2-1997

Update in Diagnosis of Thyroid Disorders

Klaus Mann, Bernhard Saller and Rudolf Hörmann, Essen, Germany

Introduction

Functional disorders of the thyroid are among the most common health disorders with a prevalence of approximately 5% in a general population and an even higher frequency of occurence in the elderly. During the past decade our diagnostic approach has undergone a considerable change in that laboratory tests have become increasingly important in diagnosing asymptomatic stages of the disease rather than waiting for clinical symptoms to occur. From a therapeutic point of view, interest has been shifted from treatment options to preventive measures. Availability of genetic testing of medullary thyroid carcinoma is an excellent example in this respect because it allows for reliable diagnosis of the disease long before its clinical manifestation. As a consequence, patients can be cured by preventive thyroidectomy even before they have become ill.

The effectiveness of laboratory thyroid tests is of major relevance, as is their appropriate use in a given clinical situation. In the daily practice many generalists and various specialists depend on reliable diagnosis of a thyroid disorder or its definitive exclusion. Fortunately, thyroid tests have considerably improved making this option generally possible.

Standards of laboratory practice have been set forward by the relevant societies including the American Thyroid Association, the European Thyroid Association, and also the German Endocrine Society and guidelines for thyroid testing have been issued in order to assure analytical and clinical performance goals for patients as well as to achieve a cost effective use of these techniques. Despite their undisputed usefulness such guidelines may hardly substitute for personal experience and expertise of the thyroid specialist which may dictate deviation from rules in certain situations.

In the present report we will give an update on thyroid tests that reflects the vast experience in dealing with thyroid problems at our university hospital and provide critical comments on practical aspects of the usage of various diagnostic tests.

In this respect it is important to keep in mind that Germany still is a country with moderate iodine deficiency.

In Vitro Tests

Effective usage of in vitro tests mandates as a prerequisite to have some clinical information on the patient and to consider the diagnostic setting. At least three clinical situations may be discerned.

First, the patient who on clinical grounds is highly likely to have thyroid disease, second, the entirely asymptomatic patient with a low a priori probability of thyroid disease and third, the patient in whom thyroid testing is severely hampered by interfering factors, such as intake of various drugs, and/or the presence of nonthyroidal illness (NTI).

With a thyroid disease being clinically unlikely, screening of serum basal thyrotropin (TSH) levels may be the single most effective means of excluding thyroid dysfunction. Indeed, this is the approach we favor.

In case of substantial clinical suspicion use of a combination of thyroid in vitro parameters seems to be more appropriate, i.e.

measurement of TSH and free thyroxine (FT4) in suspected hypothyroidism and

assessment of TSH, FT4 and free (FT3) or total triiodothyronine in suspected hyperthyroidism.

Serum TSH

Modern assay techniques permit to reliably distinguish between normal TSH values in euthyroid subjects and suppressed TSH levels in hyperthyroid patients, obviating the former need for TRH testing. Analytical assay sensitivity has dramatically improved over the past years down to 0.001 mU/l. However, since analytical sensitivity per se has little clinical relevance, sensitivity of a TSH assay should be given in terms of its functional sensitivity currently defined as the point of the interassay profile where the coefficient of interassay variability (CV) is 20%. Functional sensitivity should be below 0.10 mU/l. Tests not fulfilling this criterion should no longer be used. Table 1 summarizes criteria for quality assessment of TSH assays to be employed for routine diagnostic purpose.

Experience in our own laboratory with more than 12 000 samples per year has shown that functional assay sensitivity is the most important performance criterion and should be assessed independently in each laboratory. In addition, control samples with TSH concentrations of about 0.1 mU/l, 0.3 mU/l and 4.0 mU/l should be included in every run in order to early recognize imprecision of TSH determinations. It is the manufacturer|s and the laboratory|s responsibility, to correctly define analytical and clinical performance of a TSH assay.

·	Functional sensitivity <0.1 mU/l
·	Cross reactivity with other glycoprotein hormones (LH, FSH, HCG) <0.01 %
·	Parallel course of sample dilutions and the standard curve.
·	Full recovery of a TSH standard added to patient's sample.
·	Estimates of WHO- or Medical Research Council (MRC) standards ±5% of the expected values.
·	Clear-cut separation of euthyroid and hyperthyroid patients (with an overlap of less than 1%).
·	Lack of interference with heterophile antibodies.
·	Absense of a high dose "hook" effect at TSH concentrations of <300 mU/l

Table 1: Criteria of quality assessment for routine TSH assays

When these quality measures are operative retesting of an inappropriate TSH value has been a rare necessity in our experience. Nonspecific interference will best be detected in a situation where examination of a patient is done by a thyroid expert who should notice apparent discrepancies between the presentation of the patient and results of in vitro tests. In case of discrepant laboratory results we recommend to retest the sample and to check for parallelity with standard curve in diluted samples. If necessary, a new specimen from the patient should be collected and TRH stimulation should be performed. When using this approach, retesting the sample in a different type of TSH assay and the need for checking for the presence of heterophile antibodies is hardly ever necessary. In our setting it is important to note that low normal or suppressed TSH values may be frequently found in patients with secondary hypothyroidism due to pituitary abnormalities. In such situations clinical information is particularly helpful to distinguish primary hyperthyroidism with suppressed TSH from secondary hypothyroidism with inappropriately low TSH values.

Suspicion of secondary hypothyroidism is an important condition where screening for thyroid dysfunction by basal TSH alone may be inappropriate or misleading. In a considerable portion of patients TSH values may be found within the normal range despite manifest hypothyroidism as evidenced by decreased FT4 values. The condition can only reliably be diagnosed by interpreting TSH in relation to free thyroid hormone concentrations (FT4). Since determination of TSH alone is unable to distinguish between subclinical and overt thyroid dysfunction, each abnormal TSH value has to be followed or accompanied by assessment of peripheral hormone status.

TRH testing has become unneccessary in most thyroid disorders except for hypothalamic or pituitary diseases.

Thyroid Hormones

Thyroid function is reflected by free thyroid hormone concentrations which constitute only a minute fraction of the total amount of thyroid hormones in the circulation. Total thyroid hormone concentrations may therefore fail to adequately reflect thyroid function and may vary depending on influences on thyroid hormone binding proteins. The most common situations causing alterations in binding protein concentrations are pregnancy, liver diseases, and use of estrogens. These considerations make determination of free thyroid hormone concentrations most desirable. The sole determination of total T4 without a direct or indirect estimate of its protein binding has nowadays to be considered inappropriate. The methods for direct determination of free thyroid hormones have definitely been improved over the past years. Methods may be separated into one step and two step procedures. The one step procedures are based on the use of T4 or T3 analogues carrying a radioactive, enzymatic, luminescent or fluorescent label. These analogues compete with the free thyroid hormones for binding to specific antibodies, but fail to interact itself with serum binding proteins. Alternatively to labelling the hormone analogue, some new methods employ labelled antibodies instead of labelled hormone analogues. Two step procedures first achieve extraction of thyroid hormones with the use of a solid phase antibody and assess concentration of extracted hormones in a second independent step. Two step assays and modern one step procedures show less interference with unspecific factors (Table 2) and appear to be more reliable in patients with severe nonthyroidal illness.

·	Severe nonthyroidal illness (NTI)
·	Binding protein abnormalities and variations
·	Presence of antibodies to thyroid hormones
·	Drugs (e.g. furosemid, salicylates, heparin, barbiturates)

Table 2: Criteria of quality assessment for routine TSH assays

As a rule, thyroid hormone measurements should always be interpreted in connection with serum TSH. Interpretation is straight forward in most cases except for severely ill patients with NTI syndrome and rarely for patients with TSH producing pituitary adenoma or thyroid hormone resistance (Table 3).

**LOW TSH IN ABSENCE OF OVERT HYPERTHYROIDISM**
·	subclinical hyperthyroidism
·	secondary hyperthyroidism
·	severe nonthyroidal illness (NIT)
·	drug interference (dopamine, high doses of glucocorticoids)

	ELEVATED TSH IN THE ABSENCE OF OVERT HYPOTHYROIDISM
·	subclinical hypothyroidism
·	thyroid hormone resistance
·	TSH producing pituitary adenoma
·	Recovery from nonthyroidal illness (NTI)

Table 3: Conditions with low TSH in the absence of overt hyperthyroidism and with elevated TSH values in the absence of overt hypothyroidism

Thyroid hormone resistance is characterized by a clinically euthyroid or hyperthyroid state, abnormally elevated free thyroid hormone concentrations, and normal or even increased TSH values. Hyperthyroidism in the presence of an increased or normal TSH is also found in secondary hyperthyroidism due to a TSH producing pituitary adenoma. Differential diagnosis can be done by TRH stimulation which can significantly increase TSH values only in thyroid hormone resistance and by determination of free alpha-subunit which is characteristically elevated in TSH-producing adenomas.

Table 4 shows the results of in vitro thyroid testing in a patient with TSH producing pituitary adenoma and with thyroid hormone resistance syndrome. Thyroid Autoantibodies

	Diagnosis	total T4 (nmol/l)	FT4 (pmol/l)	total T3 (nmol/l)	TSH (mU/l)	TSH after TRH (mU/l)

Patient U. R.	TSH producing pituitary adenoma	191	42	4.39	6.0	8.0
Patient C. K.	thyroid hormone resistance syndrome	214	44	3.50	4.8	44

Table 4: Results of in vitro thyroid testing with TSH-producing pituitary adenoma (patient U. R.) and in a patient with thyroid hormone resistance syndrome (patient C. K.). Both patients show similar elevations of total T4 (reference range 58-154 nmol/l), FT4 (reference range 10-25 pmol/l), total T3 (reference range 1.23-3.08 nmol/l). Basal TSH levels were also elevated in both patients. Significant stimulation by TRH, however, couldonly be achieved in thyroid hormone resistance syndrome.

Thyroid Autoantiboidies

Thyroid autoantibody determination has originally evolved and been established as an aid to the diagnosis of autoimmune thyroid disease (ATD). As methods have been advanced during the last decade and have become more sensitive and more reliable, antibodies turned out to be markers of autoimmunity that may precede onset of clinically overt disease for a long period of time. Usefulness of antibody determination has nowadays to be judged as for its

diagnostic efficiency,

its predictive character and

its prognostic value.

TSH Receptor Antibodies (TRAb)

Antibodies against the human TSH receptor (TRAb) are considered to be the causal agents that target autoimmunity to TSH receptor and result in uncontrolled hyperstimulation of the thyroid gland and hyperthyroidism. Assays to detect these pathological antibodies in Graves| patients have been very efficient. A simple method using solubilized porcine thyroid membranes has become commercially available as a standard routine method. From our long-term experience with this method, we would recommend standardization of the assay in TSH equivalents mandating a TSH standard curve to be included. By this way, sensitivity and specificity of the method could be enhanced resulting in better separation of insignificant and significant TRAb. Cut-off values may best be found by establishing receiver operating curves (ROC) and should not solely rely on the manufacturer's guidelines (Figure 1).

Figure 2 depicts a scheme of the proposed diagnostic strategy in hyperthyroidism and the role of autoantibody determination. The incidence of detectable TRAb in the sera of patients with untreated active Graves' hyperthyroidism tends to considerably decline during the course of antithyroid drug therapy with after one year of treatment about half of the patients converting to negative antibody status (Table 5). Despite of their pathogenetic relevance and demonstration of treatment associated changes, use of TRAb determination has been disappointing with respect to prediction of remission or relapse of hyperthyroidism after withdrawal of antithyroid medication. A great number of retrospective and prospective studies have addressed this problem. From a clinical point of view we can briefly summarize that only persistence of high antibody titers is a rather specific indicator of persistence or imminent relapse of Graves' hyperthyroidism.

View figure 1

View figure 2

Graves' Disease
before antithyroid treatment	N = 111	89%
after 3-12 month of antithyroid treatment	N = 73	56%

Hashimoto thyroiditis and primary myxedema	N = 37	8%

Autonomously functioning thyroid nodules	N = 275	1%

Nontoxic goiter	N = 108	8%

Healthy controls	N = 40	0%

Table 5: Incidence of TRAb in thyroid patients with and controls

It is important to note that TSH receptor antibodies do pass the placenta barrier and the presence of markedly elevated antibody titres in the blood of the mother indicates a risk of the newborn to develop intrauterine and/or neonatal hyperthyroidism.

Although TRAb are very useful in the clinical setting, their measurement has some limitations that should not be overlooked. These relate to the use of non-human thyroid tissue and to assessment of receptor binding instead of functional activity at the receptor. The latter may be particularly relevant for prognostic implications of antibody determination, because we could clearly demonstrate dissociation of TSH binding inhibiting antibodies and T3- release stimulating antibodies in some patients with Graves' disease during the course of antithyroid therapy. Similarly, with the use of more advanced techniques based on expression of recombinant human TSH receptor in stably transfected cell lines we observed a discordant (positive/negative) behaviour of binding inhibiting and stimulatory activities at recombinant TSH receptor in about one third of patients that have been treated up to 6-12 months with antithyroid drugs. This discrimination is not possible with the TRAb assay, in which both types of antibodies give a positive result. In patients with untreated Graves' disease, stimulatory and receptor binding activities were correlated (Figure 5).

View figure 5

Establishment of a reliable and practical functional, i.e. based on measurement of stimulation or inhibition of the TSH receptor, TRAb assay seems therefore to be a desirable goal which we are currently pursueing at our laboratory. It is an intriguing question, if assessment of functional antibody activity would improve reliability of antibody determination as a prognostic marker. The method would certainly allow to definitively characterize a subgroup of patients with autoimmune thyroiditis that present with TRAb in the binding test but what appear to be blocking antibodies in the functional test.

Thyroid Peroxidase Antibodies (TPOAb)

Determination of thyroid peroxidase (TPO) antibodies has been improved by introduction of quantitative assays (RIA, IRMA, ELISA) and the use of purified human or recombinant TPO as the antigen. The reference preparation used is the Medical Research Council (MRC) 66-387. Compatibility of different assays is still impaired owing to the presence of an individual antibody spectrum showing variable nonparallel reactivity with the same antigen.

TPO antibodies are found to be present in about 90% of patients with autoimmune thyreoiditis (Hashimoto thyroiditis and primary myxedema) and about 75% of patients with active Graves' disease. Interestingly, TPOAb can be detected also in patients with non-immune thyroid diseases or even in older persons without evidence of thyroid disorders. This limited specificity of TPOAb determination may be overcome by higher cut-off values, which result, however, in a reduced sensitivity in the diagnosis of clinical autoimmune thyroid disease (Table 6). TPOAb may also be detected in association with other autoimmune disorders like insulin dependent diabetes mellitus (IDDM), Addisons' disease or systemic lupus erythematodes.

		100 mU/l	>200 mU/l	>500 mU/l

Grave's Disease
before antithyroid treatment	n = 51	76%	67%	53%
after 3-12 months of antithyroid treatment	n = 75	68%	60%	47%

Hashimoto thyroiditis and primary myxedama	n = 35	89%	77%	63%
Autonomously functioning nodules	n = 51	16%	10%	6%

Nontoxic goiter	n = 41	2%	0%	0%

Healthy controls
<= 60 y	n = 36	0%	0%	0%
> 60 y	n = 33	12%	6%	3%

Table 6: Incidence of elevated titres of TPOAb in patients with various thyroid diseases and in healthy controls at different cut-off values

Thyroglobulin Antibodies

Thyroglobulin antibodies should be measured by quantitative assays (RIA, IRMA, ELISA) and are detected in about 60 to 70% of patients with autoimmune thyreoditis and in 20 to 40% of Graves' patients. Because of a lower sensitivity compared to TPO antibodies their value is limited and we do not advocate their use as a routine primary tool in diagnosing autoimmune thyroid disease.

Tumor Markers

Thyroglobulin (Tg) measurement is available as a marker of differentiated thyroid carcinoma only after total thyroidectomy. Otherwise, elevations of Tg may be caused by a variety of benign diseases including goiter, Graves' disease and autonomously functioning thyroid nodules and do not indicate thyroid malignancy. Suppressed Tg in patients without prior thyroidectomy is seen under thyroid hormone medication, particularly when thyrotoxicosis factitia is present.

Modern immunoassay techniques have nowadays mostly replaced RIA methods, but still encounter a variety of methodological problems: Tg levels may vary among different methods used by as much as 65%. This may be improved in the future by adoption of a universal standard preparation. Major differences that are presumably related to different specificities of the anti-Tg antibodies used in various methods may still remain.

Owing to lack of appropriate standardization, values that have been reported for sensitivity may not be directly comparable. As with the TSH assay the best way would be to use functional sensitivity defined as the lowest Tg- concentration that is detectable with an interassay-CV below 20%. The functional sensitivity should be below 1 ng/ml.

Good assay precision is also important for measuring high serum Tg concentrations. When very high serum concentrations of Tg (>1000 ng/ml) are being measured, a high dose "hook" effect may occur. Testing the serum in a 1:10 dilution may identify this problem. Tg antibodies which are present in about 20–30% of patients with thyroid carcinoma, still constitute a major problem of interference in Tg assays. Therefore Tg measurement routinely must include validation by recovery of an external addition of Tg. Although recovery studies are useful to identify problems with interference, demonstration of intact recovery does not necessarily guarantee correctness of the value. Determination of TgAb may be of additional value in this setting. Interpretation of Tg-values should be made in appreciation of the clinical presentation of the patient.

Calcitonin is available as a sensitive and specific tumor marker in the diagnosis of medullary thyroid carcinoma. Sensitivity of assay procedures has recently been improved. As for Tg, the results from different methods are not directly comparable so as to require separate standardization by each laboratory. Elevation of calcitonin almost always indicates the presence of medullary thyroid carcinoma, except for slightly elevated levels that are found in other neuroendocrine tumors, such as carcinoid, lung cancer or in pheochromocytoma and in patients with renal failure. The sensitivity of calcitonin measurement is improved by stimulation with pentagastrin. Figure 6 shows an example of a patient with MEN 2A before and after thyroidectomy for medullary thyroid carcinoma.As for thyroglobulin assays, a high dose “hook” effect may occur at very high concentrations of calcitonin.

View figure 6

Genetic testing for familiar medullary thyroid carcinoma (FMTC) and multiple endocrine neoplasia type 2 (MEN 2)

Identification of RET proto-oncogen mutations as the cause of familiar medullary thyroid carcinoma (FMTC) and multiple endocrine neoplasia type 2 (MEN 2) has enabled genetic testing for identification of gene carriers before clinical manifestation of disease. In addition, patients with apparent non-familiar forms of medullary thyroid cancer can be screened for the presence of hereditary disease. Mutations within the RET proto-oncogen on chromosome 10q13 have been identified being responsible for 97% of cases with FMTC and MEN 2. In case of the presence of a RET proto-oncogen mutation, development of medullary thyroid carcinoma almost unvariably occurs during the lifetime of the patient. The availability of the test and its highly predictive value allows the adoption of preventive measures. Current recommendations call for total thyroidectomy to be performed in gene carriers possibly before the age of six years.

It should be noted that genetic testing is cost effective as compared to biochemical evaluation by calcitonin testing, particularly as subjects with no mutation being detectable can be excluded from long-term biochemical surveillance programmes. Generally, validation of the result by a second independent sample is required. Patients should best be treated at a specialized center. Table 7 briefly summarizes the experience gained at our institution with this novel test in MEN 2 patients.

	Mutation (Affected codon and Change in Nucleotide Sequence)	No. of Affected Families	No. of Affected Family Members	MTC	Pheo	pHPT

MEN 2A	634 TGS -> CGC	4	12	10	9	2

MEN 2A	634 TGC -> TAC	3	16	14	4	1

MEN 2A	611 TGC -> TAC	1	2	2	1	0

MEN 2A	620 TGC -> CGC	1	1	1	1	0

MEN 2A	790 TTG -> TTC	1	6	4	3	0

MEN 2B	918 ATG -> ACG	3	3	3	2	0

Table 7: Results of genetic testing in patients with MEN 2 treated at our institute and relation to the clinical phenotype. Genetic testing has been performed in collaboration with Dr. W. Hoeppner, Institute for Hormone and Fertilitiy Research, Hamburg, Germany. MTC = medullary thyroid carcinoma, Pheo = pheochromocytoma, pHPT = primary hyperparathyroidism.

Out of 68 patients with an apparent sporadic form of medullary thyroid carcinoma, 3 cases turned out to be familiar disease by genetic testing. Thus, genetic screening is recommended in each patient with medullary thyroid carcinoma.

In Vivo Diagnostics

Ultrasonography, owing to its practicability and lack of invasiveness, has evolved as a first line method in thyroid imaging. Additional techniques including thyroid szintigraphy are added more selectively when adequate for answering specific questions.

Ultrasonography

Technically, ultrasonography of the thyroid requires the use of a linear sector scanner in a B-Mode with a 5 to 7,5 mHz frequency. In addition a 3.5 to 5 mHz transducer may be advantageous for a particularly large thyroid gland and substernally located parts of the thyroid. Focal lesions exceeding a size of three mm in diameter should be reliably identified. Color Doppler sonography may aid in visualising vascularisation of the entire gland and of thyroid nodules. An example of diffuse hypervascularisation in a patient with active Graves' disease is depicted in Figure 7. Hypervascularisation within a thyroid nodule may indicate malignancy. However, further studies are needed to define the role of this technique in the diagnostic workup of thyroid nodules. Figure 8 shows Color doppler imaging of an autonomously functioning thyroid nodules and Figure 9 of a medullary thyroid cancer.

The documentation of a thyroid ultrasonography examination should include:

calculation of thyroid volume

echo pattern of the thyroid gland (normal / hypoechoic; homogeneous/inhomogeneous)

localization and size in three dimensions of focal lesions and nodules

structure (solid/liquid/calcified) and echoic pattern (normal/hypoechoic/hyperechoic) of focal lesions and nodules

neighbouring organs such as lymph nodes and the parathyroid glands.

View figure 7

View figure 8

View figure 9

Scintigraphy

Scintigraphic examination of the thyroid gland permits a judgement of the functional activity of the thyroid as well as estimates of the regional distribution of the activity. Interpretation of scintigraphic images will be done in conjunction with the result of ultrasonography.

Scintigraphy with 99m-Technetium is indicated in case of:

Palpable or sonographically localized nodule > 1 cm

Suspicion of autonomously functioning thyroid tissue

Differential diagnosis of Graves' hyperthyroidism versus hyperthyroid state of painless and postpartum thyroiditis.

Documentation of successful ablation of autonomously functioning thyroid nodules following radioiodine therapy.

Szintigraphy with 123-Iodine is indicated:

For the location of ectopic thyroid tissue

For the differential diagnosis of mediastinal mass

For perchlorate discharge test.

Scintigraphy with 131-Iodine is indicated:

For dose calculation before radioiodine therapy.

During the follow-up of therapy of differentiated thyroid carcinoma.

Fine Needle Aspiration

We prefer fine needle aspiration with cytological examination over thyroid biopsy, because diagnostic accuracy of the two methods is about equal and the former is less traumatic and causes less side effects, such as bleeding complications or potential translocation of malignant cells than the latter. We recommend puncture after local desinfection without anaesthesia with the use of a canule 0.6 to 0,7 mm in diameter. For smaller nodules, the correct targeting of the needle must be supervised by ultrasonography.

Indications for fine needle aspiration generally include:

· Any nodule exceeding 1.0 cm in size, except for scintigraphically documented autonomously functioning nodules which are known to rarely harbor carcinoma. Smaller lesions may in most cases be sufficient to be followed up by ultrasonography after 3-6 months, thereafter at yearly intervals. In that case the delay in diagnosis of a differentiated thyroid microcarcinoma would not adversely affect the prognosis of the patient.

· Rapidly growing focal lesions.

· Suspicion of an intrathyroidal metastasis of a non-thyroidal tumor.

· Purulent thyroiditis

· Subacute thyroiditis de Quervain if diagnosis is ambiguous

· Chronic autoimmune thyroiditis in case of a suspicion of lymphoma

· Aspiration of cysts.

Sensitivity and specificity of cytology has been reported to be approximately 90 and 95 % respectively, three prerequisites being attainment of an appropriate sample, interpretation by an experienced cytologist and correlation to clinical features. While papillary carcinoma may cytologically be readily recognizable, follicular carcinoma may hardly be distinguished from follicular adenoma, except by demonstration of capsular or vascular invasion but not by cytomorphological criteria. For that reason, the term follicular neoplasia has been coined to comprise benign or malignant follicular tumors. Cytological finding of follicular neoplasia requires surgery, preferably hemithyroidectomy, and careful examination of histological sections.

Prof. Klaus Mann

Prof. Klaus Mann is head of the Department of Endocrinology at the University of Essen. He and his coworkers Prof. Dr. Rudolf Hörmann and Dr. Bernhard Saller have a long-lasting clinical and scientific interest in the field of thyroid diseases. As the representative of the Thyroid Section of the German Endocrine Society he presently is responsible for preparation and distribution of national guidelines for diagnosis and treatment of thyroid diseases. main areas of work have been thyroid autoimmunity, iodine deficiency and excess and hyperthyroidism in pregnancy and trophoblastic tumors. As a model for specific pharmacological interaction with the TSH receptor an hCG derived experimental TSH receptor antagonist was developed. Clinical and molecular experience extends to a variety of rare diseases such as multiple endocrine neoplasia, thyroid hormone resistance and TSH producing tumors.

References

Boscato LM, Stuart MC. Heterophilic antibodies: a problem for all immunoassays. Clin Chem 1988; 34:27-33.

Davies PH, Franklyn JA. The effects of drugs on tests of thyroid function. Eur J Pharmacol 1991; 40: 439-451.

Feldt-Rasmussen U, Schlumberger M. European interlaboratory comparison of serum thyroglobulin measurement.Endocrinol Invest 1988: 11: 175-188.

Fraser CG, Petersen PH. Desirable standards for laboratory tests if they are to fulfill medical needs. Clin Chem 1993; 39: 1447-1455.

Hay ID, Bayer MF, Kaplan MM, Klee GG, Larsen PR, Spencer CA. American Thyroid Association asessment of current free thyroid hormone and thyrotropin measurements and guidelines for future clinical assays. Clin Chem 1991; 37: 2002-2008.

Helfland M, Crapo LM. Screening for thyroid disease. Ann Intern Med 1990; 112: 840-849.

NACB Symposium: Standards of laboratory practice symposium on thyroid-function testing. Clin Chem 1996; 42: 119-192.

Saller B, Esser I, Horn K, Jockenhövel F, Klett M, Köbberling J, Moll C, v z Mühlen A, Raue F, Schober O, Schürmeyer Th, Schuppert F, Mann K (1997) Diagnostik und Therapie von Schilddrüsenkrankheiten - Empfehlungen zur Qualitätssicherung - Sektion Schilddrüse d. Deutschen Gesellschaft für Endokrinologie. Teil I - Diagnostik von Schilddrüsenkrankheiten. Internist 1997; 38: 177-185.

Spencer CA, Takeuchi M, Kazarosyn M, MacKenzie F, Beckett GJ, Wilkinson E. Interlaboratory/ intermethod differences in functional sensitivity of immunometric assays for thyrotropin (TSH): impact on reliability of measurement of subnormal concentrations. Clin Chem 1995: 41: 367-374.

·	Any nodule exceeding 1.0 cm in size, except for scintigraphically documented autonomously functioning nodules which are known to rarely harbor carcinoma. Smaller lesions may in most cases be sufficient to be followed up by ultrasonography after 3-6 months, thereafter at yearly intervals. In that case the delay in diagnosis of a differentiated thyroid microcarcinoma would not adversely affect the prognosis of the patient.
·	Rapidly growing focal lesions.
·	Suspicion of an intrathyroidal metastasis of a non-thyroidal tumor.
·	Purulent thyroiditis
·	Subacute thyroiditis de Quervain if diagnosis is ambiguous
·	Chronic autoimmune thyroiditis in case of a suspicion of lymphoma
·	Aspiration of cysts.