Autoimmune thyroid disease (AITD) causes cellular damage and alters thyroid gland function by humoral and cell-mediated mechanisms. Cellular damage occurs when sensitized T-lymphocytes and/or autoantibodies bind to thyroid cell membranes causing cell lysis and inflammatory reactions. Alterations in thyroid gland function result from the action of stimulating or blocking autoantibodies on cell membrane receptors. Three principal thyroid autoantigens are involved in AITD. These are thyroperoxidase (TPO), thyroglobulin (Tg) and the TSH receptor. Other autoantigens, such as the Sodium Iodide Symporter (NIS) have also been described, but as yet have no diagnostic role in thyroid autoimmunity.^[248] TSH receptor autoantibodies (TRAb) are heterogeneous and may either mimic the action of TSH and cause hyperthyroidism as observed in Graves' disease or alternatively, antagonize the action of TSH and cause hypothyroidism. The latter occurs most notably in the neonate as a result of a mother with antibodies due to AITD. TPO antibodies (TPOAb) appear involved in the tissue destructive processes associated with the hypothyroidism observed in Hashimoto's and atrophic thyroiditis. The appearance of TPOAb usually precedes the development of thyroid dysfunction. Some studies suggest that TPOAb may be cytotoxic to the thyroid.^[249,250] The pathologic role of TgAb remains unclear. In iodide sufficient areas, TgAb is primarily determined as an adjunct test to serum Tg measurement, because the presence of TgAb can interfere with the methods that quantitate Tg [Section-3 E6]. In iodide deficient areas, serum TgAb measurements may be useful for detecting autoimmune thyroid disease in patients with a nodular goiter and for monitoring iodide therapy for endemic goiter.

Laboratory tests that determine the cell-mediated aspects of the autoimmune process are not currently available. However, tests of the humoral response, i.e. thyroid autoantibodies, can be assessed in most clinical laboratories. Unfortunately, the diagnostic and prognostic use of thyroid autoantibody measurements is hampered by technical problems as discussed below. Although autoantibody tests have inherent clinical utility in a number of clinical situations, these tests should be selectively employed.

TPOAb and/or TgAb are frequently present in the sera of patients with AITD.^[251] However, occasionally patients with AITD have negative thyroid autoantibody test results. TRAb are present in most patients with a history of or who currently have Graves' disease. During pregnancy, the presence of TRAb is a risk factor for fetal or neonatal thyroid dysfunction as a result of the transplacental passage of maternal TRAb.^[252,253] The prevalence of thyroid autoantibodies is increased when patients have non-thyroid autoimmune diseases such as type 1 diabetes and pernicious anemia.^[254] Aging is also associated with the appearance of thyroid autoantibodies and increased prevalence of AITD.^[255] The clinical significance of low levels of thyroid autoantibodies in euthyroid subjects is still unknown.^[256] However, longitudinal studies suggest that TPOAb may be a risk factor for future thyroid dysfunction, including post-partum thyroiditis (PPT) as well as the development of autoimmune complications from treatment by a number of therapeutic agents.^[50,257,258] These include amiodarone therapy for heart disease, interferon-alpha therapy for chronic hepatitis C and lithium therapy for psychiatric disorders.^[75,259-262] The use of thyroid autoantibody measurements for monitoring the treatment for AITD is generally not recommended.^[263] This is not surprising since treatment of AITD addresses the consequence (thyroid dysfunction) and not the cause (autoimmunity) of the disease. However, changes in autoantibody concentrations often reflect a change in disease activity.

Nomenclature of Thyroid Antibody Tests

The nomenclature used for thyroid autoantibodies has proliferated, particularly in the case of TSH receptor antibodies (LATS, TSI, TBII, TSH-R and TRAb). The terms used in this monograph, TgAb, TPOAb and TRAb are those recommended internationally. These terms correspond to the molecular entities (immunoglobulins) which react with the specified autoantigens recognized by the laboratory test. Method differences may bias the measurement of these molecular entities, e.g.: methods may detect only IgG or IgG plus IgM; TPOAb or Ab directed to TPO and other membrane autoantigens; TSH inhibiting and/or TSH stimulating TRAb.

The use of thyroid autoantibody measurements has been hampered by specificity problems. Studies show that results vary widely depending on the method used. This is due to differences in both the sensitivity and specificity of the methods and the absence of adequate standardization. In the past few years, studies at the molecular level have shown that autoantibodies react with their target autoantigens, by binding to "conformational" domains or epitopes. The term "conformational" refers to the requirement for a specific three-dimensional structure for each of the epitopes recognized by the autoantibodies. Accordingly, assay results critically depend on the molecular structure of the antigen used in the test. Small changes in the structure of a given epitope may result in a decrease or a loss in autoantigen recognition by the antibodies targeted to this epitope. Recently, dual specificity TGPO antibodies, that recognize both Tg and TPO, have been demonstrated in the blood of patients with AITD.^[264]

Guideline 29. Thyroid Antibody Method Sensitivity & Specificity Differences

•  

  Recognize and understand that the results of thyroid antibody tests are method-dependent.

•  

  Thyroid antibody methods recognize different epitopes in the heterogeneous antibody populations present in serum.

•  

  Thyroid antibody assay differences reflect different receptor preparations (receptor assays) or cells (bioassays) used in the assay.

•  

  Assay differences can result from contamination of the antigen reagent with other autoantigens.

•  

  Assay differences can result from the inherent assay design (i.e. competitive versus non-competitive immunoassay) as well as the signal used.

•  

  Assay differences can result from the use of different secondary standards.

It has been known for years that autoantibodies are directed against few epitopes as compared to heterologous antibodies. Current methods differ widely in epitope recognition. Specificity differences can result from misrecognition of an epitope that leads to a bias regarding the autoantibody population tested. This results in vastly different reference intervals, even when methods are standardized to the same international reference preparation. Whatever the targeted autoantigen, thyroid autoantibodies are clearly not unique molecular entities but, rather, mixtures of immunoglobulins that only have in common their ability to interact with Tg, TPO or the TSH receptor.

Differences in the sensitivity of autoantibody tests may arise from the design of the assay (e.g. competitive RIA versus two-site IMA) as well as the physical method used for the signal (e.g. radioisotope versus chemiluminiscence). Differences in specificity may occur as a result of contamination of the autoantigen preparation by other autoantigens (e.g. thyroid microsomes versus purified TPO). Further, misrecognition of an epitope may lead to an underestimation of the total amount of circulating autoantibody present, resulting in decreased sensitivity.

Guideline 30. Functional Sensitivity of Thyroid Antibody Tests

Functional sensitivity of thyroid autoantibody tests should:

•  

  Be determined with human serum pools containing a low autoantibody concentration

•  

  Be determined using the same protocol as described for TSH (Guideline 20) but with the between-run precision assessment made over a 6 to 12 month time-period to represent the appropriate clinical assessment interval.

Functional sensitivity should be determined with human serum pools containing a low autoantibody concentration. The protocol for functional sensitivity should be the same protocol as described for TSH (Guideline 20). The between-run precision for TgAb tests used for monitoring TgAb-positive DTC patients should be assessed across a longer time-period (6 to 12 months) consistent with the interval used for serial monitoring in clinical practice.

Standardization of thyroid autoantibody tests is currently suboptimal. International Reference Preparations, MRC 65/93 for TgAb, MRC 66/387 for TPOAb are available from the National Council for Biological Standards and Control in London, UK (www.mrc.ac.uk). These preparations were made from a pool of serum from patients with autoimmune thyroid disease and were prepared and lyophilized 35 years ago!

Guideline 31. For Manufacturers Standardizing Thyroid Antibody Assays

•  

  Assays should be standardized against MRC International Reference Preparations:- MRC 65/93 for TgAb, MRC 66/387 for TPOAb and MRC 90/672 for TRAb

•  

  New International Reference Preparations should be prepared for TgAb and TPOAb.

•  

  Secondary standards should be fully characterized to avoid bias between different methods.

•  

  Reference preparations or recombinant antigen preparations should be used when available.

It is well known that lyophilized antibodies are prone to degradation over time. Degradation of the antibodies may have introduced a bias in the binding activity of these reference preparations towards more stable antibodies of unknown clinical relevance. Due to the scarcity of these preparations, they are only used as primary standards for calibrating assay methods. Commercial kits contain secondary standards that differ for each method. Currently, assay calibrations vary with the experimental conditions as well as the antigen preparation used by the manufacturer. This may introduce additional bias in detecting the heterogeneous antibodies present in patient specimens. In the case of TRAb, the reference preparation MRC 90/672 is more recent (1990) but currently used by few manufacturers.

Thyroid Peroxidase (TPO) is a 110 kD membrane bound hemo-glycoprotein with a large extracellular domain, and a short transmembrane and intracellular domain. TPO is involved in thyroid hormone synthesis at the apical pole of the follicular cell. Several isoforms related to differential splicing of TPO RNA have been described. TPO molecules may also differ with respect to their three-dimensional structure, extent of glycosylation and heme binding. Most of the TPO molecules do not reach the apical membrane and are degraded intracellularly.

Guideline 32. Preferred TPOAb Methodology

• Sensitive, specific TPOAb immunoassays, using suitable preparations of highly purified native or recombinant human TPO as the antigen, should replace the older insensitive, semi-quantitative anti-microsomal antibody (AMA) agglutination tests. (Consensus Level 90%)
  
• The clinical significance of a low TPOAb concentration requires more study.

TPO autoantibodies were initially described as anti-microsomal autoantibodies (AMA) since they were found to react with crude preparations of thyroid cell membranes. The microsomal antigen was later identified as TPO.^[265] Older AMA immunofluorescence assays as well as passive tanned red cell agglutination tests are still currently in use in addition to the newer, more sensitive competitive and non-competitive TPOAb immunoassays. These new immunoassay methods are currently replacing the older AMA agglutination tests because they are quantitative, more sensitive and can easily be automated. However, there is wide variability in the sensitivity and specificity of these new TPOAb methods. Some of this variability stems from differences in the TPO preparations used in the various assay kits. When extracted from human thyroid tissue, TPO may be used as a crude membrane preparation or may be purified by different methods. The assay specificity may also differ because of contamination by other thyroid antigens - notably Tg and/or variations in the three-dimensional structure of TPO. The use of recombinant human TPO (rhTPO) eliminates the risk of contamination but does not solve the problem of the differences in TPO structure that depend upon the technique used to isolate TPO. Most current TPOAb assays are quantitated in international units using the reference preparation MRC 66/387. Unfortunately, the use of this primary standard does not alleviate between-method variations as is evident from the broad variability in sensitivity limits claimed by the different kit manufacturers (range <0.3 to <20 kIU/L) and the differences in normal reference intervals.

TPOAb Prevalence & Reference Intervals

The estimate of TPOAb prevalence depends on the sensitivity and specificity of the method employed. The recent NHANES III United States survey of ~17,000 subjects without apparent thyroid disease, reported detectable TPOAb levels in 12 % of subjects using a competitive immunoassay method.^[18] Whether low levels of TPOAb detected in healthy individuals and/or patients with non-thyroid autoimmune diseases reflect normal physiology, the prodrome of AITD, or an assay specificity problem, remains unclear.

Normal reference values for TPOAb assays are highly variable and often arbitrarily established, so that a large majority of patients with AITD test positive, and most subjects without clinical evidence of AITD test negative. The lower normal limit appears to relate to technical factors. Specifically, assays citing a low detection limit (<10 kIU/L) typically report undetectable TPOAb levels in meticulously selected normal subjects. Such methods suggest that the presence of TPOAb is a pathologic finding. In contrast, TPOAb assays reporting higher detection limits (>10kIU/L) typically cite a TPOAb "normal reference range". Since such methods appear to have no enhanced sensitivity for detecting AITD, these "normal range" values may represent non-specific assay "noise" and may not be pathologically meaningful.

The recent 20-year follow-up study of the Whickham cohort reported that detectable TPOAb titers (measured as AMA) was not only a risk factor for hypothyroidism but that a detectable AMA preceded the development of an elevated TSH (Figure 5).^[35] This suggests that a detectable TPOAb is a risk factor for AITD (Guideline 34). However, individuals with low TPOAb levels would have had undetectable AMA by the older methods used in this study.^[35] Indeed, AMA-negative subjects with TSH >2 mIU/L did have a higher long-term risk of hypothyroidism, suggesting that low TPOAb levels may be clinically significant.^[35] Thus, whether individuals with low levels of TPOAb and/or TgAb should be considered normal remains in question until more long-term follow-up studies on such individuals show that they do not have an increased risk for developing thyroid dysfunction.

Guideline 33. Reference Intervals for Thyroid Antibody Tests

Reference intervals for thyroid antibody tests should be established from 120 "Normal" subjects free from any history of thyroid disease: Subject selection should minimize the inclusion of persons with a predisposition for autoimmune thyroid disease. Normal subjects should be:

•  

  Male

•  

  Young (< 30 years of age)

•  

  Have serum TSH levels between 0.5 and 2.0 mIU/L

•  

  No goiter

•  

  No personal or family history of thyroid disease

•  

  No non-thyroid autoimmune diseases (e.g. lupus or diabetes)

The criteria employed for selecting subjects for the normal cohort used to establish an autoantibody normal reference range, is critical. Such a cohort should be comprised of young, biochemically euthyroid (TSH 0.5 to 2.0 mIU/L) male subjects with no goiter and no family history of AITD. This rigorous selection process would be least likely to include subjects with a predisposition to AITD.

Clinical Uses of TPOAb Measurements

TPOAb is the most sensitive test for detecting autoimmune thyroid disease.^[266] As shown schematically in Figure 5, TPOAb is typically the first abnormality to appear in the course of developing hypothyroidism secondary to Hashimotos' thyroiditis. In fact, when TPOAb is measured by a sensitive immunoassay, >95% of subjects with Hashimotos thyroiditis have detectable levels of TPOAb. Such methods also detect TPOAb in most (~85%) patients with Graves' disease.^[254] Patients with TPOAb detected in early pregnancy are at risk for developing post-partum thyroiditis.^[50] Patients with Down's syndrome have an increased risk of thyroid dysfunction due to autoimmune thyroid disease and annual screening with TSH and TPOAb is important.^[267,268]

Recent reports have suggested that the IQ of children born to mothers with increased TSH and/or detectable TPOAb during pregnancy may be compromised.^[63-65] This has prompted recommendations that all pregnant women should have TSH and TPOAb levels measured in the first trimester of their pregnancy [Section-2 A3 and Guideline 4]. Further, TPOAb measurements may have a role in infertility, since high TPOAb levels are associated with a high risk of miscarriage and failure to conceive with in-vitro fertilization.^[269]

Guideline 34. Recommended Uses for TPOAb Measurement

•  

  Diagnosis of Autoimmune Thyroid Disease

•  

  Risk factor for Autoimmune Thyroid Disease

•  

  Risk factor for hypothyroidism during Interferon alpha, Interleukin-2 or Lithium therapy

•  

  Risk factor for thyroid dysfunction during amiodarone therapy (see Guideline 5)

•  

  Risk factor for hypothyroidism in Down's Syndrome patients

•  

  Risk factor for thyroid dysfunction during pregnancy and for post-partum thyroiditis

•  

  Risk factor for miscarriage and in-vitro fertilization failure

The presence of TPOAb is well established as a risk factor for thyroid dysfunction when patients are being treated with lithium, amiodarone, interleukin-2 or interferon-alpha.^{[75,259,260,261,270]} During interferon-alpha treatment, a preexisting thyroid autoimmune disorder or detectable TPOAb titer are predisposing factors for the development of thyroid disease during therapy.^[262] There appears however, to be no increased frequency of thyroid dysfunction during interferon-beta therapy.^[271] The presence of TPOAb before therapy shows a sensitivity of 20%, a specificity of 95% and a predictive value of 66.6% for the development of thyroid dysfunction.^[272]

Thyroglobulin (Tg), the prothyroid globulin, is a high molecular weight (660 kDa) soluble glycoprotein made up of two identical subunits. Tg is present with a high degree of heterogeneity due to differences in post-translational modifications (glycosylation, iodination, sulfation etc). During the process of thyroid hormone synthesis and release, Tg is polymerized and degraded. Consequently, the immunologic structure of Tg is extremely complex. The characteristics of Tg preparations may vary widely depending on the starting human thyroid tissue and the purification process used. This is the first clue to explain why TgAb assays, as well as Tg assays [Section-3 E2] are so difficult to standardize.

TgAb Methodology

As with TPOAb methods, the design of TgAb assays has evolved from immunofluorescence of thyroid tissue sections, to passive tanned red cell agglutination methods and now to the competitive and noncompetitive immunoassays. This technical evolution has improved both the sensitivity and specificity of serum TgAb measurements. However, because the older and newer methods are still being used concurrently in clinical laboratories, the sensitivity and specificity of available methods can vary widely depending on the laboratory. Assays are calibrated with purified or crude preparations of TgAb by pooling patient sera or blood donor material. These various secondary standards are often, but not always, calibrated against the primary standard (MRC 65/93). However, standardization with MRC 65/93 does not ensure that different methods are quantitatively or qualitatively similar. Other reasons for method differences relate to the heterogeneity of TgAb itself. The heterogeneity of TgAb is restricted in patients with AITD compared with other thyroid disorders such as differentiated thyroid carcinomas (DTC) in which the heterogeneity of TgAb appears less restricted.^[273] This reflects differences in the expression of the different autoantibodies that may be normally expressed at very low levels in healthy individuals.^[274] The inter-method variability of serum TgAb values may also reflect qualitative differences in TgAb affinity and epitope specificity in different serum samples from patients with different underlying thyroid and immunological conditions. Another reason for inter-method differences is that assay designs are prone to interference by high levels of circulating antigen (Tg), as is commonly the case with Graves' disease and metastatic DTC.^[275]

Guideline 35. For Manufacturers Developing TgAb Methods

•  

  The epitope specificity of TgAb methods should be broad not restricted, since TgAb epitope specificity may be wider for TgAb-positive patients with DTC compared to patients with autoimmune thyroid disease.

TgAb Prevalence & Reference Intervals

As with TPO antibodies, the prevalence and normal cut-off values for thyroglobulin antibodies depends on the sensitivity and specificity of the assay method.^[276] The NHANES III survey reported a TgAb prevalence of ~10% for the general population, measured by competitive immunoassay.^[18] The TgAb prevalence in DTC patients appears to be two-fold higher than the normal population (~20 versus 10 %, respectively).^[276] As with TPOAb, the clinical significance of low TgAb levels, that would be undetectable by the older agglutination methods, remains unclear. It has been suggested that low levels may represent " natural " antibody in normal individuals or a " scavenger " antibody response to antigen release following thyroid surgery or radioactive iodide therapy. Alternatively, low levels might represent underlying silent AITD.^[256] Different TgAb methods report different normal threshold values, as discussed for TPOAb [Section-3 D5(a)]. Specifically, some TgAb methods report that normal subjects should have values below the assay detection level, other methods report a "normal range". When TgAb measurements are used as an adjunct test to serum Tg measurements, the significance of low TgAb levels relates less to the pathophysiology of its presence but more to the potential for low TgAb levels to interfere with the serum Tg method.

Guideline 36. TgAb Measurement in Non-Neoplastic Conditions

•  

  In iodide sufficient areas, it is not usually necessary or cost-effective to order both TPOAb and TgAb, because TPOAb-negative patients with detectable TgAb rarely display thyroid dysfunction.

•  

  In iodide deficient areas, serum TgAb measurements may be useful for detecting autoimmune thyroid disease when patients have a nodular goiter.

•  

  Monitoring iodide therapy for endemic goiter.

Sensitivity and Precision of TgAb Measurement

Sensitive quantitative TgAb determination is a critical adjunct test for serum Tg measurement. Qualitative agglutination tests are not sufficiently sensitive to detect the low TgAb concentrations that can interfere with serum Tg measurements.^[276] As with TPOAb assays [Section-3 D5(a)], the absolute values reported by different TgAb immunoassays are highly variable which precludes the use of different manufacturers tests for serial monitoring of DTC patients. There appear to be two classes of TgAb immunoassay. One class is characterized by low detection limits (<10 kIU/L) and an undetectable normal reference limit. Such methods suggest that the presence of TgAb is a pathologic finding. The other class of assay reports higher detection limits (>10kIU/L) and cites a TgAb "normal reference range". These detectable "normal range" values are likely to represent non-specific assay "noise" caused by assay insensitivity or problems with specificity since these low "normal range" values show no evidence of interference with serum Tg measurements [Section-3 E6].

Guideline 37. TgAb Measurement in Differentiated Thyroid Carcinomas (DTC)

The TgAb concentration should be measured in ALL patient sera prior to Tg analysis because low levels of TgAb can interfere with serum Tg measurements causing either falsely low, undetectable or high values depending on the Tg method used.

•  

  TgAb should be measured in every serum specimen sent to the laboratory for Tg testing.

•  

  Serial TgAb measurements should be made on all TgAb-positive DTC patients using the same manufacturer's method because serial TgAb values have prognostic significance for monitoring response to DTC treatment.

•  

  TgAb methods should be immunoassay not agglutination, because low levels of TgAb can interfere with serum Tg measurements made by most methods, and serial measurements must be quantitative not qualitative.

•  

  Serum Tg recovery tests do not reliably detect the presence of TgAb and should be discouraged as a method for detecting TgAb (Guideline 46).

•  

  Before changing the TgAb method, the laboratory should inform physician users and evaluate the relationship between the old and proposed new method values. Patients should be re-baselined if the difference between the methods is >10% CV.

Clinical Uses of TgAb Measurement

There is some debate over the clinical utility of serum TgAb measurement for assessing the presence of thyroid autoimmunity. The United States NHANES III study reported that 3 % of subjects with no risk factors for thyroid disease had detectable TgAb without associated presence of TPOAb.^[18] Since this cohort had no associated TSH elevation, TgAb measurements do not appear to be a useful diagnostic test for AITD in areas of iodide sufficiency.^[256,279] In iodide deficient areas however, TgAb is believed to be useful for detecting AITD, especially for patients with a nodular goiter. TgAb measurements are also useful for monitoring iodide therapy for endemic goiter, since iodinated Tg molecules are more immunogenic.

Serum TgAb testing is primarily used as an adjunct test when serum Tg measurements are requested. The clinical utility of TgAb measurements in sera from DTC patients is two-fold. First, sensitive and specific TgAb screening of sera in these cancer patients is necessary, because even low antibody concentrations can interfere with the Tg measurements made by most Tg methods [see Section-3 E6].^[275,276] Second, serial TgAb measurements themselves may serve as a surrgogate tumor marker test for TgAb-positive patients in whom Tg testing may be unreliable.^[276] Specifically, TgAb-positive patients who are rendered disease-free typically become TgAb-negative within 1-4 years.^{[276,277,278]} In contrast, patients who have persistent disease after treatment retain detectable TgAb concentrations. In fact, a rise in the TgAb level is often the first indication of recurrence in such patients.^[276]

The TSH receptor is a member of the superfamily of receptors with seven transmembrane domains linked to G proteins. The 60kb TSH receptor gene located on the long arm of chromosome 14q31 has been cloned and sequenced.^[272] Exons 1-9 code for the extracellular domain of the receptor (397 amino acids) and exon 10 codes for the transmembrane region (206 amino acids). Activation of G proteins by the hormone receptor complex results in stimulation of cAMP production by adenylate cyclase and inositol phosphate turnover by phospholipases.^[280] Site-directed mutagenesis has shown that the 3-dimensional receptor structure is important for the interaction with TSH and/or TRAbs. There are three broad types of TRAb measured by either bioassay or receptor assay (Table 6). Receptor, or TSH Binding Inhibitory Immunoglobulin (TBII) assays do not measure biologic activity directly but assess whether the specimen contains immunoglobulins that can block the binding of TSH to an in vitro receptor preparation. TSH stimulating antibodies (TSAb) appear to bind the N-terminal portion of the extracellular domain and mimic the actions of TSH by inducing post-receptor signal transduction and cell stimulation. In contrast, the C-terminal region is more important for TSH receptor blocking antibodies (abbreviated TBAb or TSBAb) which block stimulation by either TSAb or TSH, causing hypothyroidism.^[281] Thyroid growth-stimulating immunoglobulins (TGI) are less well characterized in this regard.

It has now been shown that the lack of correlation between TRAb levels and the clinical status of patients is largely because circulating TRAb's are heterogeneous. The fact that TRAb heterogeneity can coexist within an individual patient and change over time is one reason why it has been difficult to develop diagnostically accurate TRAb tests.^[282,283] Indeed, the clinical presentation of Graves' patients who exhibit both TSAb and TBAb/TSBAb will likely depend on the relative concentration and affinity of the predominant antibody. A shift from stimulating to blocking TRAb may explain the spontaneous remission of Graves' disease during pregnancy as well as radioiodide induction of transient hypothyroidism.^[281,284] It is important to note that bioassays that use cell preparations to measure the biologic effects of TRAb (stimulation, inhibition of TSH activity or growth) can detect functional changes in TRAb heterogeneity. In contrast, the receptor, or TSH Binding Inhibitory Immunoglobulin (TBII) type of assays, which are used by many clinical laboratories, merely measure the ability of a serum or IgG preparation to block the binding of a TSH preparation and do not measure the biological response (Table 6). This fundamental difference in assay design explains why bioassays and receptor assays usually display a weak correlation (r 5 0.31-0.65).^[283,285]

TRAb Methodology

The first report that there was a thyroid stimulator that differed from TSH with respect to its longer half-life (Long Acting Thyroid Stimulator or LATS) was published in 1956 using an in vivo bioassay.^[286] LATS was later identified as an immunoglobulin. Like TSH, TRAbs stimulate both cAMP and the inositol phosphate pathways of the thyroid follicular cell, and thus both stimulate and block both thyroid hormone synthesis and the growth of the gland.^[283]

The types of methods developed for TRAb measurements are classified relative to their functional activity, as shown in Table 6. Studies in mice and FRTL-5 cell lines as well as humans, show that a high concentration of human chorionic gonadotropin (hCG) is also a weak TRAb agonist and can stimulate cAMP, iodide transport, and cell growth.^[56] The marked hCG elevations secondary to choriocarcinoma can in rare cases cause a false positive TRAb result. However, the increase in hCG typically seen with normal pregnancy or in patients treated for a hydatiform mole is usually not high enough to elicit a false positive result.

Bioassays (TSAb, TBAb/TSBAb and TGI)

Most current bioassays are based on TSH receptor activation of second messenger (cAMP) production from a cell preparation (FRTL-5/ CHO TSH-R) exposed to a serum specimen or IgG preparation.^[287-289] The recent cloning of the TSH receptor has benefited bioassays by facilitating the development of TSH receptor transfected cell lines.^[290,291] Although these bioassays are available in several commercial laboratories in the United States and Asia, they are less available in Europe because of regulations that affect the use of genetically altered organisms. Unfortunately, the correlation between TRAb assay results and clinical presentation is still poor. For example, the diagnostic sensitivity for Graves' disease using TRAb bioassays ranges from 62.5 to 81%.^[283] New approaches employing chimeric assays may be able to target the loci of TRAb epitopes and TSH binding sites and thus provide a better correlation between assay response and clinical outcome.^{[281,284,292-294]}

Receptor (TBII) Assays

Thyroid binding inhibiting immunoglobulin (TBII) assays are commercially available and are used by many clinical laboratories. These methods quantify the inhibition of the binding of 125I-labeled TSH to either solubilized porcine receptors, or more recently, recombinant human TSH receptors.^[295-297] This type of method does not distinguish between stimulating and blocking TRAbs. TBII activity is typically quantified against a TRAb-positive serum calibrated against a reference calibrator serum. The most frequently used calibrator serum has been the MRC reference serum, LATS-B. A WHO standard (MRC 90/672) has recently become available. The inherent heterogeneity of TRAb in patient serum and the source of receptors used (porcine versus recombinant human) are likely causes for the wide variability observed between TBII methods, despite the use of the same standard.^[283,298] Although TBII methods based on recombinant human TSH receptor are now available and may have a higher diagnostic sensitivity for Graves' disease, they do not appear to offer improved specificity or sensitivity for predicting response to anti-thyroid drug (ATD) therapy.^[297,299]

TRAb Reference Intervals

Guideline 38. TSH Receptor Antibody (TRAb) Tests

Clinical laboratory TRAb assays:

•  

  Receptor or TSH binding inhibition tests (TBII) that do not measure stimulatory activity directly but detect factors in the serum specimen that block the binding of a labeled TSH preparation to an in-vitro TSH receptor preparation. These tests are the more commonly used TRAb assays in clinical laboratories.

•  

  TSH receptor bioassays (TSAb) that use cells (FRTL-5 cells, or more recently CHO transfected with human TSH receptor) to detect thyroid stimulating immunoglobulins (TSAb) that either stimulate cAMP or iodide uptake. These tests are not routinely available in all countries.

•  

  In general, there is a poor correlation between TSAb and TBII results (60-75%). TSAb assays claim to be positive in 80-100% and TBII assays positive in 70 to 90% of untreated Graves' hyperthyroid patients. Neither test has high specificity or sensitivity for predicting remission from Graves' hyperthyroidism.

•  

  Normal hCG as well as abnormal hCG production in choriocarcinoma are known to interact with the TSH receptor which could lead to false positive results. This might be observed in rare cases of choriocarcinoma but not in normal pregnancy or treated hydatiform mole in which the level of hCG is not high enough to cause a false positive result.

Despite the adoption of a new international reference preparation MRC 90/672, TRAb values are still method-dependent and reference intervals vary depending on the selection of the "normal" population used to determine the cut-off level for a positive result. This cut-off is generally defined as two standard deviations from the mean of normal subjects.

The clinical use of TRAb measurements for the diagnosis and follow-up of AITD remains a matter of controversy and differs geographically. The differential diagnosis of hyperthyroidism can be resolved in most patients without resorting to TRAb testing. Nevertheless, the presence of TRAb may distinguish Graves' disease from factitious thyrotoxicosis and other manifestations of hyperthyroidism such as subacute or post-partum thyroiditis and toxic nodular goiter.

TRAb measurements have also been proposed as a means for predicting the course of Graves' disease. A declining TRAb level is often seen in hyperthyroid patients in clinical remission after treatment with antithyroid drugs (ATD). After ATD withdrawal, very high levels of TRAb correlate quite well with prompt relapse, but this situation involves very few patients. Conversely, a significant number of patients with undetectable or low TRAb levels will relapse. A meta-analysis of the relationship between TRAb levels and the risk of relapse has shown that 25% of patients are misclassified by TRAb assays.^[263] This suggests that after ATD therapy, a follow-up of the patients is necessary whatever the TRAb level at the time of ATD withdrawal and that TRAb measurement is not cost effective for this purpose.^[263]

There is general agreement that TRAb measurements can be used to predict fetal and/or neonatal thyroid dysfunction in pregnant women with a previous history of AITD.^[8,252] High levels of TRAb in the mother during the third trimester of pregnancy suggest a risk of thyroid dysfunction in the offspring.^[8,282] Two to 10% of pregnant women with very elevated TRAb deliver newborns with hyperthyroidism.^[8] The risk for neonatal hyperthyroidism is negligible following successful treatment of hyperthyroidism with antithyroid drugs, but can develop after radioiodide treatment if TRAb levels remain elevated.^[8] Euthyroid pregnant women (+/- L-T4 treatment) who have had prior radioiodide therapy for Graves' disease should have TRAb levels measured both in early pregnancy, when an elevated value is a significant risk factor for fetal hyperthyroidism, and during the third trimester, to evaluate for the risk of neonatal hyperthyroidism.^[8] Pregnant women who take antithyroid drugs (ATD) for Graves' disease should have TRAb measured in the third trimester. High TRAb levels in such patients should prompt a thorough clinical and biochemical evaluation of the neonate for hyperthyroidism, both at birth (cord blood) and at 4 - 7 days, after the effects of the transplacental passage of ATD have disappeared.^[300] It is worth noting that the TBII receptor assays are often used for this purpose since they detect both stimulating (TSAb) and in rare cases, blocking antibodies (TBAb/TSBAb) which cause transient hypothyroidism in 1:180,000 of newborns.^[301] It is also advisable to test for both stimulating and blocking antibodies because the expression of thyroid dysfunction may be different in the mother and the infant.^[253]

Guideline 39. Clinical Uses of TRAb Measurement

•  

  To investigate the etiology of hyperthyroidism when the diagnosis is not clinically obvious.

•  

  A declining TRAb concentration during long-term antithyroid drug therapy is suggestive of remission. However TRAb measurements can be misleading in 25% of such patients.

•  

  TRAb measurements are useful to diagnose Graves' disease patients and for relating TRAb values to a treatment algorithm.

•  

  To evaluate patients suspected of "euthyroid Graves' opthalmopathy". Undetectable TRAb however, does not exclude the condition.

•  

  Although TSAb assays have theoretical advantages, some believe that TBII tests, that detect both stimulating (TSAb) and the rare cases of blocking (TBAb/TSBAb) antibodies, are equally useful.

•  

  For pregnant women with a past or present history of Graves' disease. Note: Pregnant women who are euthyroid after receiving prior antithyroid drug treatment for Graves' disease have a negligible risk for fetal or neonatal hyperthyroidism.

•  

  Euthyroid pregnant women (± L-T4 treatment) who have had prior radioiodide treatment for Graves' disease should have TRAb measured both early in pregnancy when a high value is a risk factor for fetal hyperthyroidism (2-10%), and during the third trimester to evaluate the risk of neonatal hyperthyroidism.

•  

  Pregnant women who take antithyroid drugs (ATD) for Graves' disease to maintain a euthyroid state during pregnancy should have TRAb measured in the third trimester. A high TBII value should prompt a clinical and biochemical evaluation of the neonate for hyperthyroidism, both at birth (cord blood) and at 4 - 7 days after the effects of transplacental passage of ATD have been lost.

•  

  The assessment of the risk of fetal and neonatal thyroid dysfunction necessitates the detection of either blocking or stimulating TRAb when mothers have no intact thyroid following past therapy for Graves' hyperthyroidism.

•  

  To identify neonates with transient hypothyroidism due to the presence of TSH receptor blocking antibodies.

Guideline 40. Improvements Needed in Thyroid Antibody Tests

•  

  Current thyroid autoantibody assays should be submitted to a comparative study of their analytical and clinical performances.

•  

  A comparison study of the antigen preparations currently in use would facilitate the identification of the method(s) best suited for clinical thyroid autoantibody testing.

•  

  The characteristics of the antigen preparations used in the test should be stated for all thyroid autoantibody assays.

•  

  Reference preparations of antigens should be made available.

The role of TRAb in thyroid-associated opthalmopathy (TAO) is uncertain.^[302] TAO appears to be exacerbated by radioiodide therapy.^[303] Furthermore, TRAb and other thyroid antibody levels increase significantly after radioiodide therapy.^[304-306] This suggests that TRAb measurements prior to radioiodide therapy may be useful to predict the risk of TAO but as yet there are no prospective studies to document this observation.

It is important that a well-structured comparative study of the commercially available thyroid autoantibody assays be performed. This would provide irrefutable evidence that differences exist in the performance of current assay methods.^[296] It would also help to convince clinical laboratory scientists to avoid using assays that have poor clinical performance and encourage manufacturers to improve their products or drop them from the market.

Guideline 41. For Manufacturers Developing Thyroid Antibody Tests

•  

  Absolute or "gold standard" methods remain a target for the future.

•  

  The kit package insert should document the methods used to produce the antigen reagents, the assay design and all experimental conditions affecting the antigen-antibody interactions.

•  

  The specificity of the secondary standards should be selected relative to the interactions between the autoantibodies in patient sera and their specific antigen.

•  

  TPOAb and TgAb IMAs should be checked for hook effects using ~20 specimens with antibody concentrations >1,000 kIU/L and ~20 specimens with values above 10,000 kIU/L.

•  

  TgAb methods should be checked for high antigen (Tg) effects by spiking a range of sera containing low TgAb concentration to Tg levels >10,000 µg/L (ng/ml) and >100,000 µg/L (ng/ml).

1. Nohr SB, Laurberg P, Borlum KG, Pedersen Km, Johannesen PL, Damm P. Iodine deficiency in pregnancy in Denmark. Regional variations and frequency of individual iodine supplementation. Acta Obstet Gynecol Scand 1993;72:350-3.
2. Glinoer D. Pregnancy and iodine. Thyroid 2001;11:471-81.
3. Hollowell JG, Staehling NW, Hannon WH, Flanders DW, Gunter EW, Maberly GF et al. Iodine nutrition in the Unites States. Trends and public health implications: iodine excretion data from National Health and Nutrition Examination Surveys I and III (1971-1974 and 1988-1994). J Clin Endocrinol Metab 1998;83:3398-400.
4. Wartofsky L, Glinoer D, Solomon d, Nagataki S, Lagasse R, Nagayama Y et al. Differences and similarities in the diagnosis and treatment of Graves disease in Europe, Japan and the United States. Thyroid 1990;1:129-35.
5. Singer PA, Cooper DS, Levy EG, Ladenson PW, Braverman LE, Daniels G et al. Treatment guidelines for patients with hyperthyroidism and hypothyroidism. JAMA 1995;273:808-12.
6. Singer PA, Cooper DS, Daniels GH, Ladenson PW, Greenspan FS, Levy EG et al. Treatment Guidelines for Patients with Thyroid Nodules and Well-differentiated Thyroid Cancer. Arch Intern Med 1996;156:2165-72.
7. Vanderpump MPJ, Ahlquist JAO, Franklyn JA and Clayton RN. Consensus statement for good practice and audit measures in the management of hypothyroidism and hyperthyroidism. Br Med J 1996;313:539-44.
8. Laurberg P, Nygaard B, Glinoer D, Grussendorf M and Orgiazzi J. Guidelines for TSH-receptor antibody measurements in pregnancy: results of an evidence-based symposium organized by the European Thyroid Association. Eur J Endocrinol 1998;139:584-6.
9. Cobin RH, Gharib H, Bergman DA, Clark OH, Cooper DS, Daniels GH et al. AACE/AAES Medical/Surgical Guidelines for Clinical Practice: Management of Thyroid Carcinoma. Endocrine Pract 2001;7:203-20.
10. Ladenson PW, Singer PA, Ain KB, Bagchi N, Bigos ST, Levy EG et al. American Thyroid Association Guidelines for detection of thyroid dysfunction. Arch Intern Med 2000;160:1573-5.
11. Brandi ML, Gagel RJ, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C et al. Consensus Guidelines for Diagnosis and Therapy of MEN Type 1 and Type 2. J Clin Endocrinol Metab 2001;86:5658-71.
12. Werner and Ingbar's "The Thyroid". A Fundamental and Clinical Text. Lippincott-Raven, Philadelphia 2000. Braverman LE and Utiger RD eds.
13. DeGroot LJ, Larsen PR, Hennemann G, eds. The Thyroid and Its Diseases. (www.thyroidmanager.org) 2000.
14. Piketty ML, D'Herbomez M, Le Guillouzic D, Lebtahi R, Cosson E, Dumont A et al. Clinical comparision of three labeled-antibody immunoassays of free triiodothyronine. Clin Chem 1996;42:933-41.
15. Sapin R, Schlienger JL, Goichot B, Gasser F and Grucker D. Evaluation of the Elecsys free triiodothyronine assay; relevance of age-related reference ranges. Clin Biochem 1998;31:399-404.
16. Robbins J. Thyroid hormone transport proteins and the physiology of hormone binding. In "Hormones in Blood". Academic Press, London 1996. Gray CH, James VHT, eds. pp 96-110.
17. Demers LM. Thyroid function testing and automation. J Clin Ligand Assay 1999;22:38-41.
18. Hollowell JG, Staehling NW, Hannon WH, Flanders WD, Gunter EW, Spencer CA et al. Serum thyrotropin, thyroxine and thyroid antibodies in the United States population (1988 to 1994):|NHANES III. J Clin Endocrinol Metab 2002;87:489-99.
19. Wardle CA, Fraser WD and Squire CR. Pitfalls in the use of thyrotropin concentration as a first-line thyroid-function test. Lancet 2001;357:1013-4.
20. Spencer CA, LoPresti JS, Patel A, Guttler RB, Eigen A, Shen D et al. Applications of a new chemiluminometric thyrotropin assay to subnormal measurement. J Clin Endocrinol Metab 1990;70:453-60.
21. Meikle, A. W., J. D. Stringham, M. G. Woodward and J. C. Nelson. Hereditary and environmental influences on the variation of thyroid hormones in normal male twins. J Clin Endocrinol Metab1988;66:588-92.
22. Andersen S, Pedersen KM, Bruun NH and Laurberg P. Narrow individual variations in serum T4 and T3 in normal subjects: a clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metab 2002;87:1068-72.
23. Cooper, D. S., R. Halpern, L. C. Wood, A. A. Levin and E. V. Ridgway. L-thyroxine therapy in subclinical hypothyroidism. Ann Intern Med 1984;101:18-24.
24. Biondi B, Fazio E, Palmieri EA, Carella C, Panza N, Cittadini A et al. Left ventricular diastolic dysfunction in patients with subclinical hypothyroidism. J Clin Endocrinol Metab 1999;2064-7.
25. Hak AE, Pols HAP, Visser TJ, Drexhage HA, Hofman A and Witteman JCM. Subclinical Hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Ann Intern Med 2000;132:270-8.
26. Michalopoulou G, Alevizaki M, Piperingos G, Mitsibounas D, Mantzos E, Adamopoulos P et al. High serum cholesterol levels in persons with 'high-normal' TSH levels: should one extend the definition of subclinical hypothyroidism? Eur J Endocrinol 1998;138:141-5.
27. Beck-Peccoz P, Brucker-Davis F, Persani L, Smallridge RC and Weintraub BD. Thyrotropin-secreting pituitary tumors. Endocrine Rev 1996;17:610-38.
28. Brucker-Davis F, Oldfield EH, Skarulis MC, Doppman JL and Weintraub BD. Thyrotropin-secreting pituitary tumors: diagnostic criteria, thyroid hormone sensitivity and treatment outcome in 25 patients followed at the National Institutes of Health. J Clin Endocrinol Metab 76 1999;:1089-94.
29. Oliveira JH, Persani L, Beck-Peccoz P and Abucham J. Investigating the paradox of hypothyroidism and increased serum thyrotropin (TSH) levels in Sheehan's syndrome: characterization of TSH carbohydrate content and bioactivity. J Clin Endocrinol Metab 2001;86:1694-9.
30. Uy H, Reasner CA and Samuels MH. Pattern of recovery of the hypothalamic-pituitary thyroid axis following radioactive iodine therapy in patients with Graves' disease. Amer J Med 1995;99:173-9.
31. Hershman JM, Pekary AE, Berg L, Solomon DH and Sawin CT. Serum thyrotropin and thyroid hormone levels in elderly and middle-aged euthyroid persons. J Am Geriatr Soc 1993;41:823-8.
32. Fraser CG. Age-related changes in laboratory test results. Clinical applications. Drugs Aging1993;3:246-57.
33. Fraser CG. 2001. Biological Variation: from principles to practice. AACC Press, Washington DC.
34. Drinka PJ, Siebers M and Voeks SK. Poor positive predictive value of low sensitive thyrotropin assay levels for hyperthyroidism in nursing home residents. South Med J 1993;86:1004-7.
35. Vanderpump MPJ, Tunbridge WMG, French JM, Appleton D, Bates D, Rodgers H et al. The incidence of thyroid disorders in the community; a twenty year follow up of the Whickham survey. Clin Endocrinol 1995;43:55-68.
36. Sawin CT, Geller A, Kaplan MM, Bacharach P, Wilson PW, Hershman JM et al. Low serum thyrotropin (thyroid stimulating hormone) in older persons without hyperthyroidism. Arch Intern Med1991;151:165-8.
37. Parle JV, Maisonneuve P, Sheppard MC, Boyle P and Franklyn JA. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year study. Lancet 2001;358:861-5.
38. Nelson JC, Clark SJ, Borut DL, Tomei RT and Carlton EI. Age-related changes in serum free thyroxine during childhood and adolescence. J Pediatr 1993;123:899-905.
39. Adams LM, Emery JR, Clark SJ, Carlton EI and Nelson JC. Reference ranges for newer thyroid function tests in premature infants. J Pediatr 1995;126:122-7.
40. Lu FL, Yau KI, Tsai KS, Tang JR, Tsao PN and Tsai WY. Longitudinal study of serum free thyroxine and thyrotropin levels by chemiluminescent immunoassay during infancy. T'aiwan Erh K'o i Hseh Hui Tsa Chih 1999;40:255-7.
41. Zurakowski D, Di Canzio J and Majzoub JA. Pediatric reference intervals for serum thyroxine,triiodothyronine, thyrotropin and free thyroxine. Clin Chem 1999;45:1087-91.
42. Fisher DA, Nelson JC, Carlton Ei and Wilcox RB. Maturation of human hypothalamic-pituitary-thyroid function and control. Thyroid 2000;10:229-34.
43. Fisher DA, Schoen EJ, La Franchi S, Mandel SH, Nelson JC, Carlton EI and Goshi JH. The hypothalamic-pituitary-thyroid negative feedback control axis in children with treated congenital hypothyroidism. J Clin Endocrinol Metab 2000;85:2722-7.
44. Penny R, Spencer CA, Frasier SD and Nicoloff JT. Thyroid stimulating hormone (TSH) and thyroglobulin (Tg) levels decrease with chronological age in children and adolescents. J Clin Endocrinol Metab 1983;56:177-80.
45. Verheecke P. Free triiodothyronine concentration in serum of 1050 euthyroid children is inversely related to their age. Clin Chem 1997;43:963-7.
46. Glinoer D, De Nayer P, Bourdoux P, Lemone M, Robyn C, van Steirteghem A et al. Regulation of maternal thyroid function during pregnancy. J Clin Endocrinol Metab 1990;71:276-87.
47. Glinoer D. The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocrinol Rev 1997;18:404-33.
48. Weeke J, Dybkjaer L, Granlie K, Eskjaer Jensen S, Kjaerulff E, Laurberg P et al. A longitudinal study of serum TSH and total and free iodothyronines during normal pregnancy. Acta Endocrinol1982;101:531-7.
49. Pedersen KM, Laurberg P, Iversen E, Knudsen PR, Gregersen HE, Rasmussen OS et al. Amelioration of some pregnancy associated variation in thyroid function by iodine supplementation. J Clin Endocrinol Metab 1993;77:1078-83.
50. Nohr SB, Jorgensen A, Pedersen KM and Laurberg P. Postpartum thyroid dysfunction in pregnant thyroid peroxidase antibody-positive women living in an area with mild to moderate iodine deficiency:Is iodine supplementation safe? J Clin Endocrinol Metab 2000;85:3191-8.
51. Panesar NS, Li CY and Rogers MS. Reference intervals for thyroid hormones in pregnant Chinese women. Ann Clin Biochem 2001;38:329-32.
52. Nissim M, Giorda G, Ballabio M, D'Alberton A, Bochicchio D, Orefice R et al. Maternal thyroid function in early and late pregnancy. Horm Res 1991;36:196-202.
53. Talbot JA, Lambert A, Anobile CJ, McLoughlin JD, Price A, Weetman AP et al. The nature of human chorionic gonadotropin glycoforms in gestational thyrotoxicosis. Clin Endocrinol 2001;55:33-9.
54. Jordan V, Grebe SK, Cooke RR, Ford HC, Larsen PD, Stone PR et al. Acidic isoforms of chorionic gonadotrophin in European and Samoan women are associated with hyperemesis gravidarum and may |be thyrotrophic. Clin Endocrinol 1999;50:619-27.
55. Goodwin TM, Montoro M, Mestman JH, Pekary AE and Hershman JM. The role of chorionic gonadotropin in transient hyperthyroidism of hyperemesis gravidarum. J Clin Endocrinol Metab1992;75:1333-7.
56. Hershman JM. Human chorionic gonadotropin and the thyroid: hyperemesis gravidarum and trophoblastic tumors. Thyroid 1999;9:653-7.
57. McElduff A. Measurement of free thyroxine (T4) in pregnancy. Aust NZ J Obst Gynecol 1999;39:158-61.
58. Christofides, N., Wilkinson E, Stoddart M, Ray DC and Beckett GJ. Assessment of serum thyroxine binding capacity-dependent biases in free thyroxine assays. Clin Chem 1999;45:520-5.
59. Roti E, Gardini E, Minelli R, Bianconi L, Flisi M,. Thyroid function evaluation by different commercially available free thyroid hormone measurement kits in term pregnant women and their newborns. J Endocrinol Invest 1991;14:1-9.
60. Stockigt JR. Free thyroid hormone measurement: a critical appraisal. Endocrinol Metab Clin N Am2001;30:265-89.
61. Mandel SJ, Larsen PR, Seely EW and Brent GA. Increased need for thyroxine during pregnancy in women with primary hypothyroidism. NEJM 1990;323:91-6.
62. Burrow GN, Fisher DA and Larsen PR. Maternal and fetal thyroid function. N Engl J Med1994;331:1072-8.
63. Pop VJ, De Vries E, Van Baar AL, Waelkens JJ, De Rooy HA, Horsten M et al. Maternal thyroid peroxidase antibodies during pregnancy: a marker of impaired child development? J Clin Endocrinol Metab 1995;80:3561-6.
64. Haddow JE, Palomaki GE, Allan WC, K. G. Williams JR, Gagnon J, O'Heir CE et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. NEJM1999;341:549-55.
65. Pop VJ, Kuijpens JL, van Baar AL, Verkerk G, van Son MM, de Vijlder JJ et al. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol 1999;50:147-8.
66. Radetti G, Gentili L, Paganini C, Oberhofer R, Deluggi I and Delucca A. Psychomotor and audiological assessment of infants born to mothers with subclinical thyroid dysfunction in early pregnancy. Minerva Pediatr 2000;52:691-8.
67. Surks MI and Sievert R. Drugs and thyroid function. NEJM 1995;333:1688-94.
68. Kailajarvi M, Takala T, Gronroos P, Tryding N, Viikari J, Irjala K et al. Reminders of drug effects on laboratory test results. Clin Chem 2000;46:1395-1400.
69. Brabant A, Brabant G, Schuermeyer T, Ranft U, Schmidt FW, Hesch RD et al. The role of glucocorticoids in the regulation of thyrotropin. Acta Endocrinol 1989;121:95-100.
70. Samuels MH and McDaniel PA. Thyrotropin levels during hydrocortisone infusions that mimic fasting-induced cortisol elevations: a clinical research center study. J Clin Endocrinol Metab1997;82:3700-4.
71. Kaptein EM, Spencer CA, Kamiel MB and Nicoloff JT. Prolonged dopamine administration and thyroid hormone economy in normal and critically ill subjects. J Clin Endocrinol Metab 1980;51:387-93.
72. Geffner DL and Hershman JM. Beta-adrenergic blockade for the treatment of hyperthyroidism. Am J Med 1992;93:61-8.
73. Meurisse M, Gollogly MM, Degauque C, Fumal I, Defechereux T and Hamoir E. Iatrogenic thyrotoxicosis: causal circumstances, pathophysiology and principles of treatment- reviw of the literature. World J Surg 2000;24:1377-85.
74. Martino E, Aghini-Lombardi F, Mariotti S, Bartelena L, Braverman LE and Pinchera A. Amiodarone:a common source of iodine-induced thyrotoxicosis. Horm Res 1987;26:158-71.
75. Martino E, Bartalena L, Bogazzi F and Braverman LE. The effects of amiodarone on the Thyroid. Endoc Rev 2001;22:240-54.
76. Daniels GH. Amiodarone-induced thyrotoxicosis. J Clin Endocrinol Metab 2001;86:3-8.
77. Harjai KJ and Licata AA. Effects of amiodarone on thyroid function. Ann Intern Med 1997;126:63-73.
78. Caron P. Effect of amiodarone on thyroid function. Press Med 1995;24:1747-51.
79. Bartalena L, Grasso L, Brogioni S, Aghini-Lombardi F, Braverman LE and Martino E. Serum interleukin-6 in amiodarone-induced thyrotoxicosis. J Clin Endocrinol Metab 1994;78:423-7.
80. Eaton SE, Euinton HA, Newman CM, Weetman AP and Bennet WM. Clinical experience of amiodarone-induced thyrotoxicosis over a 3-year period: role of colour-flow Doppler sonography. Clin Endocrinol 2002;56:33-8.
81. Lazarus JH. The effects of lithium therapy on thyroid and thyrotropin-releasing hormone. Thyroid1998;8:909-13.
82. Kusalic M and Engelsmann F. Effect of lithium maintenance therapy on thyroid and parathyroid function. J Psych Neurosci 1999;24:227-33.
83. Oakley PW, Dawson AH and Whyte IM. Lithium: thyroid effects and altered renal handling. Clin Toxicol 2000;38:333-7.
84. Mendel CM, Frost PH, Kunitake ST and Cavalieri RR. Mechanism of the heparin-induced increase in the concentration of free thyroxine in plasma. J Clin Endocrinol Metab 1987;65:1259-64.
85. Iitaka M, Kawasaki S, Sakurai S, Hara Y, Kuriyama R, Yamanaka K et al. Serum substances that interfere with thyroid hormone assays in patients with chronic renal failure. Clin Endocrinol1998;48:739-46.
86. Bowie LJ, Kirkpatrick PB and Dohnal JC. Thyroid function testing with the TDx: Interference from endogenous fluorophore. Clin Chem 1987;33:1467.
87. DeGroot LJ and Mayor G. Admission screening by thyroid function tests in an acute general care teaching hospital. Amer J Med 1992;93:558-64.
88. Kaptein EM. Thyroid hormone metabolism and thyroid diseases in chronic renal failure. Endocrinol Rev 1996;17:45-63.
89. Van den Berghe G, De Zegher F and Bouillon R. Acute and prolonged critical illness as different neuroendocrine paradigms. J Clin Endocrinol Metab 1998;83:1827-34.
90. Van den Berhe G. Novel insights into the neuroendocrinology of critical illness. Eur J Endocrinol2000;143:1-13.
91. Wartofsky L and Burman KD. Alterations in thyroid function in patients with systemic illness: the "euthyroid sick syndrome". Endocrinol Rev 1982;3:164-217.
92. Spencer CA, Eigen A, Duda M, Shen D, Qualls S, Weiss S et al. Sensitive TSH tests - specificity limitations for screening for thyroid disease in hospitalized patients. Clin Chem 1987;33:1391-1396.
93. Stockigt JR. Guidelines for diagnosis and monitoring of thyroid disease: nonthyroidal illness. Clin Chem 1996;42:188-92.
94. Nelson JC and Weiss RM. The effects of serum dilution on free thyroxine (T4) concentration in the low T4 syndrome of nonthyroidal illness. J Clin Endocrinol Metab 1985;61:239-46.
95. Chopra IJ, Huang TS, Beredo A, Solomon DH, Chua Teco GN. Serum thyroid hormone binding inhibitor in non thyroidal illnesses. Metabolism 1986;35:152-9.
96. Wang R, Nelson JC and Wilcox RB. Salsalate administration - a potential pharmacological model of the sick euthyroid syndrome. J Clin Endocrinol Metab 1998;83:3095-9.
97. Sapin R, Schliener JL, Kaltenbach G, Gasser F, Christofides N, Roul G et al. Determination of free triiodothyronine by six different methods in patients with non-thyroidal illness and in patients treated with amiodarone. Ann Clin Biochem 1995;32:314-24.
98. Docter R, van Toor H, Krenning EP, de Jong M and Hennemann G. Free thyroxine assessed with three assays in sera of patients with nonthyroidal illness and of subjects with abnormal concentrations of thyroxine-binding proteins. Clin Chem 1993;39:1668-74.
99. Wilcox RB, Nelson JC and Tomei RT. Heterogeneity in affinities of serum proteins for thyroxine among patients with non-thyroidal illness as indicated by the serum free thyroxine response to serum dilution. Eur J Endocrinol 1994;131:9-13.
100. Liewendahl K, Tikanoja S, Mahonen H, Helenius T, Valimaki M and Tallgren LG. Concentrations of iodothyronines in serum of patients with chronic renal failure and other nonthyroidal illnesses: role of free fatty acids. Clin Chem 1987;33:1382-6.
101. Sapin R, Schlienger JL,Gasser F, Noel E, Lioure B, Grunenberger F. Intermethod discordant free thyroxine measurements in bone marrow-transplanted patients. Clin Chem 2000;46:418-22.
102. Chopra IJ. Simultaneous measurement of free thyroxine and free 3,5,3'-triiodothyronine in undiluted serum by direct equilibriium dialysis/radioimmunoassay: evidence that free triiodothyronine and free thyroxine are normal in many patients with the low triiodothyronine syndrome. Thyroid 1998;8:249-57.
103. Hamblin PS, Dyer SA, Mohr VS, Le Grand BA, Lim C-F, Tuxen DB, Topliss DJ and Stockigt JR. Relationship between thyrotropin and thyroxine changes during recovery from severe hypothyroxinemia of critical illness. J Clin Endocrinol Metab 1986;62:717-22.
104. Brent GA and Hershman JM. Thyroxine therapy in patients with severe nonthyroidal illnesses and low serum thyroxine concentrations. J Clin Endocrinol Metab 1986;63:1-8.
105. De Groot LJ. Dangerous dogmas in medicine: the nonthyroidal illness syndrome. J Clin Endocrinol Metab 1999;84:151-64.
106. Burman KD and Wartofsky L. Thyroid function in the intensive care unit setting. Crit Care Clin2001;17:43-57.
107. Behrend EN, Kemppainen RJ and Young DW. Effect of storage conditions on cortisol, total thyroxine and free thyroxine concentrations in serum and plasma of dogs. J Am Vet Med Assoc 1998;212:1564-8.
108. Oddie TH, Klein AH, Foley TP and Fisher DA. Variation in values for iodothyronine hormones,thyrotropin and thyroxine binding globulin in normal umbilical-cord serum with season and duration of storage. Clin Chem 1979;25:1251-3.
109. Koliakos G, Gaitatzi M and Grammaticos P. Stability of serum TSH concentratin after non refriferated storage. Minerva Endocrinol 1999;24:113-5.
110. Waite KV, Maberly GF and Eastman CJ. Storage conditions and stability of thyrotropin and thyroid hormones on filter paper. Clin Chem 1987;33:853-5.
111. Levinson SS. The nature of heterophilic antibodies and their role in immunoassay interference. J Clin Immunoassay 1992;15:108-15.
112. Norden AGM, Jackson RA, Norden LE, Griffin AJ, Barnes MA and Little JA. Misleading results for immunoassays of serum free thyroxine in the presence of rheumatoid factor. Clin Chem 1997;43:957-62.
113. Covinsky M, Laterza O, Pfeifer JD, Farkas-Szallasi T and Scott MG. Lambda antibody to Esherichia coli produces false-positive results in multiple immunometric assays. Clin Chem 2000;46:1157-61.
114. Martel J, Despres N, Ahnadi CE, Lachance JF, Monticello JE, Fink G, Ardemagni A, Banfi G, Tovey J, Dykes P, John R, Jeffery J and Grant AM. Comparative multicentre study of a panel of thyroid tests using different automated immunoassay platforms and specimens at high risk of antibody interference. Clin Chem Lab Med 2000;38:785-93.
115. Howanitz PJ, Howanitz JH, Lamberson HV and Ennis KM. Incidence and mechanism of spurious increases in serum Thyrotropin. Clin Chem 1982;28:427-31.
116. Boscato, L. M. and M. C. Stuart. Heterophilic antibodies: a problem for all immunoassays. Clin Chem1988;34:27-33.
117. Kricka LJ. Human anti-animal antibody interference in immunological assays. Clin Chem1999;45:942-56.
118. Sapin R and Simon C. False hyperprolactinemia corrected by the use of heterophilic antibody-blocking agent. Clin Chem 2001;47:2184-5.
119. Feldt-Rasmussen U, Petersen PH, Blaabjerg O and Horder M. Long-term variability in serum thyroglobulin and thyroid related hormones in healthy subjects. Acta Endocrinol (Copenh)1980;95:328-34.
120. Browning MCK, Ford RP, Callaghan SJ and Fraser CG. Intra-and interindividual biological variation of five analytes used in assessing thyroid function: implications for necessary standards of performance and the interpretation of results. Clin Chem 1986;32:962-6.
121. Lum SM and Nicoloff JT. Peripheral tissue mechanism for maintenance of serum triiodothyronine values in a thyroxine-deficient state in man. J Clin Invest 1984;73:570-5.
122. Spencer CA and Wang CC. Thyroglobulin measurement:- Techniques, clinical benefits and pitfalls. Endocrinol Metab Clin N Amer 1995;24:841-63.
123. Weeke J and Gundersen HJ. Circadian and 30 minute variations in serum TSH and thyroid hormones in normal subjects. Acta Endocrinol 1978;89:659-72.
124. Brabant G, Prank K, Hoang-Vu C and von zur Muhlen A. Hypothalamic regulation of pulsatile thyrotropin secretion. J Clin Endocrinol Metab 1991;72:145-50.
125. Fraser CG, Petersen PH, Ricos C and Haeckel R. Proposed quality specifications for the imprecision and inaccuracy of analytical systems for clinical chemistry. Eur J Clin Chem Biochem 1992;30:311-7.
126. Rodbard, D. Statistical estimation of the minimal detectable concentration ("sensitivity") for radioligand assays. Anal Biochem 1978;90:1-12.
127. Ekins R and Edwards P. On the meaning of "sensitivity". Clin Chem 1997;43:1824-31.
128. Fuentes-Arderiu X and Fraser CG. Analytical goals for interference. Ann Clin Biochem 1991;28:393-5.
129. Petersen PH, Fraser CG, Westgard JO and Larsen ML. Analytical goal-setting for monitoring patients when two analytical methods are used. Clin Chem 1992;38:2256-60.
130. Fraser CG and Petersen PH. Desirable standards for laboratory tests if they are to fulfill medical needs. Clin Chem 1993;39:1453-5.
131. Stockl D, Baadenhuijsen H, Fraser CG, Libeer JC, Petersen PH and Ricos C. Desirable routine analytical goals for quantities assayed in serum. Discussion paper from the members of the external quality assessment (EQA) Working Group A on analytical goals in laboratory medicine. Eur J Clin Chem Clin Biochem 1995;33:157-69.
132. Plebani M, Giacomini A, Beghi L, de Paoli M, Roveroni G, Galeotti F, Corsini A and Fraser CG. Serum tumor markers in monitoring patients: interpretation of results using analytical and biological variation. Anticancer Res 1996;16:2249-52.
133. Browning MC, Bennet WM, Kirkaldy AJ and Jung RT. Intra-individual variation of thyroxin,triiodothyronine and thyrotropin in treated hypothyroid patients: implications for monitoring replacement therapy. Clin Chem 1988;34:696-9.
134. Harris EK. Statistical principles underlying analytic goal-setting in clinical chemistry. Am J Clin Pathol 1979;72:374-82.
135. Nelson JC and Wilcox RB. Analytical performance of free and total thyroxine assays. Clin Chem1996;42:146-54.
136. Evans SE, Burr WA and Hogan TC. A reassessment of 8-anilino-1-napthalene sulphonic acid as a thyroxine binding inhibitor in the radioimmunoassay of thyroxine. Ann Clin Biochem 1977;14:330-4.
137. Karapitta CD, Sotiroudis TG, Papadimitriou A and Xenakis A. Homogeneous enzyme immunoassay for triiodothyronine in serum. Clin Chem 2001;47:569-74.
138. De Brabandere VI, Hou P, Stockl D, Theinpont LM and De Leenheer AP. Isotope dilution-liquid chromatography/electrospray ionization-tandem mass spectrometry for the determination of serum thyroxine as a potential reference method. Rapid Commun Mass Spectrom 1998;12:1099-103.
139. Tai SSC, Sniegoski LT and Welch MJ. Candidate reference method for total thyroxine in human serum: Use of isotope-dilution liquid chromatography-mass spectrometry with electrospray ionization. Clin Chem 2002;48:637-42.
140. Thienpont LM, Fierens C, De Leenheer AP and Przywara L. Isotope dilution-gas chromatography/mass spectrometry and liquid chromatography/electro-spray ionization-tandem mass spectrometry for the determination of triiodo-L-thyronine in serum. Rapid Commun Mass Spectrom1999;13:1924-31.
141. Sarne DH, Refetoff S, Nelson JC and Linarelli LG. A new inherited abnormality of thyroxine-binding globulin (TBG-San Diego) with decreased affinity for thyroxine and triiodothyronine. J Clin Endocrinol Metab 1989;68:114-9.
142. Schussler GC. The thyroxine-binding proteins. Thyroid 2000;10:141-9.
143. Beck-Peccoz P, Romelli PB, Cattaneo MG, Faglia G, White EL, Barlow JW et al. Evaluation of free T4 methods in the presence of iodothyronine autoantibodies. J Clin Endocrinol Metab 1984;58:736-9.
144. Sakata S, Nakamura S and Miura K. Autoantibodies against thyroid hormones or iodothyronine. Ann Intern Med 1985;103:579-89.
145. Despres N and Grant AM. Antibody interference in thyroid assays: a potential for clinical misinformation. Clin Chem 1998;44:440-54.
146. Hay ID, Bayer MF, Kaplan MM, Klee GG, Larsen PR and Spencer CA. American Thyroid Association Assessment of Current Free Thyroid Hormone and Thyrotropin Measurements and Guidelines for Future Clinical Assays. Clin Chem 1991;37:2002 - 2008.
147. Ekins R. The science of free hormone measurement. Proc UK NEQAS Meeting 1998;3:35-59.
148. Wang R, Nelson JC, Weiss RM and Wilcox RB. Accuracy of free thyroxine measurements across natural ranges of thyroxine binding to serum proteins. Thyroid 2000;10:31-9.
149. Nelson JC, Wilcox BR and Pandian MR. Dependence of free thyroxine estimates obtained with equilibrium tracer dialysis on the concentration of thyroxine-binding globulin. Clin Chem1992;38:1294-1300.
150. Ekins R. The free hormone hypothesis and measurement of free hormones. Clin Chem 1992;38:1289-93.
151. Ekins RP. Ligand assays: from electrophoresis to miniaturized microarrays. Clin Chem 1998;44:2015-30.
152. Ekins R. Analytic measurements of free thyroxine. Clin Lab Med 1993;13:599-630.
153. Nusynowitz, M. L. Free-thyroxine index. JAMA 1975;232:1050.
154. Larsen PR, Alexander NM, Chopra IJ, Hay ID, Hershman JM, Kaplan MM et al. Revised nomenclature for tests of thyroid hormones and thyroid-related proteins in serum. J Clin Endocrinol Metab 1987;64:1089-94.
155. Burr WA, Evans SE, Lee J, Prince HP, Ramsden DB. The ratio of thyroxine to thyroxine-binding globulin measurement in the evaluation of thyroid function. Clin Endocrinol 1979;11:333-42.
156. Attwood EC and Atkin GE. The T4: TBG ratio: a re-evaluation with particular reference to low and high serum TBG levels. Ann Clin Biochem 1982;19:101-3.
157. Szpunar WE, Stoffer SS and DiGiulio W. Clinical evaluation of a thyroxine binding globulin assay in calculationg a free thyroxine index in normal, thyroid disease and sick euthyroid patients. J Nucl Med1987;28:1341-3.
158. Nelson JC and Tomei RT. Dependence of the thyroxin/thyroxin-binding globulin (TBG) ratio and the free thyroxin index on TBG concentrations. Clin Chem 1989;35:541-4.
159. Sterling K and Brenner MA. Free thyroxine in human serum: Simplified measurement with the aid of magnesium precipitation. J Clin Invest 1966;45:153-60.
160. Schulssler GC and Plager JE. Effect of preliminary purification of 131-Thyroxine on the determination of free thyroxine in serum. J Clin Endocrinol 1967;27:242-50.
161. Nelson JC and Tomei RT. A direct equilibrium dialysis/radioimmunoassay method for the measurement of free thyroxin in undiluted serum. Clin Chem 1988;34:1737-44.
162. Tikanoja SH. Ultrafiltration devices tested for use in a free thyroxine assay validated by comparison with equilibrium dialysis. Scand J Clin Lab Invest 1990;50:663-9.
163. Ellis SM and Ekins R. Direct measurement by radioimmunoassay of the free thyroid hormone concentrations in serum. Acta Endocrinol (Suppl) 1973;177:106-110.
164. Weeke J and Orskov H. Ultrasensitive radioimmunoassay for direct determination of free triiodothyronine concentration in serum. Scand J Clin Lab Invest 1975;35:237-44.
165. Surks MI, Hupart KH, Chao P and Shapiro LE. Normal free thyroxine in critical nonthyroidal illnessess measured by ultrafiltration of undiluted serum and equilibrium dialysis. J Clin Endocrinol Metab 1988;67:1031-9.
166. Holm SS andreasen L, Hansen SH, Faber J and Staun-Olsen P. Influence of adsorption and deproteination on potential free thyroxine reference methods. Clin Chem 2002;48:108-114.
167. Jaume JC, Mendel CM, Frost PH,Greenspan FS, Laughton CW. Extremely low doses of heparin release lipase activity into the plasma and can thereby cause artifactual elevations in the serum-free thyroxine concentrations as measured by equilibrium dialysis. Thyroid 1996;6:79-83.
168. Stevenson HP, Archbold GP, Johnston P, Young IS, Sheridan B. Misleading serum free thyroxine results during low molecular weight heparin treatment. Clin Chem 1998;44:1002-7.
169. Laji K, Rhidha B, John R, Lazarus J and Davies JS. Artifactual elevations in serum free thyroxine and triiodothyronine concentrations during heparin therapy. QJM 2001;94:471-3.
170. Lim CF, Bai Y, Topliss DJ, Barlow JW and Stockigt JR. Drug and fatty acid effects on serum thyroid hormone binding. J Clin Endocrinol Metab 1988;67:682-8.
171. Czako, G., M. H. Zweig, C. Benson and M. Ruddel. On the albumin-dependence of measurements of free thyroxin. II Patients with non-thyroidal illness. Clin Chem 1987;33:87-92.
172. Csako G, Zwieg MH, Glickman J, Ruddel M and K. J. Direct and indirect techniques for free thyroxin compared in patients with nonthyroidal illness. II. Effect of prealbumin, albumin and thyroxin-binding globulin. Clin Chem 1989;35:1655-62.
173. Csako G, Zweig MH, Glickman J, Kestner J and Ruddel M. Direct and indirect techniques for free thyroxin compared in patients with nonthyroidal illness. I. Effect of free fatty acids. Clin Chem1989;35:102-9.
174. Ross HA and Benraad TJ. Is free thyroxine accurately measurable at room temperature? Clin Chem1992;38:880-6.
175. Van der Sluijs Veer G, Vermes I, Bonte HA and Hoorn RKJ. Temperature effects on Free Thyroxine Measurement: Analytical and Clinical Consequences. Clin Chem 1992;38:1327-31.
176. Fisher DA. The hypothyroxinemia of prematurity. J Clin Endocrinol Metab 1997;82:1701-3.
177. Stockigt JR, Stevens V, White EL and Barlow JW. Unbound analog radioimmunoassays for free thyroxin measure the albumin-bound hormone fraction. Clin Chem 1983;29:1408-10.
178. Aravelo G. Prevalence of familial dysalbuminemic hyperthyroxinemia in serum samples received for thyroid testing. Clin Chem 1991;37:1430-1.
179. Sapin R and Gasser F. Anti-solid phase antibodies interfering in labeled-antibody assays for free thyroid hormones. Clin Chem 1995;45:1790-1.
180. Inada M and Sterling K. Thyroxine transport in thyrotoxicosis and hypothyroidism. J Clin Invest1967;46:1442-50.
181. Lueprasitsakul W, Alex S, Fang SL, Pino S, Irmscher K, Kohrle J et al. Flavonoid administration immediately displaces thyroxine (T4) from serum transthyretin, increases serum free T4 and decreases serum thyrotropin in the rat. Endocrinol 1990;126:2890-5.
182. Stockigt JR, Lim CF, Barlow J, Stevens V, Topliss DJ, Wynne KN. High concentrations of furosemide inhibit plasma binding of thyroxine. J Clin Endocrinol Metab 1984;59:62-6.
183. Hawkins RC. Furosemide interference in newer free thyroxine assays. Clin Chem 1998;44:2550-1.
184. Wang R, Nelson JC and Wilcox RB. Salsalate and salicylate binding to and their displacement of thyroxine from thyroxine-binding globulin, transthyrin and albumin. Thyroid 1999;9:359-64.
185. Munro SL, Lim C-F, Hall JG, Barlow JW, Craik DJ, Topliss DJ and Stockigt JR. Drug competition for thyroxine binding to transthyretin (prealbumin): comparison with effects on thyroxine-binding globulin. J Clin Endocrinol Metab 1989;68:1141-7.
186. Stockigt JR, Lim C-F, Barlow JW and Topliss DJ. 1997. Thyroid hormone transport. Springer Verlag,Heidelberg. 119 pp.
187. Surks MI and Defesi CR. Normal free thyroxine concentrations in patients treated with phenytoin or carbamazepine: a paradox resolved. JAMA 1996;275:1495-8.
188. Ross HA. A dialysis method for the measurement of free iodothyronine and steroid hormones in blood. Experientia 1978;34:538-9.
189. Sapin R. Serum thyroxine binding capacity-dependent bias in five free thyroxine immunoassays:assessment with serum dilution experiments and impact on diagnostic performance. Clin Biochem2001;34:367-71.
190. Law LK, Cheung CK and Swaminathan R. Falsely high thyroxine results by fluorescence polarization in sera with high background fluorescence. Clin Chem 1988;34:1918.
191. Kricka LJ. Interferences in Immunoassay - still a threat. Clin Chem 2000;46:1037-8.
192. McBride JH, Rodgerson DO and Allin RE. Choriogonadotrophin interference in a sensitive assay for Thyrotropin. Clin Chem 1987;33:1303-4.
193. Ritter D, Stott R, Grant N and Nahm MH. Endogenous antibodies that interfere with Thyroxine fluorescence polarization assay but not with radioimmunoassay or EMIT. Clin Chem 1993;39:508-11.
194. DeGroot LJ, Larsen PR, Refetoff S and Stanbury JB. The Thyroid and its Diseases. Fifth Edition,1984;John Wiley & Sons, Inc., New York:266-7.
195. Beck-Peccoz P, Amr S, Menezes-Ferreira NM, Faglia G and Weintraub BD. Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism: effect of treatment with thyrotropin-releasing hormone. N Engl J Med 1985;312:1085-90.
196. Beck-Peccoz P and Persani L. Variable biological activity of thyroid-stimulating hormone. Eur J Endocrinol 1994;131:331-40.
197. Persani L, Ferretti E, Borgato S, Faglia G and Beck-Peccoz P. Circulating thyrotropin bioactivity in sporadic central hypothyroidism. J Clin Endocrinol Metab 2000;85:3631-5.
198. Rafferty B and Gaines Das R. Comparison of pituitary and recombinant humaN thyroid-stimulating hormone (rhTSH) in a multicenter collaborative study: establishment of the first World Health Organization reference reagent for rhTSH. Clin Chem 1999;45:2207-15.
199. Persani L, Borgato S, Romoli R, Asteria C, Pizzocaro A and Beck-Peccoz P. Changes in the degree of sialylation of carbohydrate chains modify the biological properties of circulating thyrotropin isoforms in various physiological and pathological states. J Clin Endocrinol Metab 1998;83:2486-92.
200. Gershengorn MC and Weintraub BD. Thyrotropin-induced hyperthyroidism caused by selective pituitary resistance to thyroid hormone. A new syndrome of "inappropriate secretion of TSH". J Clin Invest 1975;56:633-42.

201. Faglia G, Beck-Peccoz P, Piscitelli G and Medri G. Inappropriate secretion of thyrotropin by the pituitary. Horm Res 1987;26:79-99.
202. Spencer CA, Takeuchi M and Kazarosyan M. Current status and performance goals for serum thyrotropin (TSH) assays. Clinical Chemistry 1996;42:141-145.
203. Laurberg P. Persistent problems with the specificity of immunometric TSH assays. Thyroid1993;3:279-83.
204. Spencer CA, Schwarzbein D, Guttler RB, LoPresti JS and Nicoloff JT. TRH stimulation test responses employing third and fourth generation TSH assays. J Clin Endocrinol Metab 1993;76:494-498.
205. Vogeser M, Weigand M, Fraunberger P, Fischer H and Cremer P. Evaluation of the ADVIA Centaur TSH-3 assay. Clin Chem Lab Med 2000;38:331-4.
206. Spencer CA, Takeuchi M, Kazarosyn M, MacKenzie F, Beckett GJ and Wilkinson E. Interlaboratory/intermethod differences in functional sensitivity of immunometric assays for hyrotropin (TSH): impact on reliability of measurement of subnormal concentration. Clin Chem1995;41:367-74.
207. Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark F, Evans JG, Young E, Bird T and Smith PA. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol1977;7:481-93.
208. Rago T, Chiovato L, Grasso L, Pinchera A and Vitti P. Thyroid ultrasonography as a tool for detecting thyroid autoimmune diseases and predicting thyroid dysfunction in apparently healthy subjects. J Endocrinol Invest 2001;24:763-9.
209. Hershman JM and Pittman JA. Utility of the radioimmunoassay of serum thyrotropin in man. Ann Intern Med 1971;74:481-90.
210. Becker DV, Bigos ST, Gaitan E, Morris JC, Rallison ML, Spencer CA, Sugawara M, Middlesworth LV and Wartofsky L. Optimal use of blood tests for assessment of thyroid function. JAMA1993;269:2736.
211. Canaris GJ, Manowitz NR, Mayor G and Ridgway EC. The Colorado Thyroid Disease Prevalence Study. Arch Intern Med 2000;160:19-27.
212. Skamene A and Patel YC. Infusion of graded concentrations of somatostatin in man: pharmacokinetic and differential inhibitory effects on pituitary and islet hormones. Clin Endocrinol 1984;20:555-64.
213. Berghout A, Wiersinga WM, Smits NJ and Touber JL. Interrelationships between age, thyroid volume,thyroid nodularity and thyroid function in patients with sporadic nontoxic goiter. Am J Med1990;89:602-8.
214. Parle JV, Franklyn JA, Cross KW, Jones SC and Sheppard MC. Prevalence and follow-up of abnormal thyrotropin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol 1991;34:77-83.
215. Danese D, Sciacchitano S, Farsetti A andreoli M and Pontecorvi A. Diagnostic accuracy of conventional versus sonography-guided fine-needle aspiration biopsy of thyroid nodules. Thyroid1998;8:15-21.
216. McDermott MT and Ridgway EC. Subclinical hypothyroidism is mild thyroid failure and should be treated. J Clin Endocrinol Metab 2001;86:4585-90.
217. Chu JW and Crapo LM. The treatment of subclinical hypothyroidism is seldom necessary. J Clin Endocrinol Metab 2001;86:4591-9.
218. Lewis GF, Alessi CA, Imperial JG and Refetoff S. Low serum free thyroxine index in ambulating elderly is due to a resetting of the threshold of thyrotropin feedback suppression. JCEM 1991;73:843-9.
219. Pearce CJ and Himsworth RL. Total and free thyroid hormone concentrations in patients receiving maintenance replacement treatment with thyroxine. Br Med J 1984;288:693-5.
220. Fish LH, Schwarz HL, Cavanaugh MD, Steffes MW, Bantle JP, Oppenheimer JH. Replacement dose,metabolism and bioavailability of levothyroxine in the treatment of hypothyroidism. N Engl J Med1987;316:764-70.
221. Sawin CT, Herman T, Molitch ME, London MH and Kramer SM. Aging and the thyroid. Decreased requirement for thyroid hormone in older hypothyroid patients. Amer J Med 1983;75:206-9.
222. Davis FB, LaMantia RS, Spaulding SW, Wemann RE and Davis PJ. Estimation of a physiologic replacement dose of levothyroxine in elderly patients with hypothyroidism. Arch Intern Med 1984;144.
223. Arafah BM. Estrogen therapy may necessitate an increase in thyroxine dose for hypothyroidism. NEJM 2001;344:1743-9.
224. Scheithauer BW, Kovacs K, Randall RV and Ryan N. Pituitary gland in hypothyroidism. Histologic and immunocytologic study. Arch Pathol Lab Med 1985;109:499-504.
225. Ain KB, Pucino F, Shiver T and Banks SM. Thyroid hormone levels affected by time of blood sampling in thyroxine-treated patients. Thyroid 1993;3:81-5.
226. Chorazy PA, Himelhoch S, Hopwood NJ, Greger NG and Postellon DC. Persistent hypothyroidism in an infant receiving a soy formula: case report and review of the literature. Pediatrics 1995;96:148-50.
227. Dulgeroff AJ and Hershman JM. Medical therapy for differentiated thyroid carcinoma. Endocrinol Rev1994;15:500-15.
228. Pujol P, Daures JP, Nsakala N, Baldet L, Bringer J and Jaffiol C. Degree of thyrotropin suppression as a prognostic determinant in differentiated thyroid cancer. J Clin Endocrinol Metab 1996;81:4318-23.
229. Cooper DS, Specker B, Ho M, Sperling M, Ladenson PW, Ross DS, Ain KB, Bigos ST, Brierley JD,Haugen BR, Klein I, Robbins J, Sherman SI, Taylor T and Maxon HR 3rd. Thyrotropin suppression and disease progression in patients with differentiated thyroid cancer: results from the National thyroid Cancer Treatment Cooperative Registry. Thyroid 1999;8:737-44.
230. Hurley DL and Gharib H. Evaluation and management of multinodular goiter. Otolaryngol Clin North Am 1996;29:527-40.
231. Bayer MF, Macoviak JA and McDougall IR. Diagnostic performance of sensitive measurements of serum thyrotropin during severe nonthyroidal illness: Their role in the diagnosis of hyperthyroidism. Clin Chem 1987;33:2178-84.
232. Lum SM, Kaptein EM and Nicoloff JT. Influence of nonthyroidal illnesses on serum thyroid hormone indices in hyperthyroidism. West J Med 1983;138:670-5.
233. Faglia G, Bitensky L, Pinchera A, Ferrari C, Paracchi A, Beck-Peccoz P, Ambrosi B and Spada A. Thyrotropin secretion in patient with central hypothyroidism: Evidence for reduced biological activity of immunoreactive thyrotropin. J Clin Endocrinol Metab 1979;48:989-98.
234. Faglia G, Beck-Peccoz P, Ballabio M and Nava C. Excess of beta-subunit of thyrotropin (TSH) in patients with idiopathic central hypothyroidism due to the secretion of TSH with reduced biological activity. J Clin Endocrinol Metab 1983;56:908-14.
235. Faglia G. The clinical impact of the thyrotropin-releasing hormone test. Thyroid 1998;8:903-8.
236. Trejbal D, Sulla I, Trejbalova L, Lazurova I, Schwartz P and Machanova Y. Central hypothyroidism -various types of TSH responses to TRH stimulation. Endocr Regul 1994;28:35-40.
237. Faglia G, Ferrari C, Paracchi A, Spada A and Beck-Peccoz P. Triiodothyronine response to thyrotropin releasing hormone in patients with hypothalamic-pituitary disorders. Clin Endocrinol 1975;4:585-90.
238. Horimoto M, Nishikawa M, Ishihara T, Yoshikawa N, Yoshimura M and Inada M. Bioactivity of thyrotropin (TSH) in patients with central hypothyroidism: comparison between in vivo 3,5,3'-triiodothyronine response to TSH and in vitro bioactivity of TSH. J Clin Endocrinol Metab1995;80:1124-8.
239. Refetoff S, Weiss RE and Usala SJ. The syndromes of resistance to thyroid hormone. Endocr Rev1993;14:348-99.
240. Weiss RE, Hayashi Y, Nagaya T, Petty KJ, Murata Y, Tunca H, Seo H and Refetoff S. Dominant inheritance of resistance to thyroid hormone not linked to defects in the thyroid hormone receptors alpha or beta genes may be due to a defective co-factor. J Clin Endocrinol Metab 1996;81:4196-203.
241. Snyder D, Sesser D, Skeels M et al. Thyroid disorders in newborn infants with elevated screening T4. Thyroid 1997;7 (Suppl 1):S1-29 (abst).
242. Refetoff S. 2000. Resistance to Thyroid Hormone. In The Thyroid. Braverman LE and Utiger RD,editor. Lippincott Williams & Wilkins, Philadelphia. 1028-43.
243. Beck-Peccoz P and Chatterjee VKK. The variable clinical phenotype in thyroid hormone resistance syndrome. Thyroid 1994;4:225-32.
244. Persani L, Asteria C, Tonacchera M, Vitti P, Krishna V, Chatterjee K and Beck-Peccoz P. Evidence for the secretion of thyrotropin with enhanced bioactivity in syndromes of thyroid hormone resistance. J Clin Endocrinol Metab 1994;78:1034-9.
245. Sarne DH, Sobieszczyk S, Ain KB and Refetoff S. Serum thyrotropin and prolactin in the syndrome of generalized resistance to thyroid hormone: responses to thyrotrophin-releasing hormone stimulation and triiodothyronine suppression. J Clin Endocrinol Metab 1990;70:1305-11.
246. Ercan-Fang S, Schwartz HL, Mariash CN and Oppenheimer JH. Quantitative assessment of pituitary resistance to thyroid hormone from plots of the logarithm of thyrotropin versus serum free thyroxine index. J Clin Endocrinol Metab 2000;85:2299-303.
247. Safer JD, Colan SD, Fraser LM and Wondisford FE. A pituitary tumor in a patient with thyroid hormone resistance: a diagnostic dilemma. Thyroid 2001;11:281-91.
248. Marcocci C and Chiovato L. 2000. Thyroid -directed antibodies. In Thyroid. B. L. a. U. RD, editor. Lippincott Williams and Wilkins, Philadelphia. 414-31.
249. Chiovato L, Bassi P, Santini F, Mammoli C, Lapi P, Carayon P and Pinchera A. Antibodies producing complement-mediated thyroid cytotoxicity in patients with atrophic or goitrous autoimmune thyroiditis. J Clin Endocrinol Metab 1993;77:1700-5.
250. Guo J, Jaume JC, Rapoport B and McLachlan SM. Recombinant thyroid peroxidase-specific Fab converted to immunoglobulin G (IgG)molecules: evidence for thyroid cell damage by IgG1, but not IgG4, autoantibodies. J Clin Endocrinol Metab 1997;82:925-31.
251. Doullay F, Ruf J, Codaccioni JL and Carayon P. Prevalence of autoantibodies to thyroperoxidase in patients with various thyroid and autoimmune diseases. Autoimmunity 1991;9:237-44.
252. Radetti G, Persani L, Moroder , Cortelazzi D, Gentili L, Beck-Peccoz P. Transplacental passage of anti-thyroid autoantibodies in a pregnant woman with auto-immune thyroid disease. Prenatal Diagnosis1999;19:468-71.
253. Heithorn R, Hauffa BP and Reinwein D. Thyroid antibodies in children of mothers with autoimmune thyroid disorders. Eur J Pediatr 1999;158:24-8.
254. Feldt-Rasmussen. Anti-thyroid peroxidase antibodies in thyroid disorders and non thyroid autoimmune diseases. Autoimmunity 1991;9:245-51.
255. Mariotti S, Chiovato L, Franceschi C and Pinchera A. Thyroid autoimmunity and aging. Exp Gerontol1999;33:535-41.
256. Ericsson UB, Christensen SB and Thorell JI. A high prevalence of thyroglobulin autoantibodies in adults with and without thyroid disease as measured with a sensitive solid-phase immunosorbent radioassay. Clin Immunol Immunopathol 1985;37:154-62.
257. Feldt-Rasmussen U, Hoier-Madsen M, Rasmussen NG, Hegedus L and Hornnes P. Anti-thyroid peroxidase antibodies during pregnancy and postpartum. Relation to postpartum thyroiditis. Autoimmunity 1990;6:211-4.
258. Premawardhana LD, Parkes AB, AMMARI F, John R, Darke C, Adams H and Lazarus JH. Postpartum thyroiditis and long-term thyroid status: prognostic influence of Thyroid Peroxidase Antibodies and ultrasound echogenicity. J Clin Endocrinol Metab 2000;85:71-5.
259. Johnston AM and Eagles JM. Lithium-associated clinical hypothyroidism. Prevalence and risk factors. Br. J Psychiatry 1999;175:336-9.
260. Bell TM, Bansal AS, Shorthouse C, Sandford N and Powell EE. Low titre autoantibodies predict autoimmune disease during interferon alpha treatment of chronic hepatitis C. J Gastroenterol Hepatol1999;14:419-22.
261. Ward DL and Bing-You RG. Autoimmune thyroid dysfunction induced by interfereon-alfa treatment for chronic hepatitis C: screening and monitoring recommendations. Endoc Pract 2001;7:52-8.
262. Carella C, Mazziotti G, Morisco F, Manganella G, Rotondi M, Tuccillo C, Sorvillo F, Caporaso N and Amato G. Long-term outcome of interferon-alpha-induced thyroid autoimmunity and prognostic influence of thyroid autoantibody pattern at the end of treatment. J Clin Endocrinol Metab2001;86:1925-9.
263. Feldt-Rasmussen U, Schleusener H and Carayon P. Meta-analysis evaluation of the impact of thyrotropin receptor antibodies on long term remission after medical therapy of Graves' disease. J Clin Endocrinol Metab 1994;78:98-103.
264. Estienne V, Duthoit C, Di Costanzo, Lejeune PJ, Rotondi M, Kornfeld S et al. Multicenter study on TGPO autoantibodies prevalence in various thyroid and non-thyroid diseases: relationships with thyroglobulin and thyroperoxidase autoantibody parameters. Eur J Endocrinol 1999;141:563-9.
265. Czarnocka B, Ruf J, Ferrand M et al. Purification of the human thyroid peroxidase and its identification as the microsomal antigen involved in autoimmune thyroid diseases. FEBS Lett1985;190:147-52.
266. Mariotti S, Caturegli P, Piccolo P, Barbesino G and Pinchera A. Antithyroid peroxidase autoantibodies in thyroid diseases. J Clin Endocrinol Metab 1990;71:661-9.
267. Rubello D, Pozzan GB, Casara D, Girelli ME, Boccato s, Rigon F, Baccichetti C, Piccolo M, Betterle C and Busnardo B. Natural course of subclinical hypothyroidism in Down's syndrome: prospective study results and therapeutic considerations. J Endocrinol Invest 1995;18:35-40.
268. Karlsson B, Gustafsson J, Hedov G, Ivarsson SA and Anneren G. Thyroid dysfunction in Down's syndrome: relation to age and thyroid autoimmunity. Arch Dis Child 1998;79:242-5.
269. Bussen S, Steck T and Dietl J. Increased prevalence of thyroid antibodies in euthyroid women with a history of recurrent in-vitro fertilization failure. Hum Reprod 2000;15:545-8.
270. Phan GQ, Attia P, Steinberg SM, White DE and Rosenberg SA. Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma. J Clin Oncol 2001;19:3477-82.
271. Durelli L, Ferrero B, Oggero A, Verdun E, Ghezzi A, Montanari E and Zaffaroni M. Thyroid function and autoimmunity during interferon-Beta-1b Treatment: a Multicenter Prospective Study. J Clin Endocrinol Metab 2001;86:3525-32.
272. Roti E, Minelli R, Giuberti T, Marchelli C, Schianchi C, Gardini E, Salvi M, Fiaccadori F, Ugolotti G,Neri TM and Braverman LE. Multiple changes in thyroid function in patients with chronic active HCV hepatitis treated with recombinant interferon-alpha. Am J Med 1996;101:482-7.
273. Ruf J, Carayon P and Lissitzky S. Various expression of a unique anti-human thyroglobulin antibody repertoire in normal state and autoimmune disease. Eur J Immunol 1985;15:268-72.
274. Ruf J, Toubert ME, Czarnocka B, Durand-Gorde JM,Ferrand M, Carayon P. Relationship between immunological structure and biochemical properties of human thyroid peroxidase. Endocrinol1989;125:1211-8.
275. Feldt-Rasmussen U and Rasmussen A K. Serum thyroglobulin (Tg)in presence of thyroglobulin autoantibodies (TgAb). Clinical and methodological relevance of the interaction between Tg and TgAb in vivo and in vitro. J Endocrinol Invest 1985;8:571-6.
276. Spencer CA, Wang C, Fatemi S, Guttler RB, Takeuchi M and Kazarosyan M. Serum Thyroglobulin Autoantibodies: Prevalence, influence on serum thyroglobulin measurement and prognostic significance in patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab 1998;83:1121-7.
277. Pacini F, Mariotti S, Formica N and Elisei R. Thyroid autoantibodies in thyroid cancer: Incidence and relationship with tumor outcome. Acta Endocrinol 1988;119:373-80.
278. Rubello D, Casara D, Girelli ME, Piccolo M and Busnardo B. Clinical meaning of circulating antithyroglobulin antibodies in differentiated thyroid cancer: a prospective study. J Nucl Med1992;33:1478-80.
279. Nordyke RA, Gilbert FI, Miyamoto LA and Fleury KA. The superiority of antimicrosomal over antithyroglobulin antibodies for detecting Hashimoto's thyroiditis. Arch Intern Med 1993;153:862-5.
280. Di Cerbo A, Di Paoloa R, Menzaghi C, De Filippis V, Tahara K, Corda D et al. Graves'immunoglobulins activate phospholipase A2 by recognizing specific epitopes on the thyrotropin receptor. J Clin Endocrinol Metab 1999;84:3283-92.
281. Kung AWC, Lau KS and Kohn LD. Epitope mapping of TSH Receptor-blocking antibodies in Graves'disease that appear during pregnancy. J Clin Endocrinol Metab 2001;86:3647-53.
282. Ueta Y, Fukui H, Murakami M, Yamanouchi Y, Yamamoto R, Murao A et al. Development of primary hypothyroidism with the appearance of blocking-type antibody to thyrotropin receptor in Graves'disease in late pregnancy. Thyroid 1999;9:179-82.
283. Gupta MK. Thyrotropin-receptor antibodies in thyroid diseases: advances in detection techniques and clinical application. Clin Chem Acta 2000;293:1-29.
284. Kung AW, Lau KS and Kohn LD. Characterization of thyroid-stimulating blocking antibodies that appeared during transient hypothyroidism after radioactive iodine therapy. Thyroid 2000;10:909-17.
285. Filetti S, Foti D, Costante G and Rapoport B. Recombinant human thyrotropin (TSH) receptor in a radioreceptor assay for the measurement of TSH receptor antibodies. J Clin Endocrinol Metab1991;72:1096-101.
286. Adams DD and Purves HD. Abnormal responses in the assay of thyrotropin. Proc Univ Otago Med Sch 1956;34:11-12.
287. Morgenthaler NG. New assay systems for thyrotropin receptor antibodies. Current Opinion Endocrinol Diabetes 1998;6:251-60.
288. Kamijo K, Nagata A and Sato Y. Clinical significance of a sensitive assay for thyroid-stimulating antibodies in Graves' disease using polyethylene glycol at high concentration and porcine thyroid cells. Endocrinol J 1999;46:397-403.
289. Takasu N, Yamashiro K, Ochi Y, Sato Y, Nagata A, Komiya I et al. TSBAb (TSH-Stimulation Blocking Antibody) and TSAb (Thyroid Stimulating Antibody) in TSBAb-positive patients with hypothyroidism and Graves' patients with hyperthyroidism. Horm Metab Res 2001;33:232-7.
290. Costagliola S, Swillens S, Niccoli P, Dumont JE, Vassart G and Ludgate M. Binding assay for thyrotropin receptor autoantibodies using the recombinant receptor protein. J Clin Endocrinol Metab1992;75:1540-44.
291. Morgenthaler NG, Hodak K, Seissler J, Steinbrenner H, Pampel I, Gupta M et al. Direct binding of thyrotropin receptor autoantibody to in vitro translated thyrotropin receptor: a comparison to radioreceptor assay and thyroid stimulating bioassay. Thyroid 1999;9:466-75.
292. Akamizu T, Inoue D, Kosugi S, Kohn LD and Mori T. Further studies of amino acids (268-304) in thyrotropin (TSH)-lutropin/chorionic gonadotropin (LH/CG) receptor chimeras: Cysteine-301 is important in TSH binding and receptor tertiary structure. Thyroid 1994;4:43-8.
293. Grasso YZ, Kim MR, Faiman C, Kohn LD, Tahara K and Gupta MK. Epitope heterogeneity of thyrotropin-blocking antibodies in Graves' patients as detected with wild-type versus chimeric thyrotropin receptors. Thyroid 1999;9:521-37.
294. Kim WB, Chung HK, Lee HK, Kohn LD, Tahara K and Cho BY. Changes in epitopes for thyroid stimulation antibodies in Graves' disease sera during treatment of hyperthyroidism: Therapeutic implications. J Clin Endocrinol Metab 1997;82:1953-9.
295. Shewring G and Smith BR. An improved radioreceptor assay for TSH receptor. Methods Enzymol1982;17:409-17.
296. Costagliola S, Morganthaler NG, Hoermann R, Badenhoop K, Struck J, Freitag D, Poertl S, Weglohner W, Hollidt JM, Quadbeck B, Dumont JE, Schumm-Draeger PM, Bergmann A, Mann K, Vassart G and Usadel KH. Second generation assay for thyrotropin receptor antibodies has superior diagnostic sensitivity for Graves' disease. J Clin Endocrinol Metab 1999;84:90-7.
297. Schott M, Feldkamp J, Bathan C, Fritzen R, Scherbaum WA and Seissler J. Detecting TSH-Receptor antibodies with the recombinant TBII assay: Technical and Clinical evaluation. 32 2000;:429-35.
298. Feldt-Rasmussen U. Analytical and clinical performance goals for testing autoantibodies to thyroperoxidase, thyroglobulin and thyrotropin receptor. Clin Chem 1996;42:160-3.
299. Giovanella L, Ceriani L and Garancini S. Clinical applications of the 2nd. generation assay for anti-TSH receptor antibodies in Graves' disease. Evaluation in patients with negative 1st. generation test. Clin Chem Lab med 2001;39:25-8.
300. Momotani N, Noh JY, Ishikawa N and Ito K. Effects of propylthiouracil and methimazole on fetal thyroid status in mothers with Graves' hyperthyroidism. J Clin Endocrinol Metab 1997;82:3633-6.
301. Brown RS, Bellisario RL, Botero D, Fournier L, Abrams CA, Cower ML et al. Incidence of transient congenital hypothyroidism due to maternal thyrotropin receptor-blocking antibodies in over one million babies. J Clin Endocrinol Metab 1996;81:1147-51.
302. Gerding MN, van der Meer Jolanda WC, Broenink M, Bakker O, W. WM and Prummel MF. Association of thyrotropin receptor antibodies with the clinical features of Graves' opthalmopathy. Clin Endocrinol 2000;52:267-71.
303. Bartelena L, Marcocci C, Bogazzi F, Manetti L, Tanda ML, Dell'Unto E et al. Relation between therapy for hyperthyroidism and the course of Graves' disease. N Engl J Med 1998;338:73-8.
304. Bech K. Immunological aspects of Graves' disease and importance of thyroid stimulating immunoglobulins. Acta Endocrinol (Copenh) Suppl 1983;103:5-38.
305. Feldt-Rasmussen U. Serum thyroglobulin and thyroglobulin autoantibodies in thyroid diseas et al.lergy1983;38:369-87.
306. Nygaard B, Metcalfe RA, Phipps J, Weetman AP and Hegedus L. Graves' disease and thyroid-associated opthalopathy triggered by 131I treatment of non-toxic goitre. J Endocrinol Invest1999;22:481-5.
307. Ericsson UB, Tegler L, Lennquist S, Christensen SB, Stahl E and Thorell JI. Serum thyroglobulin in differentiated thyroid carcinoma. Acta Chir Scand 1984;150:367-75.
308. Haugen BR, Pacini F, Reiners C, Schlumberger M, Ladenson PW, Sherman SI, Cooper DS, Graham KE, Braverman LE, Skarulis MC, Davies TF, DeGroot LJ, Mazzaferri EL, Daniels GH, Ross DS,Luster M, Samuels MH, Becker DV, Maxon HR, Cavalieri RR, Spencer CA, McEllin K, Weintraub BD and Ridgway EC. A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab 1999;84:3877-85.
309. Spencer CA, LoPresti JS, Fatemi S and Nicoloff JT. Detection of residual and recurrent differentiated thyroid carcinoma by serum Thyroglobulin measurement. Thyroid 1999;9:435-41.
310. Schlumberger M, C. P., Fragu P, Lumbroso J, Parmentier C and Tubiana M. Circulating thyrotropin and thyroid hormones in patients with metastases of differentiated thyroid carcinoma: relationship to serum thyrotropin levels. J Clin Endocrinol Metab 1980;51:513-9.
311. Pacini F, Fugazzola L, Lippi F, Ceccarelli C, Centoni R, Miccoli P, Elisei R and Pinchera A. Detection of thyroglobulin in fine needle aspirates of nonthyroidal neck masses: a clue to the diagnosis of metastatic differentiated thyroid cancer. J Clin Endocrinol Metab 1992;74:1401-4.
312. Spencer CA, Takeuchi M and Kazarosyan M. Current Status and Performance Goals for Serum Thyroglobulin Assays. Clin Chem 1996;42:164-73.
313. Feldt-Rasmussen U and Schlumberger M. European interlaboratory comparison of serum thyroglobulin measurement. J Endocrinol Invest 1988;11:175-81.
314. Feldt-Rasmussen U, Profilis C, Colinet E, Black E, Bornet H, Bourdoux P et al. Human thyroglobulin reference material (CRM 457) 2nd part: Physicochemical characterization and certification. Ann Biol Clin 1996;54:343-348.
315. Schlumberger M J. Papillary and Follicular Thyroid Carcinoma. NEJM 1998;338:297-306.
316. Hjiyiannakis P, Mundy J and Harmer C. Thyroglobulin antibodies in differentiated thyroid cancer. Clin Oncol 1999;11:240-4.
317. Spencer CA. Recoveries cannot be used to authenticate thyroglobulin (Tg) measurements when sera contain Tg autoantibodies. Clin Chem 1996;42:661-3.
318. Massart C and Maugendre D. Importance of the detection method for thyroglobulin antibodies for the validity of thyroglobulin measurements in sera from patients with Graves' disease. Clin Chem2002;48:102-7.
319. Mariotti S, Barbesino G, Caturegli P, Marino M, Manetti L, Pacini F, Centoni R and Pinchera A. Assay of thyroglobulin in serum with thyroglobulin autoantibodies: an unobtainable goal? J Clin Endocrinol Metab 1995;80:468-72.
320. Black EG and Hoffenberg R. Should one measure serum thyroglobulin in the presence of anti-thyroglobulin antibodies? Clin Endocrinol 1983;19:597-601.
321. Schneider AB and Pervos R. Radioimmunoassay of human thyroglobulin: effect of antithyroglobulin autoantibodies. J Clin Endocrinol Metab 1978;47:126-37.
322. Spencer CA, Platler BW and Nicoloff JT. The effect of 125-I thyroglobulin tracer heterogeneity on serum Tg RIA measurement. Clin Chem Acta 1985;153:105-115.
323. Bugalho MJ, Domingues RS, Pinto AC, Garrao A, Catarino AL, Ferreira T, Limbert E and Sobrinho L. Detection of thyroglobulin mRNA transcripts in peripheral blood of individuals with and without thyroid glands: evidence for thyroglobulin expression by blood cells. Eur J Endocrinol 2001;145:409-13.
324. Bellantone R, Lombardi CP, Bossola M, Ferrante A,Princi P, Boscherini M et al. Validity of thyroglobulin mRNA assay in peripheral blood of postoperative thyroid carcinoma patients in predicting tumor recurrence varies according to the histologic type: results of a prospective study. Cancer 2001;92:2273-9.
325. Bojunga J, Roddiger S, Stanisch M, Kusterer K, Kurek R, Renneberg H, Adams S, Lindhorst E, Usadel KH and Schumm-Draeger PM. Molecular detection of thyroglobulin mRNA transcripts in peripheral blood of patients with thyroid disease by RT-PCR. Br J Cancer 2000;82:1650-5.
326. Smith B, Selby P, Southgate J, Pittman K, Bradley C and Blair GE. Detection of melanoma cells in peripheral blood by means of reverse transcriptase and polymerase chain reaction. Lancet1991;338:1227-9.
327. Luppi M, Morselli M, Bandieri E, Federico M, Marasca R, Barozzi P, Ferrari MG, Savarino M,Frassoldati A and Torelli G. Sensitive detection of circulating breast cancer cells by reverse-transcriptase polymerase chain reaction of maspin gene. Ann Oncol 1996;7:619-24.
328. Ghossein RA and Bhattacharya S. Molecular detection and characterisation of circulating tumour cells and micrometastases in solid tumours. Eur J Cancer 2000;36:1681-94.
329. Ditkoff BA, Marvin MR, Yemul S, Shi YJ, Chabot J, Feind C et al. Detection of circulating thyroid cells in peripheral blood. Surgery 1996;120:959-65.
330. Arturi F, Russo D, Giuffrida D et al. Early diagnosis by genetic analysis of differentiated thyroid cancer metastases in small lymph nodes. J Clin Endocrinol Metab 1997;82:1638-41.
331. Ringel MD, Balducci-Silano PL anderson JS, Spencer CA, Silverman J, Sparling YH, Francis GL,Burman KD, Wartofsky L, Ladenson PW, Levine MA and Tuttle RM. Quantitative reverse transcription-polymerase chain reaction of circulating thyroglobulin messenger ribonucleic acid for monitoring patients with thyroid carcinoma. J Clin Endocrinol Metab 1998;84:4037-42.
332. Biscolla RP, Cerutti JM and Maciel RM. Detection of recurrent thyroid cancer by sensitive nested reverse transcription-polymerase chain reaction of thyroglobulin and sodium/iodide symporter messenger ribonucleic acid transcripts in peripheral blood. J Clin Endocrinol Metab 2000;85:3623-7.
333. Takano T, Miyauchi A, Yoshida H, Hasegawa Y, Kuma K and Amino N. Quantitative measurement of thyroglobulin mRNA in peripheral blood of patients after total thyroidectomy. Br J Cancer2001;85:102-6.
334. Chelly J, Concordet JP, Kaplan JC and Kahn A. Illegitimate transcription: transcription of any gene in any cell type. Proc Natl Acad Sci USA 1989;86:2617-21.
335. Premawardhana LDKE, Phillips DW, Prentice LM and Smith BR. Variability of serum thyroglobulin levels is determined by a major gene. Clin Endocrinol 1994;41:725-9.
336. Bertelsen JB and Hegedus L. Cigarette smoking and the thyroid. Thyroid 1994;4:327-31.
337. Knudsen N, Bulow I, Jorgensen T, Perrild H, Oversen L and Laurberg P. Serum Tg - a sensitive marker of thyroid abnormalities and iodine deficiency in epidemiological studies. J Clin Endocrinol Metab 2001;86:3599-603.
338. Van den Briel T, West CE, Hautvast JG, Vulsma T, de Vijlder JJ and Ategbo EA. Serum thyroglobulin and urinary iodine concentration are the most appropriate indicators of iodine status and thyroid function under conditions of increasing iodine supply in schoolchildren in Benin. J Nutr2001;131:2701-6.
339. Gardner DF, Rothman J and Utiger RD. Serum thyroglobulin in normal subjects and patients with hyperthyroidism due to Graves' disease: effects of T3, iodide, 131I and antithyroid drugs. Clin Endocrinol 1979;11:585-94.
340. Feldt-Rasmussen U, Petersen PH, Date J and Madsen CM. Serum thyroglobulin in patients undergoing subtotal thyroidectomy for toxic and nontoxic goiter. J Endocrinol Invest 1982;5:161-4.
341. Hocevar M, Auersperg M and Stanovnik L. The dynamics of serum thyroglobulin elimination from the body after thyroid surgery. 1997;23:208-10.
342. Cohen JH, Ingbar SH and Braverman LE. Thyrotoxicosis due to ingestion of excess thyroid hormone. Endocrine Rev 1989;10:113-24.
343. Mitchell ML and Hermos RJ. Measurement of thyroglobulin in newborn screening specimens from normal and hypothyroid infants. Clin Endocrinol 1995;42:523-7.
344. Smallridge RC, De Keyser FM, Van Herle AJ, Butkus NE and Wartofsky L. Thyroid iodine content and serum thyroglobulin: clues to the natural history of destruction-induced thyroiditis. J Clin Endocrinol Metab 1986;62:1213-9.
345. Pacini F, Molinaro E, Lippi F, Castagna MG, Agate L, Ceccarelli C, Taddei D, Elisei R, Capezzone M and Pinchera A. Prediction of disease status by recombinant human TSH-stimulated serum Tg in the postsurgical follow-up of differentiated thyroid carcinoma. J Clin Endocrinol Metab 2001;86:5686-90.
346. Cobin RH. 1992. Medullary carcinoma of the thyroid. In Malignant tumors of the thyroid: clinical concepts and controversies. S. D. Cobin RH, editor. Springer-Verlag,, New York. 112-41.
347. Dunn JT. When is a thyroid nodule a sproadic medullary carcinoma? J Clin Endocrinol Metab1994;78:824-5.
348. Pacini F, Fontanelli M, Fugazzola L and et. al. Routine measurement of serum calcitonin in nodular thyroid diseases allows the preoperative diagnosis of unsuspeted sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab 1994;78:826-9.
349. Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 1993;363:458-60.
350. Hofstra RM, Landvaster RM, Ceccherini I et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature1994;367:375-6.
351. Heyningen van V. One gene-four syndromes. Nature 1994;367:319-20.
352. Becker KL, Nylen ES, Cohen R and Snider RH. Calcitonin: structure, molecular biology and actions. In: J.P. Beleziakian, L.E. Raisz, G.A.Rodan eds. Principle of bone biology, Academic Press, San Diego 1996;:471-4.
353. Motte P, Vauzelle P, Gardet P, Ghillani P, Caillou B, Parmentier C et al. Construction and clinical validation of a sensitive and specific assay for mature calcitonin using monoclonal anti-peptide antibodies. Clin Chim Acta 1988;174:35-54.
354. Zink A, Blind E and Raue F. Determination of serum calcitonin by immunometric two-site assays in normal subjects and patients with medullary thyroid carcinoma. Eur J Clin Chem Biochem1992;30:831-5.
355. Engelbach M, Gorges R, Forst T, Pfutzner A, Dawood R, Heerdt S, Kunt T, Bockisch A and Beyer J. Improved diagnostic methods in the follow-up of medullary thyroid carcinoma by highly specific calcitonin measurements. J Clin Endocrinol Metab 2000;85:1890-4.
356. Milhaud G, Tubiana M, Parmentier C and Coutris G. Epithelioma de la thyroide secretant de la thyrocalcitonine. C.R. Acad. Sci (serie D), Paris 1968;266:608-10.
357. Guilloteau D, Perdrisot D, Calmettes C and et. al. Diagnosis of medullary carcinoma of the thyroid by calcitonin assay using monoclonal antibodies. J Clin Endocrinol Metab 1990;71:1064-7.
358. Niccoli P, Wion-Barbot N, Caron P and et.al. Interest of routine measurement of serum calcitonin(CT): study in a large series of thyroidectomized patients. J Clin Endocrinol Metab 1997;82:338-41.
359. Wells SA, Baylin SB, Linehan W, Farrell RE, Cox EB, Cooper CW. Provocative agents and the diagnosis of medullary carcinoma of the thyroid gland. Ann Surg 1978;188:139-41.
360. Gagel RF. The abnormal pentagastrin test. Clin Endocrinol 1996;44:221-2.
361. Wion-Barbot N, Schuffenecker I, Niccoli P et al. Results of the calcitonin stimulation test in normal volunteers compared with genetically unaffected members of MEN 2A and familial medullary thyroid carcinoma families. Ann Endocrinol 1997;58:302-8.
362. Barbot N, Calmettes C, Schuffenecker I et al. Pentagastrin stimulation test and early diagnosis of medullary carcinoma using an immunoradiometric assay of calcitonin: comparison with genetic screening in hereditary medullary thyroid carcinoma. J Clin Endocrinol Metab 1994;78:114-20.
363. Erdogan MF, Gullu S, Baskal N, Uysal AR, Kamel N, Erdogan G. Omeprazole: calcitonin stimulation test for the diagnosis follow-up and family screening in medullary carcinoma of the thyroid gland. Ann Surg 1997;188:139-41.
364. Vieira AEF, Mello MP, Elias LLK et al. Molecular and biochemical screening for the diagnosis and management of medullary thyroid carcinoma in multiple endocrine neoplasia Type 2A. Horm Metab Res 2002;34:202-6.
365. Wells SA, Chi DD, toshima K, Dehner LP, Coffin cm, Dowton SB, Ivanovich JL, DeBenedetti MK,Dilley WG and Moley JF. Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Ann Surg 1994;220:237-50.
366. Telander RL and Moir CR. Medullary thyroid carcinoma in children. Semin Pediatr Surg 1994;3:188-93.
367. Niccoli-Sire P, Murat A, Baudin E, Henry JF, Proye C, Bigorgne JC et al. Early or prophylactic thyroidectomy in MEN2/FMTC gene carriers: results in 71 thyroidectomized patients. Eur J Endocrinol 1999;141:468-74.
368. Niccoli-Sire P, Murat A, Rohmer V, Franc S, Chabrier G, Baldet L, Maes B, Savagner F, Giraud S,Bezieau S, Kottler ML, Morange S and Conte-Devolx B. Familial medullary thyroid carcinoma(FMTC) with non-cysteine RET mutations: phenotype-genotype relationship in large series of patients. J Clin Endocrinol Metab 2001;86:3756-53.
369. Body JJ, Chanoine JP, Dumon JC and Delange F. Circulating calcitonin levels in healthy children and subjects with congenital hypothyroidism from birth to adolescence. J Clin Endocrinol Metab1993;77:565-7.
370. Gharib H, Kao PC and Heath H. Determination of silica-purified plasma calcitonin for the detection and management of medullary thyroid carcinoma: comparison of two provocative tests. Mayo Clin Proc 1987;62:373-8.
371. Telander R, Zimmerman D, Sizemore GW, van Heerden JA and Grant CS. Medullary carcinoma in children. Results of early detection and surgery. Arch Surg 1989;124:841-3.
372. Calmettes C, Ponder BA, Fisher JA and Raue F. Early diagnosis of multiple endocrine neoplasia type 2syndrome: consensus statement. European community concerted action: medullary thyroid carcinoma. Eur J Clin Invest 1992;22:755-60.
373. Modigliani E, Cohen R, Campos JM, Conte-Devolx B, Maes B, Boneu A et al. Prognostic factors for survival and biochemical cure in medullary thyroid carcinoma: results in 899 patients. Clin Endocrinol1998;48:265-73.
374. Machens A, Gimm O, Ukkat J et al. Improved prediction of calcitonin normalization in medullary thyroid carcinoma patients by quantitative lymph node analysis. Cancer 2000;88:1909-15.
375. Fugazzola L, Pinchera A, Lucchetti F et al. Disappearence rate of serum calcitonin after total thyroidectomy for medullary thyroid carcinoma. Internat J Biolog Markers 1994;9:21-4.
376. Vierhapper H, Raber W, Bieglmayer C and et.al. Routine measurement of plasma calcitonin in nodular thyroid diseases. J Clin Endocrinol Metab 1997;82:1589-93.
377. Fereira-Valbuena H, Fernandez de Arguello E, Campos G, Ryder E and Avellaneda A. Serum concentration of calcium and calcitonin in hyperthyroidism caused by Graves' disease. Invest Clin1991;32:109-14.
378. Lips CJM, Hoppener JWM and Thijssen JHH. Medullary thyroid carcinoma: role of genetic testing and calcitonin measurement. Ann Clin Biochem 2001;38:168-79.
379. Niccoli P, Brunet Ph, Roubicek C, Roux F, Baudin E, Lejeune PJ et al. Abnormal calcitonin basal levels and pentagastrin response in patients with chronic renal failure on maintenance hemodialysis. Eur J Endocrinol 1995;132:75-81.
380. Snider RH, Nylen ES and Becker KL. Procalcitonin and its component peptides in systemic inflammation: immunochemical characterization. J Invest Med 1997;47:552-60.
381. Russwurn S, Wiederhold M, Oberhoffer M et al. Molecular aspects and natural source of Procalcitonin. Clin Chem Lab Med 1999;37:789-97.
382. Niccoli P, Conte-Devolx B, Lejeune PJ, Carayon P, Henry JF, Roux F et al. Hypercalcitoninemia in conditions other than medullary cancers of the thyroid. Ann Endocrinol 1996;57:15-21.
383. Baudin E, Bidart JM, Rougier P et al. Screening for multiple endocrine neoplasia type 1 and hormonal production in apparently sporadic neuroendocrine tumors. J Clin Endocrinol Metab 1999;84:114-20.
384. DeLellis RA. C-Cell hyperplasia. In: Rosai J., Carangiu M.L., DeLellis R.A. eds: Atlas of Tumor Pathology, 3rd. series, Fasc 5: tumors of the thyroid gland. Washington DC, Armed Forces Institute of Pathology. 1992;:247-58.
385. Guyetant S, Wion-Barbot N and Rousselet MC. C-cell hyperplasia associated with chronic lymphocytic thyroiditis: a retrospective study of 112 cases. Hum Pathol 1994;25:514-21.
386. Albores-Saavedra J, Monforte H, Nadji M and Morales AR. C-Cell hyperplasia in thyroid tissue adjacent to follicular cell tumor. Hum Pathol 1988;19:795-9.
387. Mulligan LM, Marsh DJ, Robinson BG, Schuffenecker I, Zedenius J, Lips CJ et al. Genotype-phenotype correlation in multiple endocrine neoplasia type 2: report of the international RET mutation consortium. J Intern Med 1995;238:243-6.
388. Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 1996;276:1575-9.
389. Ito S, Iwashita T, Asai N, Murakami H, Iwata Y, Sobue G et al. Biological properties of RET with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma and Hirschsprung's disease phenotype. Cancer Res 1997;57:2870-2.
390. Heshmati HM, Gharib H, Khosla S et al. Genetic testing in medullary thyroid carcinoma syndromes:mutation types and clinical significance. Mayo Clin Proc 1997;72:430-6.
391. Berndt I, Reuter M, Saller B et al. A new hot spot for mutations in the RET proto-oncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A. J Clin Endocrinol Metab 1998;83:770-4.
392. Komminoth P, Roth J, Muletta-Feurer S, Saremaslani P, Seelentag WKF and Heitz PU. RET proto-oncogene point mutations in sporadic neuroendocrine tumors. J Clin Endocrinol Metab 1996;81:2041-6.
393. Conte-Devolx B, Schuffenecker I, Niccoli P, Maes B, Boneu A, Barbot N et al. Multiple Endocrine Neoplasia Type 2: Management of patients and subjects at risk. Horm Res 1997;47:221-6.
394. Smith DP, Houghton C and Ponder BA. Germline mutation of RET codon 883 in two cases of de novo MEN2B. Oncogene 1997;15:1213-7.
395. Carlson KM, Bracamontes J, Jackson CE, Clark R, Lacroix A, Wells SA Jr et al. Parent-of-origin effects in multiple endocrine neoplasia type 2B. J Hum Genet 1994;55:1076-82.
396. Moers AMJ, Landsvater RM, Schaap C, van Veen JM, de Valk IAJ, Blijham GH et al. Familial medullary thyroid carcinoma: not a distinct entity/ Genotype-phenotype correlation in a large family:familial medullary thyroid carcinoma revisited. Am J Med 1996;101:634-41.
397. Dunn JT. Iodine deficiency - the next target for elimination. N Engl J Med 1992;326:267-8.
398. Delange F. Correction of iodine deficiency: benefits and possible side effects. Eur J Endocrinol1995;132:542-3.
399. Dunn JT. Whats happening to our iodine. J Clin Endocrinol Metab 1998;83:3398-3400.
400. Knudsen N, Christiansen E, Brandt-Christensen M, Nygaard B and Perrild H. Age- and sex-adjusted iodine/creatinine ratio. A new standard in epidemiological surveys? Evaluation of three different estimates of iodine excretion based on casual urine samples and comparison to 24 h values. Eur J Clin Nutr 2000;54:361-3.
401. Aumont G and Tressol JC. Improved routine method for the determination of total iodine in urine and milk. Analyst 1986;111:841-3.
402. Unak P, Darcan S, Yurt F, Biber Z and Coker M. Determination of iodine amounts in urine and water by isotope dilution analysis. Biol Trace Elem Res Winter 1999;71-2:463-70.
403. Kilbane MT, Ajja RA, Weetman AP, Dwyer R, McDermott EWM, O'Higfins NJ and Smyth PPA. Tissue Iodine content and serum mediated 125I uptake blocking activityin breast cancer. J Clin Endocrinol Metab 2000;85:1245-50.
404. Liberman CS, Pino SC, Fang SL, Braverman LE and Emerson CH. Circulating iodine concentrations during and after pregnancy. J Clin Endocrinol Metab 1998;83:3545-9.
405. Vought RL, London WT, Lutwak L and Dublin TD. Reliability of estimates of serum inorganic iodine and daily faecal and urinary iodine excretion from single casual specimens. J Clin Endcorinol Metab1963;23:1218-28.
406. Smyth PPA, Darke C, Parkes AB, Smith DF, Hetherton AM and Lazarus JH. Assessment of goitre in an area of endemic iodine deficiency. Thyroid 1999;9:895-901.
407. Thomson CD, Smith TE, Butler KA and Packer MA. An evaluation of urinary measures of iodine and selenium status. J Trace Elem Med and Biol 1996;10:214-22.
408. Als C, Helbling A, Peter K, Haldimann M, Zimmerli B and Gerber H. Urinary iodine concentration follows a circadian rhythm: A study with 3023 spot urine samples in adults and children. J Clin Endocrinol Metab 2000;85:1367-9.
409. Lightowler H and Davis JG. Iodine intake and iodine deficiency in vegans as assessed by the duplicate-portion technique and urinary iodine excretion. Br. J Nutr 1999;80:529-35.
410. Utiger RD. Maternal hypothyroidism and fetal development. N Engl J Med 1999;341:601-2.
411. Aboul-Khair S, Crooks J, Turnbull AC and Hytten FE. The physiological changes in thyroid function during pregnancy. Clin Sci 1964;27:195-207.
412. Smyth PPA, Smith DF, Radcliff M and O'Herlihy C. Maternal iodine status and thyroid volume during pregnancy: correlation with neonatal intake. J Clin Endocrinol Metab 1997;82:2840-3.
413. Gunton JE, Hams GH, Fiegert M and McElduff A. iodine deficiency in ambulatory participants at a Sydney teaching hospital: Is Australia truly iodine replete? Med J Aust 1999;171:467-70.
414. Smyth PPA. Variation in iodine handling during normal pregnancy. Thyroid 1999;9:637-42.
415. Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron,Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium and Zinc. National Academic Press 2001
416. Koutras DA, Papadoupoulos SN, Sfontouris JG and Rigopoulos GA. Comparison of methods for measuring the plasma inorganic iodine and the absolute iodine uptake by the thyroid gland. J Clin Endocrinol Metab 1968;28:757-60.
417. Mizukami Y, Michigishi T, Nonomura A, Hashimoto T, Tonami N, Matsubara F et al. Iodine-induced hypothyroidism: a clinical and histological study of 28 patients. J Clin Endocrinol Metab 1993;76:466-71.
418. Heymann WR. Potassium iodide and the Wolff-Chaikhoff effect: relevance for the dermatologist. J Am Acad Dermatol 2000;42:490-2.s
419. Stanbury JB, Ermans AE, Bourdoux P, Todd C, Oken E, Tonglet R, Bidor G, Braverman LE and Medeiros-Neto G. Iodine-induced hyperthyroidism: occurrence and epidemiology. Thyroid 1998;8:83-100.
420. Roti E and Uberti ED. Iodine excess and hyperthyroidism. Thyroid 2001;5:493-500.
421. Baltisberger BL, Minder CE and Burgi H. Decrease of incidence of toxic nodular goitre in a region of Switzerland after full correction of mild iodine deficiency. Eur J Endocrinol 1995;132:546-9.
422. Bacher-Stier RG, Totsch M, Kemmler G, Oberaigner W and Moncayo R. Incidence and clinical characteristics of thyroid carcinoma after iodine prophylazis in an endemic goiter country. Thyroid1997;7:733-41.
423. Barakat MCD, Hetherton AM, Smyth PPA and Leslie H. Hypothyroidism secondary to topical iodine treatment in infants with spina bifida. Acta Paediat 1994;83:741-3.
424. Martino E, Safran M, Aghino-Lombardi F, Rajatanavin R, Lenziardi M, Fay M et al. Environmental iodine intake and thyroid dysfunction during chronic amiodarone therapy. Ann Intern Med1984;101:28-34.
425. Rose NR, Rasooly L, Saboori AM and Burek CL. Linking iodine with autoimmune thyroiditis. Environmental Health Perspectives 1999;107:749-52.
426. Premawardhana LDKEPA, Smyth PPA, Wijeyaratne C, Jayasinghe A, De Silva H and Lazarus JH. Increased prevalence of thyroglobulin antibodies in Sri Lankan schoolgirls - is iodine the cause? Eur J Endocrinol 2000;143:185-8.
427. Costa A, Testori OB, Cenderelli C, Giribone G and Migliardi M. Iodine content of human tissues after administration of iodine containing drugs or constrast media. J Endocrinol Invest 1978;1:221-5.
428. May W, Wu D, Eastman C, Bourdoux P and Maberly G. Evaluation of automated urinary iodine methods: problems of interfering substances identified. Clin Chem 1990;35:865-9.
429. Lauber K. Iodine determination in biological material. Kinetic measurement of the catalytic activity of iodine. Analyt Chem 1975;47:769-71.
430. Mantel M. Improved method for the determination of iodine in urine. Clin Chim Acta 1971;33:39-44.
431. Dunn JT, Crutchfield HE, Gutenkunst R and Dunn AD. Two simple methods for measuring iodine in urine. Thyroid 1993;3:119-23.
432. May SL, May WA, Bourdoux PP, Pino S, Sullivan KM and Maberly GF. Validation of a simple,manual urinary iodine method for estimating the prevalence of iodine-deficiency disorders and interlaboratory comparison with other methods. J Clin Nutr 1997;65:1441-5.
433. Ohashi T, Yamaki M, Pandav SC, Karmarkar GM and Irie M. Simple microplate method for determination of urinary iodine. Clin Chem 2000;46:529-36.
434. Rendl J, Seybold S and Borner W. Urinary iodine determined by paired-ion reverse-phase HPLC with electrochemical detection. Clin Chem 1994;40:908-13.
435. Tsuda K, Namba H, Nomura T, Yokoyama N, Yamashita S, Izumi M and Nagataki S. Automated Measurement of urinary iodine with use of ultraviolet radiation. Clin Chem 1995;41:581-5.
436. Haldimann M, Zimmerli B, Als C and Gerber H. Direct determination of urinary iodine by inductively coupled plasma mass spectormetry using isotope dilution with iodine-129. Clin Chem 1998;44:817-24.
437. Mura P, Piriou A, Guillard O, Sudre Y and Reiss D. Dosage des iodures urinares par electrode specifique: son interet au cours des dysthyroides. Ann Biol Clin 1985;44:123-6.
438. Allain P, Berre S, Krari N, Laine-Cessac P, Le Bouil A, Barbot N, Rohmer V and Bigorgne JC. Use of plasma iodine assays for diagnosing thyroid disorders. J Clin Pathol 1993;46:453-5.
439. Vander JB, Gaston EA and Dawber TR. The significance of nontoxic thyroid nodules: Final report of a15-year study of the incidence of thyroid malignancy. Ann Intern Med 1968;69:537-40.
440. Rojeski MT and Gharib H. Nodular thyroid disease: Evaluation and management. N Engl J Med1985;313:428-36.
441. Mazzaferri EL. Management of a solitary thyroid nodule. N Engl J Med 1993;328:553-9.
442. Kirkland RT and Kirkland JL. Solitary thyroid nodules in 30 children and report of a child with thyroid abscess. Pediatrics 1973;51:85-90.
443. Rallison ML, Dobyns EM, Keating FR, Rall J and Tyler E. Thyroid nodularity in children. JAMA1975;233:1069-72.
444. Khurana KK, Labrador E, Izquierdo R, Mesonero CE and Pisharodi LR. The role of fine-needle aspiration biopsy in the management of thyroid nodules in children, adolescents and young adults: A multi-institutional study. Thyroid 1999;4:383-6.
445. Aghini-Lombardi F, Antonangeli L, Martino E, Vitti P, Maccherini D, Leoli F, Rago T, Grasso L,Valeriano R, Balestrieri A and Pinchera A. The spectrum of thyroid disorders in an iodine-deficient community: the Pescopanano Survey. J Clin Endocrinol Metab 1999;84:561-6.
446. Hamburger JI, Husain M, Nishiyama R, Nunez C and Solomon D. Increasing the accuracy of fine-needle biopsy for thyroid nodules. Arch Pathol Lab Med 1989;113:1035-41.
447. Hundahl SA, Cady B, cunningham MP, Mazzaferri E, McKee RF, Rosai J, Shah JP, Fremgen AM,Stewart AK and Holzer S. Initial results from a prospective cohort study of 5583 cases of thyroid carcinoma treated in the United States during 1996. Cancer (Cytopathol) 2000;89:202-17.
448. Leenhardt L, Hejblum G, Franc B, Du Pasqueir Fediaevsky L, Delbot T, De Guillouzic D, Menegaux F, Guillausseau C, Hoang C, Turpin G and Aurengo A. Indications and limits of ultrasound-guided cytology in the management of nonpalpable thyroid nodules. J Clin Endocrinol Metab 1999;84:24-8.
449. Braga M, Cavalcanti TC, Collaco LM and Graf H. Efficacy of ultrasound-guided fine-needle aspiration biopsy in the diagnosis of complex thyroid nodules. J Clin Endocrinol Metab 2001;86:4089-91.
450. Cochand-Priollet B, Guillausseau P, Chagnon S, Hoang C, Guillausseau-Scholer C, Chanson P, Dahan H, Warnet A, Tran Ba Huy PT and Valleur P. The diagnostic value of fine-needle aspiration biopsy under ultrasonoraphy in nonfunctional thyroid nodules: a prospective study comparing cytologic and histologic findings. Am J Med 1994;97:152-7.
451. Takashima S, Fukuda H and Kobayashi T. Thyroid nodules: Clinical effect of ultrasound-guided fine needle aspiration biopsy. J Clin Ultrasound 1994;22:535-42.
452. Gharib H. Fine-needle aspiration biopsy of thyroid nodules: Advantages, limitations and effect. Mayo Clin Proc 1994;69:44-9.
453. Hamberger B, Gharib H, Melton LF III, Goellner JR and zinsmeister AR. Fine-needle aspiration biopsy of thyroid nodules. Impact on thyroid practice and cost of care. Am J Med 1982;73:381-4.
454. Grant CS, Hay ID, Gough IR, McCarthy PM and Goelliner JR. Long-term follow-up of patients with benign thyroid fine-needle aspiration cytologic diagnoses. Surgery 1989;106:980-6.
455. Liel Y and Barchana M. Long-term follow-up of patients with initially benign fine-needle aspirations. Thyroid 2001;11:775-8.
456. Belfiore A, La Rosa G, La Porta GA, Giuffrida D, Milazzo G, Lupo L, Regalbuto C and V. R. Cancer Risk in patients with cold thyroid nodules: Relevance of iodine intake, sex, age and multinodularity. J Amer Med 1992;93:363-9.
457. Tuttle RM, Lemar H and Burch HB. Clinical features associated with an increased risk of thyroid malignancy in patients with follicular neoplasia by fine-needle aspiration. Thyroid 1998;8:377-83.
458. Kumar H, Daykin J, Holder R, Watkinson JC, Sheppard M and Franklyn JA. Gender, clinical findings and serum thyrotropin measurements in the prediction of thyroid neoplasia in 1005 patients presenting with thyroid enlargement and investigated by fine-needle aspiration cytology. Thyroid 1999;11:1105-9.
459. Moosa M and Mazzaferri EL. Outcome of differentiated thyroid cancer diagnosed in pregnant women. J Clin Endocrinol Metab 1997;82:2862-6.
460. Oertel YC. A pathologist trying to help endocrinologists to interpret cytology reports from thyroid aspirates. J Clin Endocrinol Metab 2002;87:1459-61.
461. De Micco, Zoro P, Garcia S, Skoog L, Tani EM, C. PK and Henry JF. Thyroid peroxidase immunodetection as a tool to assist diagnosis of thyroid nodules on fine-needle aspiration biopsy. Eur J Endocrinol 1994;131:474-9.
462. Faroux MJ, Theobald S, Pluot M, Patey M and Menzies D. Evaluation of the monoclonal antithyroperoxidase MoAb47 in the diagnostic decision of cold thyroid nodules by fine-needle aspiration. Pathol Res Pract 1997;193:705-12.
463. Inohara H, Honjo Y, Yoshii T, Akahani S, Yoshida J, Hattori K, Okamoto S, Sawada T, Raz A and Kubo T. Expression of galectin-3 in fine-needle aspirates as a diagnostic marker differentiating benign from malignant thyroid neoplasms. Cancer 1999;85:2475-84.
464. Medeiros-Neto G, Nascimento MC, Bisi H, Alves VA, Longatto-Filho A and Kanamura CT. Differential reactivity for Galectin-3 in Hurthle Cell Adenomas and Carcinomas. Endocr Pathol2001;12:275-9.
465. Saggiorato E, Cappia S, De Guili P, Mussa A, Pancani G, Caraci P, Angeli A and Orlandi F. Galectin -3 as a presurgical immunocytodiagnostic marker of minimally invasive follicular carcinoma. J Clin Endocrinol Metabl 2001;86:5152-8.
466. Bartolazzi A, Gasbarri A, Papotti M, Bussolati G, Lucante T, Khan A, Inohara H, Marandino F,Orkandi F, Nardi F, Vacchione A, Tecce R and Larsson O. Application of an immunodiagnostic method for improving preoperative diagnosis of nodular thyroid lesions. Lancet 2001;357:1644-50.
467. Goellner JR. Problems and pitfalls in thyroid cytology. Monogr Pathol 1997;39:75-93.
468. Oertel YC, O. J. Diagnosis of benign thyroid lesions: fine-needle aspiration and histopathologic correlation. Ann Diagn Pathol 1998;2:250-63.
469. Baldet L, Manderscheid JC, Glinoer D, Jaffiol C, Coste-Seignovert B and Percheron C. The management of differentiated thyroid cancer in Europe in 1988. Results of an international survey. Acta Endocrinol (Copenh) 1989;120:547-58.
470. Baloch ZW, Fleisher S, LiVolsi VA and Gupta PK. Diagnosis of "follicular neoplasm": a gray zone in thyroid fine-needle aspiration cytology. Diagn Cytopathol 2002;26:41-4.
471. Herrmann ME, LiVolsi VA, Pasha TL, Roberts SA, Wojcik EM and Baloch ZW. Immunohistochemical expression of Galectin-3 in benign and malignant thyroid lesions. Arch Pathol Lab Med 2002;126:710-13.
472. Leteurtre E, Leroy Z, Pattou F, Wacrenier A, Carnaille B, Proye C and Lecomte-Houcke M. Why do frozen sections have limited value in encapsulated or minimally invasive follicular carcinoma of the thyroid? Amer J Clin Path 2001;115:370-4.
473. Stojadinovic A, Ghossein RA, Hoos A, Urist MJ, Spiro RH, Shah JP, Brennan MF, Shaha AR and Singh B. Hurthle cell carcinoma: a critical histopathologic appraisal. J Clin Oncol 2001;19:2616-25.
474. Carmeci C, Jeffrey RB, McDougall IR, Nowels KW and Weigel RJ. Ultrasound-guided fine-needle aspiration biopsy of thyroid masses. Thyroid 1998;8:283-9.
475. Yang GCH, Liebeskind D and Messina AV. Ultrasound-guided fine-needle aspiration of the thyroid assessed by ultrafast papanicoulaou stain: Data from 1135 biopsies with a two- six-year follow-up. Thyroid 2001;6:581-9.
476. Fisher DA, Dussault JH, Foley TP, Klein AH, LaFranchi S, Larsen PR, Mitchell NL, Murphey WH and Walfish PG. Screening for congenital hypothyroidism: results of screening one million North American infants. J Pediatr 1979;94:700.
477. Brown AL, Fernhoff PM, Milner J, McEwen C and Elsas LS. Racial differences in the incidence of congenital hypothyroidism. J Pediatr 1981;99:934-.
478. LaFranchi SH, Dussault JH, Fisher DA, Foley TP and Mitchell ML. Newborn screening for congenital hypothyroidism: Recommended guidelines. Pediatrics 1993;91:1203-9.
479. Gruters A, Delange F, Giovanelli G, Klett M, Richiccioli P, Torresani T et al. Guidelines for neonatal screening programmes for congenital hypothyroidism. Pediatr 1993;152:974-5.
480. Toublanc JE. Guidelines for neonatal screening programs for congenital hypothyroidism. Acta Paediatr1999;88 Suppl 432:13-4.
481. Vulsma T, Gons MH and de Vijlder JJ. Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. N Engl J Med 1989;321:13-6.
482. Gruneiro-Papendieck L, Prieto L, Chiesa A, Bengolea S, Bossi G and Bergada C. Usefulness of thyroxine and free thyroxine filter paper measurements in neonatal screening for congenital hypothyroidism of preterm babies. J Med Screen 2000;7:78-81.
483. Hanna DE, Krainz PL, Skeels MR, Miyahira RS, Sesser DE and LaFranchi SH. Detection of congenital hypopituitary hypothyroidism: Ten year experience in the Northwest Regional Screening Program. J Pediatr 1986;109:959-64.
484. Fisher DA. Hypothyroxinemia in premature infants: is thyroxine treatment necessary? Thyroid1999;9:715-20.
485. Wang ST, Pizzalato S and Demshar HP. Diagnostic effectiveness of TSH screening and of T4 with secondary TSH screening for newborn congenital hypothyroidism. Clin Chim Acta 1998;274:151-8.
486. Delange F. Screening for congenital hypothyroidism used as an indicator of the degree of IDD and its control. Thyroid 1998;8:1185-92.
487. Law WY, Bradley DM, Lazarus JH, John R and Gregory JW. Congenital hypothyroidism in Wales(1982-93): demographic features, clinical presentation and effects on early neurodevelopment. Clin Endocrinol 1998;48:201-7.
488. Mei JV, Alexander JR, Adam BW and Hannon WH. Use of filter paper for the collection and analysis of human whole blood specimens. J Nutr 2001;131:1631S-6S.
489. LaFranchi SH, Hanna CE, Krainz PL, Skeels MR, Miyahira RS and Sesser DE. Screening for congenital hypothyroidism with specimen collection at two time periods: Results of the Northwest Regional Screening Program. J Pediatr 1985;76:734-40.
490. Zakarija M, McKenzie JM and Eidson MS. Transient neonatal hypothyroidism: Characterization of maternal antibodies to the Thyrotropin Receptor. J Clin Endocrinol Metab 1990;70:1239-46.
491. Matsuura N, Yamada Y, Nohara Y, Konishi J, Kasagi K, Endo K, Kojima H and Wataya K. Familial neonatal transient hypothyroidism due to maternal TSH-binding inhibitor immunoglobulins. N Engl J Med 1980;303:738-41.
492. McKenzie JM and Zakaria M. Fetal and neonatal hyperthyroidism and hypothyroidism due to maternal TSH receptor antibodies. Thyroid 1992;2:155-9.
493. Vogiatzi MG and Kirkland JL. Frequency and necessity of thyroid function tests in neonates and infants with congenital hypothyroidism. Pediatr 1997;100.
494. Pohlenz J, Rosenthal IM, Weiss RE, Jhiang SM, Burant C and Refetoff S. Congenital hypothyroidism due to mutations in the sodium/iodide symporter. Identification of a nonsense mutation producing a downstream cryptic 3' splice site. J Clin Invest 1998;101:1028-35.
495. Nordyke RA, Reppun TS, Mandanay LD, Wood JC, Goldstein AP and Miyamoto LA. Alternative sequences of thyrotropin and free thyroxine assays for routine thyroid function testing. Quality and cost. Arch Intern Med 1998;158:266-72.

Page forms part of www.apls.tk, the information site on ANTIPHOSPHOLIPID SYNDROME (APS or ANTIPHOSPHOLIPID SYNDROME (APLS))

Medical Keywords: systemic antiphospholipid antibody syndrome, Antiphospholipid, Antiphospholipid Antibody Syndrome, Antiphospholipid Syndrome, APS, APLS, Hughes Syndrome, Sticky Blood, Clotting Disorder, Stroke, TIA, PE, death, Antiphospholipid Antibody Syndrome, Antiphospholipid Syndrome, APS, APLS, Hughes Syndrome, Sticky Blood, Clotting Disorder, Stroke, TIA, PE, death