between 0·1 and 0·4 mIU/l: a prospective study

Context One important aspect in the decision to treat or not elderly patients with subclinical hyperthyroidism (SCH) is the risk of progression to overt hyperthyroidism (OH). Objective To define the natural history of endogenous SCH in elderly patients with TSH between 0·1 and 0·4 mIU/l. Design Prospective study. One hundred and two women aged ≥60 years with persistently low TSH ranging from 0·1 to 0·4 mIU/l and normal free T4 and T3 were studied. Patients using L‐T4 or antithyroid drugs, previously treated for hyperthyroidism, with pituitary disease, using corticosteroids, amiodarone, dopaminergic agonists, with atrial fibrillation or heart disease were excluded. Seven patients had Graves’ disease, 91 had nodular disease and 4 presented no defined cause. The time of follow‐up ranged from 12 to 70 months (median 41 months). Results Three patients progressed to OH (elevated T4 and/or T3) and four other patients to persistently low TSH (<0·1 mIU/l) in the presence of increase in serum T3 when compared with baseline. These patients were treated. Twenty‐four women presented sustained normalization of TSH and none progressed to hypothyroidism. SCH with TSH in the 0·1–0·4 mIU/l range persisted in 71 patients, 4 of them (5·6%) being treated because of the development of atrial fibrillation or heart disease during follow‐up. The only independent predictor of progression of SCH was an initial TSH value <0·2 mIU/l. Conclusions In elderly patients with endogenous SCH and TSH between 0·1 and 0·4 mIU/l progression to clinical hyperthyroidism is uncommon (approximately 1% per year), spontaneous TSH normalization may occur, and persistence of SCH for many years is the most likely.     

Measuring TSH receptor antibody to influence treatment choices in Graves’ disease

TSH receptor antibody (TRAb) plays a key role in the pathogenesis of Graves’ disease (GD), and its levels correlate with the clinical course. The second‐ and third‐generation TRAb assays have >95% sensitivity and specificity for the diagnosis of GD and have improved the utility of TRAb to predict relapse. TRAb levels decline with antithyroid drug (ATD) therapy and after thyroidectomy. Its level increases for a year following radioactive iodine (RAI) therapy, with a gradual fall thereafter. TRAb level >12 IU/l at diagnosis of GD is associated with 60% risk of relapse at 2 years and 84% at 4 years. The prediction of risk of relapse improves further to >90% with TRAb >7·5 IU/l at 12 months or >3·85 IU/l at cessation of ATD therapy. TRAb tests are not expensive, and hence, TRAb measurements at presentation, after 12 months and/or 18 months (at cessation) of ATD therapy, could potentially guide treatment choices in GD. Elevated TRAb favours definitive treatment in the form of RAI or thyroidectomy, depending on the presence or absence of moderate‐to‐severe Graves’ ophthalmopathy (GO) and the ability to comply with radiation protection requirements. Use of ATDs in early pregnancy is associated with increased risk of congenital anomalies; early ablative treatment (RAI/surgery) should be considered in women of childbearing age at higher risk of relapse of GD. TRAb ≥5 IU/l in pregnant women with current or previously treated GD is associated with increased risk of foetal and neonatal thyrotoxicosis, and hence needs close monitoring. TRAb levels parallel the course of GO, and elevated TRAb is an indication for steroid prophylaxis to prevent progression of GO with RAI therapy.     

Benefit of short‐term iodide supplementation to antithyroid drug treatment of thyrotoxicosis due to Graves’ disease

Objective Combined treatment with anti‐thyroid drugs (ATDs) and potassium iodide (KI) has been used only for severe thyrotoxicosis or as a pretreatment before urgent thyroidectomy in patients with Graves’ disease. We compared methimazole (MMI) treatment with MMI + KI treatment in terms of rapid normalization of thyroid hormones during the early phase and examined the later induction of disease remission. Design and patients A total of 134 untreated patients with Graves’ disease were randomly assigned to one of four regimens: Group 1, MMI 30 mg; Group 2, MMI 30 mg + KI; Group 3, MMI 15 mg and Group 4, MMI 15 mg + KI. For easy handling, KI tablets were used instead of saturated solution of KI. KI was discontinued when patients showed normal free thyroxine (FT4) levels but MMI was continued with a tapering dosage until remission. Remission rate was examined during a 4‐ to 5‐year observation. Measurements Serum FT4, FT3 and TSH were measured by chemiluminescent immunoassays. TSH receptor antibody (TRAb) was assayed with TRAb‐ELISA. Goitre size was estimated by ultrasonography. Results After 2 weeks of treatment, normal FT4 was observed in 29% of patients in Group 1 and 59% (P < 0·05) of patients in Group 2. Furthermore, normal FT4 after 2 weeks of treatment was observed in 27% of patients in Group 3 and 54% (P < 0·05) of patients in Group 4. Similarly, FT3 normalized more rapidly in Groups 2 and 4 than in Groups 1 and 3. None of the patients showed an increase in thyroid hormones or aggravation of disease during combined treatment with MMI and KI. The remission rates in Groups 1, 2, 3 and 4 were 34%, 44%, 33% and 51%, respectively, and were higher in the groups receiving combined therapy but differences among four groups did not reach significance. Conclusions Combined treatment with MMI and KI improved the short‐term control of Graves’ hyperthyroidism and was not associated with worsening hyperthyroidism or induction of thionamide resistance.     

Sensitive thyrotropin and thyrotropin-receptor antibody determinations one month after discontinuation of antithyroid drug treatment as predictors of relapse in Graves' disease.

OBJECTIVE: After primary successful antithyroid drug treatment (ATDT), Graves' disease has a relapse rate of 30% to 50%. Previous studies have evaluated age, gender, goiter volume, smoking habits, and the presence of thyrotropin-receptor antibodies (TRAb) as predictive markers to facilitate an individualized patient management. Despite higher sensitivity and specificity of the new second generation human TSH-receptor assay, the predictive value of TRAb for relapse of hyperthyroidism is still controversial. In a recent prospective multicenter study we have previously shown that suppressed or low TSH values predict both early (persistence) and late relapse of Graves' disease. We now present a more detailed analysis of the predictive value of TSH and TRAb for recurrent hyperthyroidism. METHODS: Four weeks after withdrawal of ATDT, 96 patients were available for thyroid function tests, including a sensitive third-generation TSH assay and a second-generation recombinant TSH receptor assay. Relapse of Graves' disease was evaluated for a total follow-up of 2 years. RESULTS: Within 2 years, 47 of 96 patients (49%) developed relapse of hyperthyroidism. Nine patients relapsed within the first 4 weeks after withdrawal of ATDT and were thus considered to have persistent Graves' disease. Ten of 15 other patients with TSH levels below 0.3 mU/L without overt hyperthyroidism relapsed within 2 years. Twenty-five of 65 patients with normal TSH (0.3-3.0 mU/L) and 3 of 4 patients with TSH values above 3 mU/L also had recurrent hyperthyroidism. After ATDT cessation, TSH had a positive predictive value of 70% and a negative predictive value of 62% (specificity 85%) for relapse of Graves 'disease. Mean TRAb levels in the group of patients with relapse were significantly higher (11.1 IU/L +/- 0.17) than TRAb values in the remission group (4.5 IU/L +/- 0.6), p < 0.001. Using a cutoff value of 1.5 IU/L, TRAb had low positive and negative predictive values of 49% and 54%, respectively (specificity, 14%), but with a cutoff level of 10 IU/L, predictive values improved to 83% and 62%, respectively (specificity, 92%). Combination of TSH and TRAb determinations did not further improve prediction of relapse. Other factors such as gender, age, goiter volume, smoking habits, presence of thyroid-associated ophthalmopathy, and urinary iodine excretion did not show a significant influence on relapse rate. CONCLUSION: Low TSH values 4 weeks after ATDT withdrawal predict relapse of Graves' disease, both early (persistence) and, to a lesser extend, within 2 years of follow-up. Also, TRAb above 10 IU/L found in a small subset of patients, correlated with a higher relapse rate.     

ORIGINAL ARTICLE: Postpartum thyroid dysfunction and the long‐term risk of hypothyroidism: results from a 12‐year follow‐up study of women with and without postpartum thyroid dysfunction

Background The long‐term risk of hypothyroidism following postpartum thyroid dysfunction (PPTD) is uncertain. Most previous studies have been small, short‐term or have lacked a control group. Objective To ascertain the long‐term risk of hypothyroidism in women following PPTD. Design and participants A 12‐year longitudinal study of 409 women (including 71 with PPTD) who previously participated in a PPTD prevalence study. Measurements The primary outcome measure was hypothyroidism (defined as TSH greater than 4 mU/l or on thyroxine replacement) at follow‐up. Outcomes in women with and without PPTD were compared by logistic regression. Receiver operating characteristic analysis was used to determine the optimal cut‐off for baseline TSH as a predictor of hypothyroidism in the cohort. Results At follow‐up, hypothyroidism was present in 27 of 71 women who had PPTD at baseline (38%) and 14 of 338 women without PPTD (4%). From multivariate analysis, odds ratios (with 95% confidence intervals) for hypothyroidism were – 4·8 (1·6, 14·1) for PPTD; 8·2 (2·8, 24·6) for positive thyroid peroxidase antibodies (TPOAb); 9·7 (2·6, 37·0) for the hypothyroid phase of PPTD and 51·4 (19·2, 137·5) for hypothyroid PPTD with positive TPOAb. A baseline TSH above 2·6 mU/l was the optimal cut‐off for predicting hypothyroidism (sensitivity 76%, specificity 86%). Conclusions PPTD is a strong predictor of hypothyroidism in the long‐term. Women who present with postpartum hypothyroidism or have positive TPOAb are at particularly high risk, suggesting that close long‐term follow‐up is advisable if thyroxine replacement is not instituted at an early stage.     

Frequency and characteristics of TBII-seronegative patients in a population with untreated Graves' hyperthyroidism: a prospective study

Objective It is claimed that second generation thyrotropin‐binding inhibitory immunoglobulin (TBII) assays have a very high sensitivity for the diagnosis of Graves’ hyperthyroidism (GH). However, studies evaluating the accuracy of TBII have been retrospective in nature and/or GH had not been diagnosed independently of TBII. The aim of the present study, therefore, was to prospectively evaluate the frequency and characteristics of TBII‐seronegative patients in a population of untreated GH diagnosed independent of serum TBII. Design Prospective multicentre observational study. Patients A total of 259 consecutive untreated patients with a first episode of GH, diagnosed independent of serum TBII. TBII levels were measured by second generation assay and correlated to thyroid function, clinical characteristics and exposure to environmental factors. Results Serum TBII was positive in 245 (94·6%) patients and negative (< 2 IU/l) in 14 (5·4%) patients. TBII‐seronegative patients had lower fT4 (median 42·5 vs. 53·9 pmol/l, P = 0·02), T3 (median 3·55 vs. 4·90 nmol/l, P < 0·01) and fT3‐index (median 4·30 vs. 6·27, P < 0·01) compared to TBII‐seropositive patients. None of the TBII‐seronegative patients had TSH‐receptor activating mutations, Graves’ orbitopathy or pretibial myxedema. Serum TBII was positively correlated to free T3 (fT3)‐index and free T4 (fT4)‐index (P < 0·01), goitre size (P < 0·01) and the prevalence of Graves’ orbitopathy (P < 0·01). There were no significant differences between TBII‐seropositive and TBII‐seronegative patients in environmental factors. Conclusion The prevalence of TBII‐seronegativity in untreated patients with GH is 5·4% using a second generation assay. TBII‐seronegative patients have biochemically less severe thyrotoxicosis and no Graves’ orbitopathy. TBII‐seronegative and TBII‐seropositive patients apparently belong to the same population of GH, albeit the severity of the autoimmune attack is less in TBII‐seronegative patients.     

Late-night salivary cortisol for diagnosis of Cushing's syndrome by liquid chromatography/tandem mass spectrometry assay

Background Late‐night salivary cortisol (LNSC) measurements have been increasingly used by physicians as an initial diagnostic test for evaluation of patients with clinical suspicion of Cushing’s syndrome (CS). Published studies include various numbers of cases, controls and importantly, various assay methods (vast majority various immunoassays), as well as various methods to generate cut‐points. Materials and Methods The retrospective study evaluated the diagnostic utility of LNSC measurements in 249 patients evaluated for possibility of CS because of various clinical conditions using liquid chromatography/tandem mass spectrometry method (LC‐MS/MS). CS was confirmed in 47 patients (18·9%) and excluded in 202 (81·1%) patients at the time of analysis. Results Late‐night salivary cortisol was abnormal or >2·8 nmol/l in 35 of 47 patients with CS; sensitivity of 74·5% and elevated in 20 of 202 patients who were found not to have CS; specificity 90·1%. Using receiver‐operator characteristic statistics for calculation of the most optimal sensitivity and specificity, the cut‐off based on this data was LNSC > 2·1 nmol/l with sensitivity of 83·0% and specificity of 84·2%. Conclusion Analysis of data at one referral institution showed somewhat limited sensitivity of LNSC for diagnosis of CS using current reference ranges.     

Use of the 2nd generation TRAK human assay did not improve prediction of relapse after antithyroid medical therapy of Graves' disease

OBJECTIVE: Antithyroid drug treatment (ATD) is used world-wide in the treatment of thyrotoxicosis in patients with Graves' disease (GD). The main problem is a relapse rate of 30 to 50% within 2 years after the treatment has stopped. The measurement of thyrotropin receptor antibodies (TRAb) in serum has been used to confirm the diagnosis of GD in selected patients with a diagnostic specificity of 70 to 90%. However, in predicting the recurrence of thyrotoxicosis after discontinuing ATD it has been of little value. The aim of this study was to evaluate the ability of TRAb measured by the more sensitive recombinant human TSH receptor method to predict risk of recurrence of GD after discontinuing ATD. MATERIALS, PATIENTS AND METHODS: One hundred and twenty nine patients with newly diagnosed GD were included. Of these, 58 had relapse of hyperthyroidism in a follow-up of at least 11 months (median 18 months, range 11-49) after discontinuing ATD. In 122 Graves' patients TRAb were measured at the time of diagnosis and in all patients when discontinuing ATD by a competitive radioreceptor assay using recombinant human TSH receptors (TRAK human assay). RESULTS: We found an increased diagnostic specificity (99%) compared with the old TRAK porcine assay. The predictive values of a positive and negative test in relation to the prediction of a relapse of GD were found to be only 55% and 62% respectively when using a cut-off level of 1.5 IU/l, and the predictive value of a positive test decreased to 49% and of a negative test to 60% at a lower cut-off limit (1 IU/l). CONCLUSION: Our study confirms that the new TRAK human assay had a superior diagnostic sensitivity in comparison with the old TRAK porcine assay. Despite the higher diagnostic sensitivity of the TRAK human method, we could not find any improvement of predictive values for relapse of hyperthyroidism in the measurement of TRAb at the end of ATD.     

An age‐adapted approach for the use of D‐dimers in the exclusion of deep venous thrombosis

A normal D‐dimer (DD) concentration for the exclusion of deep venous thrombosis (DVT) has a low specificity in older patients and compression ultrasonography is often required. Three D‐dimer assays, STA Liatest, Tina‐quant, and Innovance, are evaluated in symptomatic outpatients suspected for DVT with emphasis on its performance in older patients by using different cut‐off levels. This study includes 466 outpatients suspected for having DVT. The diagnostic accuracy, measured as sensitivity and area under the curve of the receiver operation characteristic curve is good for all DD assays. The specificity of the DD assays combined with a low pretest probability varies from 42.6 to 51.5%. The specificity of the three DD assays in patients ≥60 years varies, however, between 24.6 and 40.9%. Several cut‐off values in different age‐subgroups are studied. For patients <60 years, the most accurate cut‐off value is 500 μg/L for all DD assays. For patients ≥60 years, a threshold of 750 μg/L has the best results with NPV of 100% for all assays and specificity of 48.5% (STA Liatest), 60.6% (Tina‐quant), and 49.2% (Innovance), respectively. For the three assays, the number needed to test (NNT) decreases in both subgroups of patients compared to the standard algorithm. A cut‐off level of 750 μg/L for patients ≥60 years improves the clinical performance of DD assays in combination with the PTP score without the loss of NPV. The NNT improves substantially with an age‐adapted algorithm. Am. J. Hematol., 2009. © 2009 Wiley‐Liss, Inc.     

甲状腺功能亢进性心脏病危险因素分析

目的 探讨甲状腺功能亢进(简称甲亢)性心脏病发生的危险因素,为控制甲亢性心脏病的发生提供科学依据.方法 2010年3月选择自2000年以来在山东省甲状腺疾病防治中心住院的982例甲亢患者,依据是否并发心脏病分为单纯甲亢组和甲亢性心脏病组,就病因、性别、年龄、病程及游离三碘甲状腺原氨酸(FT3)、游离甲状腺素(FT4)、促甲状腺素(TSH)、促甲状腺激素受体抗体(TRAb)等因素进行比较,并采用Logistic回归方法对甲亢性心脏病发病相关因素进行分析.结果 甲亢患者并发甲亢性心脏病的患病率为7.7%(76/982),甲亢性心脏病组在年龄、病程、FT3和TRAb水平上分别为[(51.4±11.5)岁、(6.3±2.1)年、21.6pmol/L、71.6 U/L],单纯甲亢组为[(37.9±9.8)岁、(2.6±1.3)年、14.9 pmol/L、49.6 U/L],组间比较,差异有统计学意义(u=9.93、15.23,T=44954、48792.5,P均＜0.05).年龄大、FT3,和TRAb水平高、病程长、毒性弥漫性甲状腺肿(相对危险度值分别为1.751、1.470、1.483、1.445、1.234)并发甲亢性心脏病的危险性大.结论 毒性弥漫性甲状腺肿、高龄、病程长、FT3和TRAb水平高是甲亢性心脏病的危险因素,及时预防和控制甲亢性心脏病的危险因素,减少甲亢性心脏病的发生与死亡.

Abstract：

Objective To study the risk factors of hyperthyroid heart diseases(HHD) by analyzing clinical features of patients in order to provide a scientific basis for prevention and treatment of HHD. Methods Nine hundred and eighty two cases were selected as objective from in-patient data of Thyroid Disease Treatment Centre of Shandong Province. The cases were divided into hyperthyroidism group and HHD group. The variables of etiology,sex, age, duration of disease, TSH, FT3, FT4 and TRAb were analyzed by comparative analysis. The risk factors were analyzed by logistic regression. Results The prevalence of hyperthyroidism complicated hyperthyroid heart disease was 7.7%(76/982), age, duration of diseases, FT3, TRAb in the HHD group were [(51.4 ± 11.5), (6.3 ±2.1) years, 21.6 pmol/L, 71.6 U/L], in hyperthyroidism group were [(37.9 ± 9.8), (2.6 ± 1.3) years, 14.9pmol/L, 49.6 U/L]. The differences were statistically significant(u = 9.93,15.23, T = 44954,48792.5, P ＜ 0.05)between the two groups. The factors of the older, higher FT3 and TRAb, longer duration, Graves disease (OR =1.751,1.470,1.483,1.445,1.234) increased the risk of HHD. Conclusions Graves disease, longer duration, old age, higher FT3 and TRAb are the risk factors of HHD. Timely prevention and control of risk factors is necessary to reduce the incidence of HHD.     

Clinical value of the first automated TSH receptor autoantibody assay for the diagnosis of Graves' disease (GD): an international multicentre trial

Background  Most recently, a new rapid and fully automated electrochemiluminescence immunoassay for the determination of TSH receptor autoantibodies (TRAb) based on the ability of TRAb to inhibit the binding of a human thyroid-stimulating monoclonal antibody (M22) has been established.
Objective  To evaluate this assay system in clinical routine based on an international multicentre trial and to compare the results with other established TRAb assays.
Patients and measurements  Totally 508 Graves' disease (GD), 142 autoimmune thyroiditis, 107 subacute thyroiditis, 109 nonautoimmune nodular goitre, 23 thyroid cancer patients and 446 normal controls were retrospectively evaluated.
Results  ROC plot analysis revealed an area under curve of 0·99 (95% CI: 0·99–1·0) indicating a high assay sensitivity and specificity. The highest sensitivity (99%) and specificity (99%) was seen at a cut-off level of 1·75 IU/l. Here, the calculated positive predictive value was 95%, whereas the negative predictive value was 100%. Applying the ROC plot-derived cut-off of 1·75 IU/l we found a sensitivity for TRAb positivity within the group of newly diagnosed GD patients of 97% which is in accordance to the sum of different nonautomated porcine TSH receptor-based assays with a sensitivity of 94% indicating an excellent analytical performance of the new assay format. Detailed comparison of the automated and the sum of manual assays revealed a near identical specificity.
Conclusion  Our results demonstrate that this new assay system has a high sensitivity for detecting GD and specificity for discriminating from other thyroid diseases. This assay may represent the future technology for rapid fully automated TRAb detection.     

Ultrasensitive TSH : a new diagnostic approach to hyperthyroidism

The value of new ultrasensitive and rapid immunoradiometric assay of thyroid stimulating hormone (TSH) for the diagnosis of hyperthyroidism was assessed in 130 patients with suspected hyperthyroidism and in 330 controls. The diagnosis was established by the clinical evaluation, thyroid scintigraphy and serum concentrations of thyroid hormones. Using the ROC (Receiver Operating Characteristic) curve methodology which allows the optimization of sensitivity and specificity, the physician can choose the "Cut-off" value between hyperthyroidism and euthyroidism. Two points of the curve seem to be interesting : using the "cut-off" value of 0.1 mUI/l, sensitivity is 0.98 and specificity is 0.98 ; using the "cut-off" value of 0.3 mUI/l, sensitivity is 1.00 and specificity is 0.92. Using the association TSH and FT4 (Free Thyroxin), sensitivity is 0.94 and specificity is 0.99. Sixty four per cent of euthyroid patients with TSH under 0.3 mUI/l have one or several hot nodules and only two have no thyroid disease. A TRH (Thyrotrophin Releasing Hormone) test was carried out in 63 patients with suspected thyrotoxicosis : basal and TRH stimulated TSH levels were under 0.1 mUI/l. This immunoradiometric assay for TSH may simplify the approach to thyroid function testing in patients with suspected thyrotoxicosis : a basal TSH under 0.3 mUI/l is sufficient to confirm a clinical suspicion of thyrotoxicosis without TRH test within four hours. In a department devoted to testing thyroid function, this new method provides a great benefit in cost and work.     

Usefulness of iodine/creatinine ratio from spot‐urine samples to evaluate the effectiveness of low‐iodine diet preparation for radioiodine therapy

Objective The success of a low‐iodine diet (LID) is best determined by measurement of 24‐h urine iodine (U‐I) excretion. The aim of this study was to determine reliable estimates for 24‐h U‐I based on spot‐urine samples and to provide cut‐offs to determine the effectiveness of LID preparation. Design We prospectively measured iodine levels in 193 patients based on 24‐h‐ and spot‐urine samples before radioactive iodine therapy. The iodine was expressed as the 24‐h U‐I excretion (μg/day) and as two different indices from spot urine, simple iodine concentration (simple I) and the iodine/creatinine (I/Cr) ratio. Poor LID preparation was defined as I excretion of >150 μg/day according to the 24‐h U‐I measurement. Results The measured 24‐h U‐I was significantly higher than the two indices from spot urine (P < 0·001). However, there were statistically significant correlations between the 24‐h U‐I values and the two spot‐urine‐based indices; the correlation coefficient was 0·539 for simple I and 0·773 for I/Cr ratio (P < 0·001). The cut‐off of I/Cr ratio for poor LID preparation was >66·2 μg/g Cr (sensitivity 96·4%, specificity 83·6%, positive predictive value 50·0% and negative predictive value 99·3%). Conclusions We demonstrated that the I/Cr ratio from spot urine could serve as a useful and reliable alternative to 24‐h urine collection as it has acceptable diagnostic values for detecting poor LID preparation.     

Graves病合并妊娠

妊娠期甲状腺激素代谢的生理性改变使Graves病的诊治更加复杂。妊娠期Graves病必须使用抗甲状腺药物（ATD）治疗,尽可能使用最低剂量的ATD维持母体游离甲状腺素（n）于非孕期的正常高值附近是最理想的选择。胎儿甲状腺功能取决于通过胎盘屏障的促甲状腺激素（TSH）受体抗体（TRAb）与ATD之间的平衡。晚孕早期母体TRAb滴度升高是胎儿发生甲状腺功能亢进的一个危险因素,此时亦应行胎儿甲状腺超声检查。临床可以通过调整孕妇ATD用量治疗胎儿甲状腺功能亢进。若妊娠期Graves病未得到控制,或孕妇曾因Graves病行放射性碘治疗或甲状腺切除术,怀孕时TRAb仍阳性者,须于分娩时检测脐带血TSH及FT4（总甲状腺素）。     

TSH-receptor antibody measurement for differentiation of hyperthyroidism into Graves' disease and multinodular toxic goitre: a comparison of two competitive binding assays

OBJECTIVES: Graves' disease is characterized by stimulating autoantibodies to the TSH-receptor (TRAb). The aim of this study was to compare the performance of a new TRAb assay based on competitive binding to recombinant human TSH-receptors (H-TRAb) with an assay employing purified porcine TSH-receptors (P-TRAb). Furthermore, to evaluate the applicability of the H-TRAb assay to discriminate between patients with hyperthyroidism due to Graves' disease (GD) and multinodular toxic goitre (MNTG). DESIGN AND MEASUREMENTS: H-TRAb and P-TRAb were measured in patients with newly diagnosed hyperthyroidism due to GD (n = 106) and MNTG (n = 94). For comparison, TRAb was measured in patients with primary autoimmune hypothyroidism, euthyroid subjects with an enlarged thyroid gland by ultrasound, and healthy controls (n = 100 for each group). Patients were consecutively included from a population survey. RESULTS: If the cut-off values recommended by the manufacturer for TSH-receptor antibody positivity were used for evaluation, the sensitivity of the H-TRAb assay vs. the P-TRAb assay in diagnosing GD was: 95.3/67.9% (P < 0.001). Specificity was (H/P-TRAb): 99/99%. The sensitivity of P-TRAb was increased if the upper 97.5% limit of measurements in controls was used as cut-off (H-TRAb vs. P-TRAb: 95.3/80.2%, P < 0.001). Specificity (H/P-TRAb): 98/98%. The difference between assay performance may partly be due to a better technical performance of the H-TRAb assay with more reliable results in the low range of measurements. However, even in GD patients with clearly measurable TRAb, 25% had a P-TRAb < 50% of the value expected from the H-TRAb measurement. This suggests that a subgroup of patients produce TRAb with a higher affinity for the human than the porcine TSH receptor. A relatively high proportion of patients with MNTG were TRAb positive (H-TRAb/P-TRAb: 17/9%). Characteristics of H-TRAb positive and negative MNTG patients were compared. There was no difference between size of thyroid gland and number of nodules by ultrasonography. H-TRAb positive patients had significantly higher serum T4 and T3 and a greater number were TPO-Ab positive. CONCLUSIONS: H-TRAb diagnosed Graves' disease with a high sensitivity and specificity than P-TRAb. The high occurrence of TRAb in multinodular toxic goitre might in part reflect an overlap between Graves' disease and multinodular toxic goitre in some patients.     

Coagulation and inflammation biomarkers may help predict the severity of community‐acquired pneumonia

Background and objective: There are limited data on the relationship between the severity of community‐acquired pneumonia (CAP) and biomarkers of inflammation and coagulation. The aim of this study was to evaluate the association between the severity of CAP and serum levels of antithrombin III (AT‐III), protein C (P‐C), D‐dimers (D‐D) and CRP, at hospital admission. Methods: This was a prospective observational study in 77 adults (62.3% men), who were hospitalized for CAP. The severity of CAP was assessed using the confusion, uraemia, respiratory rate ≥30 breaths/min, low blood pressure, age ≥65 years (CURB‐65) score. Results: Forty patients (52%) had severe CAP (CURB‐65 score 3–5). Serum levels of AT‐III were lower and levels of D‐D and CRP were higher in patients with severe CAP than in patients with mild CAP (CURB‐65 score 0–2) (P < 0.001 for all comparisons). Levels of P‐C were lower in patients with severe CAP compared with those with mild CAP, but the difference was not significant (P = 0.459). At a cut‐off point of 85%, AT‐III showed a sensitivity of 80% and a specificity of 75%, as a determinant of the need for hospitalization. At a cut‐off point of 600 ng/mL, D‐D showed a sensitivity of 90% and a specificity of 75% and at a cut‐off point of 110 mg/L, CRP showed a sensitivity of 83% and a specificity of 79%, as determinants of the need for hospitalization. Conclusions: Serum levels of AT‐III, D‐D and CRP at admission appear to be useful biomarkers for assessing the severity of CAP.     

Severe hyperthyroidism: aetiology,clinical features and treatment outcome

Background Severe hyperthyroidism (SH) is a serious medical disorder that can compromise life. There have not been systematic studies in which SH has been evaluated in detail. Here, our aims were: (1) to analyse both clinical and analytical features and outcome in patients with SH and (2) to compare these data with those found in more usual forms of hyperthyroidism. Patients and methods All patients diagnosed of SH (free thyroxine, FT4 > 100 pmol/l, NR: 11–23) seen in our endocrinology clinic in the last 15 years were studied and compared with a sample of patients with mild (mH; FT4, 23–50 pmol/l) and moderate (MH; FT4, 51–100 pmol/l) hyperthyroidism. Aetiology, clinical analytical and imaging data at diagnosis, therapeutic response and outcome were registered. Results A total of 107 patients with overt hyperthyroidism (81 females, mean age ± SD 46·9 ± 16·1 years) were evaluated. We studied a historic group with SH (n = 21; 14 females, 40·9 ± 17·2 years) and, as a comparator group, we analyszed the data of 86 hyperthyroid patients (67 females, 48·4 ± 15·5·6 years, NS) comparable in age and gender. The comparator group was classified in MH (n = 37, 26 females, 47·2 ± 16·6 years) and mH (n = 49, 41 females, 49·4 ± 14·8 years). In comparison with mH group, SH patients were significantly (P < 0·05) younger and showed a greater proportion of first episode of thyroid hyperfunction (P < 0·05). Graves’ disease was the main aetiology in the three groups, but patients with SH showed the highest titre of TSH‐receptor antibodies (TRAb) (P < 0·001). Heart rate and size of goitre were higher in SH group than in mH and MH groups (P < 0·01). Atrial fibrillation was more frequently reported in SH group than in MH and mH groups (15·8%vs. 5·4% and 0%, respectively, P < 0·05). Results from logistic regression analysis showed that younger age [OR 0·958 (95% CI, 0·923–0·995), P = 0·026], presence of asthenia [OR 4·35 (1·48–12·78), P = 0·008] and higher heart rate [OR 1·03 (1·01–1·06), P = 0·013] were independent clinical variables associated to SH. SH patients showed similar biochemical parameters in comparison with mH group, except for increased serum aspartate aminotransferase (AST) (P < 0·01) and calcium (P < 0·05) levels, and decreased serum cholesterol (P < 0·05) and albumin (P < 0·05) concentrations. Logistic regression analysis showed that only AST [OR 1·07 (1·02–1·11), P = 0·005] was an independent biochemical variable associated to SH. No differences in the type of therapy, cure rate and time in achieving cure were found in SH subjects in relation to patients with milder forms of hyperthyroidism. FT4 was the only independent predictor of cure [OR 0·98 (CI 95%, 0·97–0·99), P < 0·05]. Conclusions Graves’ disease is the most common aetiology in patients with SH. This type of hyperthyroidism is usually de novo and is accompanied by more clinical signs, symptoms, and analytical derangements, as well as higher titres of TRAb at diagnosis than milder forms of hyperthyroidism. The present data are not able to show differences in treatment modality, time to achieve cure, and remission rate among patients with mild, moderate and severe hyperthyroidism.     

Thyroglobulin measurement before rhTSH-aided 131I ablation in detecting metastases from differentiated thyroid carcinoma

Aim Thyroidectomy followed by administration of large activities of 131‐iodine (¹³¹I) is the treatment of choice for differentiated thyroid carcinoma (DTC). The serum thyroglobulin (Tg) measurement during hypothyroidism (offT4‐Tg), just before radioiodine thyroid ablation, has proved to be effective for predicting persistent/recurrent disease. However, the Tg measurement cannot be used as a corresponding value for pre‐ablative offT4‐Tg when recombinant human TSH (rhTSH) is used as stimulus before treatment. The present study was undertaken to evaluate if post‐thyroidectomy Tg values, measured before rhTSH‐stimulated radioiodine ablation is of prognostic value in patients affected by DTC. Methods We enrolled 126 patients with DTC submitted to total thyroidectomy. T4 treatment was started just after surgery to suppress TSH levels and Tg levels (onT4‐Tg) were measured just before rhTSH‐aided thyroid ablation by ¹³¹I (3700 MBq). Neck radioiodine uptake (RAIU) was measured just before ablation and a post‐treatment whole body scan (PT‐WBS) was performed. Results A significant relationship was found between thyroid remnants’ RAIU and onT4‐Tg levels (P < 0·001). The 1·10 ng/ml onT4‐Tg threshold selected by ROC curve analysis identifies patients with positive PT‐WBS with 83·3% sensitivity, 65·7% specificity, 44·5% positive predictive value (PPV) and 93·6% negative predictive value (NPV). The 0·65 ng/ml cut‐off level recognizes metastatic patients with 82·9% sensitivity, 55·2% specificity, 43·3% PPV and 97·8% NPV when compared with 12 months restaging results. Among 63 patients with initially undetectable onT4‐Tg (i.e. ≤ 0·2 ng/ml) none had positive PT‐WBS nor DTC relapse at 12‐month restaging (NPV 100%). Conclusions Based on our data we conclude that pre‐ablative onT4‐Tg is a prognostic marker and should be used instead of pre‐ablative TSH‐stimulated Tg measurement when rhTSH‐aided radioiodine ablation is done.     

Thyroid dysfunction in a UK hepatitis C population treated with interferon‐α and ribavirin combination therapy

Objective To assess the incidence of thyroid dysfunction (TD) in a UK cohort of patients with hepatitis C virus (HCV) infection treated with interferon‐α (IFNα) and ribavirin combination therapy (IFN/RBV). Design, patients and measurements A retrospective study of 288 patients who received IFN/RBV for HCV during a 2‐year period from January 2006 was performed. Thyroid function was assessed during a 24‐week or 48‐week course of IFN/RBV. If serum thyrotrophin (TSH) became undetectable (<0.01 mU/l) and serum free thyroxine (T4) was raised, a diagnostic thyroid isotope scan was performed. Results Full medical records were examined for 260 patients (172 men, 88 women) included in the study, of whom 22.3% (16.9% of men, 33.0% of women) developed TD during IFN/RBV. In total, 10.4% developed a suppressed serum TSH (0.8% Graves’ disease, 9.6% transient thyroiditis) while 11.9% developed an elevated serum TSH with 1.5% becoming permanently hypothyroid and requiring levothyroxine therapy. Women had a relative risk (RR) for developing TD of 1.96 (CI: 1.75–3.03, P = 0.004). A serum TSH ≥1.75 mU/l and a positive thyroid peroxidase (TPO) antibody titre pretherapy were associated with RRs for progression to TD of 6.02 (CI: 2.95–12.78, P < 0.0001) and 4.35 (CI: 2.58–6.52; P < 0.0001), respectively, while combination of baseline TSH and TPO antibody data predicted progression to TD with a sensitivity of 94.7%. Conclusions Although TD was common in this cohort, just 2.3% developed TD that required ongoing therapy. Pre‐IFN/RBV serum TSH and TPO antibody titre were found to predict progression to TD in this group of patients.     

The performance of STA-Liatest D-dimer assay in out-patients with suspected pulmonary embolism

Several studies have shown that d ‐dimer can reliably rule out pulmonary embolism (PE) in out‐patients. However, various assays have different sensitivities and specificities to detect thrombosis. Our aim was to evaluate the performance of STA‐Liatest D‐Di in out‐patients referred for suspected PE in a prospective outcome study. 495 consecutive patients referred to Østfold Hospital Trust‐Fredrikstad, Norway for suspected PE between February 2002 and December 2003, were recruited in a study evaluating a decision‐based algorithm combining clinical probability (CP), d ‐dimer, and multi‐slice computer tomography (MSCT). d ‐dimer was performed as a first step test. No further testing was carried out in patients with d ‐dimer ≤0·4 mg/l and low/intermediate CP. The remaining patients proceeded to MSCT. All patients were followed up for 3 months to assess the 3‐month thromboembolic risk. The final cohort consisted of 432 patients. PE was diagnosed in 102 (23%) patients. At a d ‐dimer cut‐off point of 0·4 mg/l the tests had the highest sensitivity (100%) and specificity (36%). It safely ruled out PE in 120 (28%) patients. Kappa‐coefficients for comparisons versus VIDAS and Asserachrom showed good concordance. STA‐Liatest is a reliable and effective assay that can safely rule out PE in out‐patients with a performance comparable with that of enzyme‐linked immunosorbent assay‐based d ‐dimer levels.