The purpose of this review is to summarize current knowledge of the etiology of euthyroid and toxic multinodular goiter (MNG) with respect to the epidemiology, clinical characteristics, and molecular pathology. In reconstructing the line of events from early thyroid hyperplasia to MNG we will argue the predominant neoplastic character of nodular structures, the nature of known somatic mutations, and the importance of mutagenesis. Furthermore, we outline direct and indirect consequences of these somatic mutations for thyroid pathophysiology and summarize information concerning a possible genetic background of euthyroid goiter. Finally, we discuss uncertainties and open questions in differential diagnosis and therapy of euthyroid and toxic MNG.

Thyroid ultrasound is used in the routine clinical assessment and the follow-up of thyroid disorders. The follow- up of patients with thyroid nodules is mostly based on thyroid nodule volume determinations performed by different observers. However, for the judgment of treatment effects there is uncertainty about the interobserver variation of thyroid nodule volume measurements by ultrasound because there are no prospective blinded studies available comparing the interobserver variation in thyroid nodule volume measurement. The aim of our study was therefore to determine the variation of thyroid nodule volume determinations for different observers. We conducted a prospective blinded trial. Our study population consisted of 42 probands (8 men, 34 women) with an uniform distribution of thyroid nodule sizes (25 uninodular and 17 multinodular thyroid glands). We compared the results of 3 ultrasonographers with certified experience in thyroid ultrasound. The interobserver variation for the determination of thyroid nodule volume (n = 38) was 48.96% for the ellipsoid method and 48.64% for the planimetric method. The interobserver variation for determining thyroid volume (n = 40) was 23.69% for the ellipsoid method and 17.82% for the planimetric method. A regression analysis revealed that the probability for the identification of the same nodule in nodular thyroids by all sonographers is 90%, if the nodule is at least 15mm in greatest diameter. Future investigations should not describe changes in nodule volume less than 50% as therapy effects because only volume changes of at least 49% or more can be interpreted as nodule shrinkage or growth. Reporting of nodule volume modification 50% or more and lack of information for ultrasound procedures introduce a bias in studies evaluating the effects of nodule treatments. The clinical interpretation of a shrinking/growing thyroid nodule based on volume determinations by ultrasound is not well established because it is difficult to reproduce a two-dimensional image plane for follow-up studies.

We determined the influence of different nutritional factors on the urinary iodine excretion in an East German university population. First, we assessed iodine excretion in spot urine samples. Second, we measured iodine content in the university canteen meals, where approximately 20% of the probands had regular meals. Third, we used a special food questionnaire to assess for other sources of nutritional iodine intake, namely iodine tablets, fish consumption, etc. Fourth, we determined the actual prevalence of goiter and thyroid nodules in our probands by high-resolution ultrasonography. The mean urinary iodine excretion in our cohort was 109 +/- 81 microg/g level indicating a borderline adequate iodine intake (100-200). The frequency of thyroid nodules was 30% and the frequency of goiter 11%. Thyroid volumes greater than 18 mL and 25 mL were considered to be enlarged in adult women and men respectively. Urinary iodine excretion was not related to the presence of goiter or thyroid nodules. In addition urinary iodine excretion did not vary with regular consumption of canteen meals, which contained approximately 50% of the daily recommended iodine intake. In contrast probands with regular supplementary intake of iodine tablets had significantly higher values of urinary iodine excretion (169 +/- 130 microg/g) compared to participants without (103 +/- 87 microg/g). No other single nutritional factor (e.g., salt, milk, or bread) had a statistically significant impact on urinary iodine excretion or was able to raise the urinary iodine excretion above the level of marginal iodine deficiency. In summary, the nutritional iodine intake in a Saxonian study population was found to be close to the margin of iodine deficiency. This shows insufficient supplementation of iodine through iodized salt/industrialized food production.

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Objective: Thiocyanate (SCN 2 ) has concentration dependent antithyroid properties and a role in the etiology of goiter has been suggested in several studies. In 1991 an epidemiological survey conducted in the region of Halle/Leipzig (Saxony), an area with significant air pollution, suggested an inverse relationship between urinary iodine (I 2 ) /SCN 2 excretion and goiter prevalence. 10 years later, we reinvestigated the same industrial area to clarify if the situation has changed after the elimination of most industrial waste products and moreover, if SCN 2 excretion levels alone or in combination with air pollution or smoking as a SCN 2 source are critical for thyroid function. Design and methods: We investigated a cohort of 708 probands for I 2 , SCN 2 and creatinine excretion in spot urine samples and determined the prevalence of goiter and thyroid nodules by high resolution ultrasonography. Results: Probands with goiter (n ¼ 79, 11%) had significantly higher urinary SCN 2 excretions than probands without (3.9^2.8 vs 3.1^3.4 mg SCN 2 /g creatinine) and significantly lower urinary I 2 /SCN 2 ratios than patients without thyroid disorders (41^38 vs 61^71 mg I 2 /mg SCN 2 /l). Mean urinary I 2 excretions were not different between probands with or without goiter. Smokers showed significantly elevated urinary SCN 2 /creatinine ratios in comparison to non-smokers (4.3^4.3 vs 2.4^2.1 mg SCN 2 /g creatinine). ANOVA revealed a prediction of thyroid volume through age (P , 0.001), gender (P , 0.001), body weight (P , 0.05) and smoking (P , 0.05). Conclusions: In our investigation, age, gender and smoking (raising SCN 2 levels by CN 2 inhalation) were predictive for thyroid volume and the urinary I 2 /SCN 2 ratios were able to detect probands with an increased risk of developing goiter in contrast to urinary I 2 excretion levels alone. These data suggest, that in an era and area of decreased cyanide pollution, SCN 2 may remain a cofactor in the multifactorial aetiology of goiter.European Journal of Endocrinology 154 229-235

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In our investigation, USe was not an independent risk factor for the development of goiter. The higher USe in probands with goiter in comparison with probands with normal thyroid volume is most likely a coincidence. Se does not significantly influence thyroid volume in borderline iodine sufficiency because the iodine status is most likely the more important determinant.

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