Importance of the Thyroid

Most investigators have found hypothyroidism in the DS population, with estimates of prevalence as high as 50% (Pueschel, 1990). This means that hypothyroidism is sometimes interpreted as being part of the ‘Down’s Syndrome Gestalt’, and that thyroid function should be one system that is regularly monitored and treated as appropriate (ibid). Indeed much of the controversy surrounding the failure of researchers to replicate the success of Harrell et al (1981) in treating DS children with nutritional supplements hinged on the fact that the original work included thyroid hormone treatment, indicated to be necessary by the Barnes method. Investigators announced thyroid medication did not influence Harrell’s final results (Smith et al, 1984), assessed thyroid function by T4 and TSH values and by thyroid palpitation (Bennett et al, 1983) — much less efficient and reliable methods than the Barnes method (Barnes and Galton, 1976) — or did not mention thyroid at all (Weathers, 1983;Bidder et al, 1989). These deviations from the original investigation are believed to nullify the usefulness of the repeat experiments (Rimland, 1983a and b; Davis, 1985), showing the importance of thyroid function when considering DS people. Pueschel also states that failure to recognise thyroid dysfunction early enough can lead to further disturbances to the central nervous system.

It should be noted that, although hypothyroidism is by far the most common thyroid dysfunction in DS and the one with which most researchers choose to work, a higher incidence than hyperthyroidism has also been reported (Pozzan et al, 1990). As certain parameters of thyroid function were universally found to be abnormal it is this author’s opinion that both hypo- and hyperthyroidism in DS could very well have the same root cause.

Function of the thyroid and thyroid hormones

The thyroid hormones regulate oxygen use and basal growth rate, cellular metabolism, and growth and development. There are two thyroid hormones under consideration in relation to DS (the third, calcitonin, is unrelated), T3 and T4. T4, also known as thyroxine, is manufactured in the thyroid from a glycoprotein, thyroglobulin, and is the inactive form. T3, triiodothyronine, is the active form and is made from T4. Reverse T3 (rT3) is also made from T4 but is inactive. This may be a mechanism for disposing of excessive amounts of T4. Thyroid hormones are hydrophobic molecules which usually travel in the blood bound to a protein - specialised alpha globulin or albumin - and are inactive until released. A tiny fraction of the total T3 and T4 is free T3 and T4 (FT3 and FT4), and it is the concentration of free thyroid hormones that determines the effectiveness of these hormones. As they are lipophilic, the thyroid hormones are able to diffuse across plasma membranes and bind to receptors within the cell. This binding increases a receptor’s affinity for specific DNA sequences, controlling the rate of transcription of the appropriate gene. Secretion of T3 and T4 is stimulated by thyroid stimulating hormone (TSH, also known as thyrotropin), the secretion of which is stimulated in turn by thyrotropin releasing hormone (TRH). The release of TRH depends on blood levels of TSH, T3, glucose, and on the body’s metabolic rate.

Thyroid dysfunction in Down’s syndrome

Research into thyroid function and zinc therapy in DS is still in its infancy and a clear picture has yet to form. The patterns that have emerged so far are that DS subjects exhibit:

The causes of these unusual ratios of hormones are as yet unknown. However, several authors make similar suggestions as to why TSH would be raised and T3 and T4 levels normal - i.e. why the thyroid has not been stimulated to release excess thyroid hormones. It is possible that there is some kind of dysfunction of communication between the hormone and its receptor. Napolitano et al mention some kind of resistance syndrome, Pozzan et al posit the possibility of a less active TSH, and Sustrová and Strbák also put forward the idea, amongst others, of a hormone resistance. Licastro et al (1992) have a different approach, suggesting that there may be an increased rate of T4 degradation in the periphery, and that the body needs to secrete increased amounts of T4 to maintain a homeostasis.

Licastro et al (1992) put forward two possible reasons for the lowered amounts of rT3 found in DS subjects: a decrease in formation T4 due to most of the T5 transforming into T3; or an increased conversion of rT3 into T2 (one of the precursors of T3 and T4). The latter is interesting as Lejeune states that excess SOD1 (discussed later) experimentally increases the transformation of rT3 into (inactive form) T2.

Sustrová’s and Strbák’s paper adds an interesting dimension to this picture as they separated their subjects by age into 3 groups: DS1 = 1-6 years, DS 2 = 6-15 years, and DS3 = 15-35 years. They found that all three groups had high TSH levels, high thyroxine binding globulin (TBH) levels, and low FT3 and FT4 levels. However, the T3 and T4 results told a more complicated story. DS1 had high levels of T3 and T4, DS 2 had high T3 and low T4, and DS 3 had T4 and T3 which were in lower concentration than the controls. Were the other researchers finding ‘normal’ levels of thyroid hormones because they were combining the high levels of the youngest subjects with the low measurements of the oldest? This could be true of Napolitano et al and Bucci et al whose DS subjects spanned the Sustrová’s and Strbák’s groups, though Bucci did find a significant inverse correlation between age and both T3 and FT3 levels. Licastro et al (1993a) fail to give the ages of the “children” in their 1993 paper - they could be as old as 17 or 18- but in their 1992 paper their DS subjects are 6-15 years old. Though this is the same age as the DS 2 group, Licastro et al (1993a) found normal T3 and T4 levels, thus contradicting Sustrová and Strbák. However, the idea that thyroid hormone production declines with age in DS people is worth further investigation and if true would beg many questions. Does TSH effectiveness decline? Does the ability of the thyroid to manufacture its hormones decline?

How could thyroid dysfunction be associated with the pathology of Down’s syndrome?

The thyroid hormones, along with insulin and human growth hormone, are responsible for accelerating body growth. It has been found that low rT3 levels could impair growth hormone stimulation (Lejeune), and that all DS children with elevated TSH exhibit more severe growth delay (Bucci et al). Increased weight gain often becomes apparent in many individuals with DS (Pueschel), a common symptom of hypothyroidism as the thyroid controls basal metabolic weight. Indeed Pueschel states that one cause of weight gain in DS is a decreased intracellular metabolic rate. Thyroid dysfunction interferes with the hypothalamic-pituitary-thyroid axis which modulates thymic activity, thus affecting immunity (Napolitano et al) and DS subjects are characterised by an unbalanced immune control including poor performance by the thymus (Serra and Neri, 1990). Both thyroid hormone deficiency (Barnes and Galton) and DS (Lejeune) are associated with mental retardation. Lejeune discusses the role of the thyroid in directing tubulin organisation, and points out that only three conditions exhibit neurofibrillary tangles: Alzheimer’s disease, hypothyroidism, and DS. It is interesting that many of the physical characteristics of cretinism (extreme thyroid deficiency during foetal or early life) correspond with those of DS such as enlarged tongue, open mouth, broad face and flat nose.

What role does zinc play?

Altered zinc levels have been observed in both DS subjects and in hypothyroid patients when compared to controls (Napolitano et al; Bucci et al), though the roles zinc plays are only beginning to be teased out.

Thyroid hormone receptors require zinc ions (Licastro et al, 1992; Sustrová and Strbák) which facilitate folding into their active shape (Bucci et al). Zinc is also required for binding thyroid hormone receptors to the target DNAs, called thyroid response elements (Licastro, 1992; Bucci et al). A zinc deficiency may require more of a hormone to be secreted in order that enough is taken up. Sustrová and Strbák suggest that if the pituitary receptors were affected, normal thyroid hormone concentrations would not inhibit TSH secretion. This author wonders whether TSH receptors are rendered less active by zinc deficiency, meaning more TSH must be secreted to maintain a normal level of T3 and T4.

Zinc is required by thyroid hormone deiodinase, which modulates the deiodination activity vital for the homeostasis of the thyroid hormones. Thyroid hormone deiodinase converts T4 to T3, and removes the iodine ions from excess T1 and T2 (thyroid hormone precursors) to be reused in the synthesis of more T3 and T4. Perhaps a zinc deficiency would affect the rate of conversion of T4 to rT3 via the deiodinising enzyme?

It is impossible to ignore the connection between the function of the thyroid and of the thymus, especially when discussing the importance of zinc. There is a close correlation between zinc, the thymic hormone and the pituitary-thyroid axis. Thymulin - the thymic hormone - is associated with an improvement in thyroid function (Bucci et al) and each thymulin molecule contains a zinc ion (thymic function is discussed in more detail further on).

Zinc may affect the action of the binding proteins that carry thyroid hormones, and this could interfere with the pituitary-thyroid axis (Napolitano et al).

Zinc deficiency appears to affect the utilisation of thyroid hormones in the peripheral tissues (Licastro et al, 1992).

What effect does zinc supplementation have on thyroid function?

Every piece of research this author found which measured the effects of zinc supplementation on DS thyroid function found significant changes. However these changes were different in almost every case, and sometimes contradictory. Each piece of research supplemented the subjects by os, that is 1mg of supplement per kg body weight per day. Though most stated the use of zinc sulphate, some, such as Licastro (1992), did not make clear whether the measurement was of elemental zinc or a zinc compound. This would affect the amount of elemental zinc the children were receiving. This could be one of the reasons behind variations in results. 1mg per kg per body weight is a high dose when compared with the governmental Estimated Average Requirement for the normal population. Using growth charts for children with DS (Cronk et al, 1988) to estimate bodyweight a 1-3 year old would be given 12.5mg while the EAR is 3.8mg per day, and a 15 year old would be supplemented with 55mg instead of the EAR 7.3mg.

In both their 1992 and 1993 papers, Licastro et al found that TSH levels returned to normal with zinc supplementation. Bucci et al note that it was the hypozincaemic DS subjects which exhibited high TSH and that they experienced a significant decrease after supplementation. Conversely, Napolitano et al found that TSH remained the same after 6 months supplementation and Sustrová and Strbák found that after a year of alternating three months with supplementation with three months off, ending on three months off, the TSH levels were found to rise. The only papers to measure rT3, both by Licastro et al, found a rise to normal levels after supplementation. These papers also found T3 and T4 remained the same while Napolitano et al found a rise in T3, and Sustrová and Strbák found a drop in T4. Napolitano et al found a drop in FT3 after zinc treatment, and Bucci et al found that FT4 levels reduced significantly, also reducing the FT4/FT3 ratio.

Clearly zinc deficiency is implicated in DS thyroid dysfunction, but to come closer to understanding its actions, the benefits of supplementation and the best kind of regime, it would be appropriate to:

This author believes that more research is necessary before any conclusions can be drawn beyond that of zinc having an important and beneficial part to play. As it is important for the thyroid to be functioning optimally for growth and development from as early an age as possible research which observes the effects of zinc supplementation from birth could prove to be very useful.