Nils Knudsen

Risk Factors for Goiter and Thyroid Nodules

The occurrence of thyroid diseases is determined by interplay between genetic and environmental factors. The major environmental factor that determines goiter prevalence is iodine status, but other environmental factors influencing entire populations have been identified such as goitrogens in food and drinking water. Less focus has been on individual environmental factors and the interplay between factors. The goiter prevalence is higher in certain groups in the population. The variation in goiter prevalence between the genders is well known with a higher occurrence among women. The association with age is probably dependent on iodine status, because it seems that the zenith of goiter prevalence appears earlier in life the more severe iodine deficiency the population is exposed to. The association with individual risk factors has been investigated in some studies, especially the association with tobacco smoking. In iodine-deficient areas, a strong association between tobacco smoking and goiter prevalence is found, whereas the association is less pronounced in iodine-replete areas. This was predictable from experimental studies showing thiocyanate to be the mediator of the goitrogenic effect of tobacco smoke acting as a competitive inhibitor of iodine uptake. The association with alcohol intake has only been investigated in few studies, but a low occurrence of goiter among alcohol consumers has been found. The mechanism of this association is not known. Increased goiter prevalence during pregnancy has been reported, and recently a long-term goitrogenic effect of pregnancies has also been shown. As demonstrated for tobacco smoking, this association is dependent on iodine status, because the association has only been found in areas with a suboptimal iodine intake. This indicates pregnancy-induced goiter to be the result of exacerbation of existing iodine deficiency. Recently, the use of oral contraceptives has been shown to be associated with a markedly reduced prevalence of goiter, although experimental studies have previously shown proliferative effects of estrogens on thyrocytes. Some implications for prevention of thyroid disease could be suggested. Discussion of smoking habits should be included in a consultation for goiter with a motivation to quit smoking. Iodine deficiency has particularly strong goitrogenic effects during pregnancy and for the sake of the mother as well as the fetus, sufficient iodine supply should be ensured to all pregnant women. The difference in age maximum in goiter prevalence suggests that monitoring of iodine deficiency disorders should ideally include a spectrum of age groups.

Thyroid peroxidase and thyroglobulin autoantibodies in a large survey of populations with mild and moderate iodine deficiency

background and aims Autoimmune thyroiditis is one of the most common autoimmune disorders. Autoantibodies against the thyroid gland, with thyroid peroxidase antibody (TPO‐Ab) and thyroglobulin antibody (Tg‐Ab) as the most common autoantibodies, can often be demonstrated in serum in population surveys. In the present study we evaluated if TPO‐Ab and Tg‐Ab tend to develop in parallel or whether one or the other may be more prevalent in subsets of the population.

Iodine intake before and after mandatory iodization in Denmark: results from the Danish Investigation of Iodine Intake and Thyroid Diseases (DanThyr) study

Iodine deficiency is still common in some European countries. In Denmark an iodine fortification programme was introduced in 1998 and a monitoring programme was established prior to iodization. This study reports the change in urinary iodine excretion caused by fortification and investigates determinants of iodine intake after fortification. Iodine excretion in casual urine samples was assessed in 4649 subjects in 1997-8 and in 3570 comparable subjects in 2004-5 in women 18-22, 25-30, 40-45 and 60-65 years of age and in men 60-65 years of age living in Aalborg (western part of Denmark) or Copenhagen (eastern part of Denmark). These areas had moderate and mild iodine deficiency, respectively, before iodine fortification. All subjects filled in a FFQ and a questionnaire regarding lifestyle factors. Iodine excretion, expressed as the estimated 24 h urinary iodine excretion and as urinary iodine concentration, increased significantly in all age and sex groups. However, the iodine intake was still below the recommended in the youngest age groups in both cities and in women 40-45 years of age living in Aalborg. Intake of milk and salt had strong significant direct associations with iodine excretion (P < 0.001). It is concluded that although the median iodine intake in the whole study population is at the recommended level, some groups still have an intake below the recommended. It is important to have a moderate milk intake to obtain a sufficient iodine intake in Denmark.

A cautious iodization programme bringing iodine intake to a low recommended level is associated with an increase in the prevalence of thyroid autoantibodies in the population

Autoantibodies against the thyroid gland with thyroid peroxidase antibody (TPO‐Ab) and thyroglobulin antibody (Tg‐Ab) as the most common can often be demonstrated in serum. The effect of public iodization programmes on antibody prevalence is uncertain.

Thyroglobulin as a marker of iodine nutrition status in the general population

OBJECTIVE The iodine status of a population is traditionally evaluated by either urinary iodine (UI) excretion or by some measure of thyroid volume and the prevalence of goitre. In this prospective study of a mandatory iodization programme, we aimed to evaluate serum thyroglobulin (Tg) as a marker of iodine status in the population. METHODS Two identical cross-sectional studies were performed before (1997-1998, n=4649) and after (2004-2005, n=3570) the initiation of the Danish iodization programme in two areas with mild and moderate iodine deficiency. Serum Tg was measured from blood samples. Thyroid volume was measured by ultrasonography. RESULTS Before iodization, the median serum Tg was considerably higher in moderate than in mild iodine deficiency. Iodization led to a lower serum Tg in all examined age groups. The marked pre-iodization difference in Tg level between the regions was eliminated. The prevalence of Tg above the suggested reference limit (40 microg/l) decreased from 11.3 to 3.7% (P<0.0001). Using bootstrapping, we demonstrated a higher efficacy of Tg than of thyroid volume to show a difference between pre- and post-iodization values. CONCLUSION We found serum Tg to be a suitable marker of iodine nutrition status in the population. The results may suggest that the Danish iodization programme has led to a sufficient iodine intake, even if the median UI excretion is still marginally low according to WHO criteria.

The TSH upper reference limit: where are we at?

The diagnosis of subclinical hypothyroidism—serum TSH levels above and T4 levels within the laboratory reference ranges—depends critically on the upper limit of the TSH reference interval. Calls have been made to lower the current upper TSH reference limit of 4.0 mU/l to 2.5 mU/l to exclude patients with occult hypothyroidism. However, data from population studies do not indicate that the distribution of TSH is altered owing to inclusion of such individuals. The opposite suggestion has also been put forward; the TSH upper reference limit is often too low, especially in the elderly, in women and in white individuals, which may lead to unnecessary or even harmful therapy. Studies in elderly individuals have shown that although aging may be associated with increased TSH levels, paradoxically, overt hypothyroidism in this population may be associated with a less robust TSH response than in young individuals. This Review highlights the interindividual and intraindividual variability of TSH levels and discusses the current controversy that surrounds the appropriateness of reference ranges defined on the basis of age, race, sex and amount of iodine intake. Moreover, the current evidence on lowering or increasing the upper limit of the TSH reference interval is reviewed and the need to individualize levothyroxine treatment in patients with elevated TSH levels is discussed.

Thiocyanate in food and iodine in milk: from domestic animal feeding to improved understanding of cretinism.

Transport of iodine in the mammary gland into breast milk plays a central role in various fields of prevention of thyroid diseases. First, a sufficient content of iodine in the mothers milk is necessary for normal brain development in the breastfed child. This is attained by expression during lactation in the mammary gland of the sodium iodide symporter (NIS), also responsible for iodine transport in the thyroid. Milk iodine content varies with the iodine intake of the mother, and urinary iodine excretion in groups of mothers seems to be a valuable indicator of the iodine status of their breastfed children. Second, iodine in dairy products provides a considerable part of iodine intake in many populations. Thiocyanate from rapeseed feeding of cows decreases milk iodine content, probably by competitive inhibition of NIS in the mammary gland. Alterations in feeding of dairy cows may alter the iodine content of consumer milk, and this may influence the risk of thyroid diseases in the population. Thiocyanate inhibition of iodine transport into milk may also be operative in humans with a high thiocyanate intake. This could further impair iodine status in breastfed children in low-iodine intake areas of the world. It can be speculated that a low-iodine content of mothers milk because of inhibition of NIS in the mammary gland may be one factor of importance for development of myxedematous cretinism.

Evaluating iodine deficiency in pregnant women and young infants—complex physiology with a risk of misinterpretation

OBJECTIVE To review methods for evaluating iodine deficiency in pregnant women and young infants and to discuss factors to be considered in the interpretation of their results. DESIGN Review of the literature regarding the various methods available for assessing iodine status. SETTING Population surveys and research studies. SUBJECTS Pregnant women and young infants. RESULTS Several factors to consider when assessing iodine status in pregnant women and young infants include: 1) the urinary iodine (UI) concentration (microg l-1) is not interchangeable with 24 h UI excretion (microg per 24 h); 2) the concentration of iodine in a spot or casual urine sample cannot be used to diagnose iodine deficiency in an individual; 3) a moderate fall in the concentration of serum free T4 during pregnancy is not a sign of maternal iodine deficiency; 4) an increase in the concentration of serum thyroglobulin (Tg) during pregnancy is not a sign of maternal iodine deficiency; 5) a higher concentration of TSH and Tg in cord blood than in maternal blood is not a sign of iodine deficiency in the mother or neonate; and 6) thyroid function in a full-term foetus, a neonate or a small child is not more sensitive to a mild iodine deficiency than in the mother. CONCLUSIONS If the iodine status of pregnant women and small children is not to be misjudged, the above six factors need to be taken into account.

Alcohol consumption is associated with reduced prevalence of goitre and solitary thyroid nodules

OBJECTIVE Goitre prevalence is dependent on iodine intake and smoking habits, but further risk factors have only been examined briefly. We examined the association between alcohol consumption and the prevalence of thyroid enlargement and nodularity.

Smoking is negatively associated with the presence of thyroglobulin autoantibody and to a lesser degree with thyroid peroxidase autoantibody in serum : a population study

BACKGROUND Autoimmune thyroid diseases are common and the prevalence of circulating thyroid antibodies (thyroid peroxidase antibody, TPO-Ab and thyroglobulin antibody, Tg-Ab) is high in the population. The knowledge of a possible association between lifestyle factors and circulating thyroid antibodies is limited. AIM To evaluate the correlation between smoking habits and the presence of circulating TPO-Ab and Tg-Ab. MATERIAL AND METHODS In a cross-sectional comparative population study performed in two areas of Denmark with moderate and mild iodine deficiency, 4649 randomly selected subjects from the population in some predefined age groups between 18 and 65 years were examined. Blood tests were analysed for TPO-Ab and Tg-Ab using assays based on the RIA technique. The participants answered questionnaires, were clinically examined and blood and urine samples collected. RESULTS Data were analysed in multivariate logistic regression models. There was a negative association between smoking and the presence of thyroid autoantibodies in serum. This association was observed for the presence of TPO-Ab and/or Tg-Ab, TPO-Ab (without respect to Tg-Ab status), Tg-Ab (without respect to TPO-Ab status) and both antibodies together. The association between smoking and thyroid autoantibodies was stronger for Tg-Ab than for TPO-Ab. There was no association between smoking and TPO-Ab measured alone or between smoking and TPO-Ab when Tg-Ab was included in the model as an explanatory variable. CONCLUSION Smoking was negatively associated with the presence of thyroid autoantibodies with the strongest association between smoking and Tg-Ab. The study design precludes any conclusions as to the cause of the negative association between smoking thyroid autoantibodies.