Hormonal and Metabolic Evaluation in Down's Syndrome: Preliminary Evidence for TSH Dysregulation in Hyperthyrotropinemic Patients

Dear Editor

Patients with Down's Syndrome (DS) are particularly vulnerable to the development of hypothyroidism ([Bhaumik et al., 1991]), but an inappropriate TSH secretion, rather than a true hypothyroidism, could account for the increased TSH concentrations ([Selikowitz, 1993]).

To further explore thyroid function in DS, also for the therapeutic implications, we have studied the TSH response to TRH in a group of patients with this disorder and correlated the results with the concentration of metabolic indexes of thyroid function, such as CoQ10 ([Mancini et al., 1991]), and SHBG ([Doumoulin et al., 1995]), and intellective evaluation.

A group of 13 patients with DS, 8 males and 5 females, aged 14 - 37 ys, participated in this study. The diagnosis of subclinical hypothyroidism had been suspected in 5 of them, and a L-thyroxine therapy had been performed in 2, and suspended at least three months before the present study.

The intellective level of DS subjects was evaluated through the administration of the adult Wecksler scale (WAIS) after the age of 16, of the children Wecksler scale (WISC) before the age of 16. All patients underwent specialistic examinations to exclude sensorial defects.

A group of 10 normal subjects, 5 males and 5 females, aged 25 - 42 and 21 - 59 ys, respectively, was studies as normal controls. As DS patients exhibited a higher BMI than controls, the results were also compared with a group of ten overweight subjects, 5 males and 5 females, aged 18 - 25 and 20 - 27 ys, respectively, with BMI matched (27 ± 1.30 kg/mq) with Down patients (mean ± ES 28 ± 1.09 kg/mq).

The thyroid function was evaluated through the measurement of basal thyroid hormone levels (T3, T4, FT3, FT4), SHBG and CoQ10 determination, the lipid profile assessment, and a standard TRH-test (Relefact, Hoechst, 200 µg iv).

Plasma CoQ10 was measured by a high performance liquid chromatography method, using an ultraviolect detector (275 nm), as previously described ([Mancini et al., 1991]).

Basal thyroid hormones and TSH levels are reported in Table [1]. Higher basal TSH levels were observed in DS vs. normal and obese subjects, while they did not show any alteration in basal thyroid hormone levels. The research for antithyroid antibodies was positive only in 2 patients.

Table 1 Hormonal profile, metabolic indexes (CoQ10 and SHBG), and intellective scores of DS patients, distinguished on the basis of TSH values (mean ± SEM) FT3 (pmol/l) FT4 (pmol/l) TSH Basal (mU/l) TSH Peak (mU/l) CoQ10 (µmol/l) SHBG males (nmol/l) SHBG females (nmol/l) QI‐V QI‐NV QI‐T ABS O‐I ABS G - I Down patients 6.31 ± 0.46 24.19 ± 9.91 2.34 ± 0.4 13.39 ± 1.92 0.69 ± 0.07 20.44 ± 1.39 52.54 ± 10.34 Group A 6.58 ± 0.57 13.5 ± 1.03 4.86 ± 0.49 12.50 ± 2.16 0.71 ± 0.14 20.32 ± 1.22 48.35 ± 30.6 43.8 ± 0.8 45.4 ± 2.2 40.8 ± 0.73 169 ± 24.0 164.5 ± 12.8 Group B 6.08 ± 0.65 33.2 ± 18.1 2.05 ± 0.28 15.37 ± 3.11 0.67 ± 0.06 20.63 ± 3.61 55.3 ± 5.8 47.0 ± 0.89 # 49.2 ± 3.0 45.0 ± 1.10 # 160.3 ± 17.4 138.3 ± 19.7 Normal control 6.73 ± 0.30 15.45 ± 0.77 1.16 ± 0.21* 8.82 ± 2.15 0.77 ± 0.06 23.50 ± 2.70 60.70 ± 12.40 Obese controls 7.58 ± 0.31 14.16 ± 6.56 0.54 ± 0.13 * 7.83 ± 0.23 0.75 ± 0.06 21.56 ± 1.63 57.28 ± 7.5 * = p < 0.05 vs. Down patients

Despite a trend toward a higher TSH response to TRH in DS, no significant difference in TSH peak response was observed vs. normal and obese controls.

The patients were distinguished in two groups according to basal TSH levels (high TSH values, > 3.5 mU/l, group A, n = 6; normal TSH values, < 3.5 mU/l: group B, n = 7). The comparison of thyroid hormones, CoQ10, SHBG, and the scores of the tests of intellective levels in the two groups is shown in Table [1]. Significant differences were observed in groups A and B when considering the QI‐V and QI‐T results. No difference was observed in the thyroid function of the two groups, even when evaluated with the metabolic indexes (CoQ10 and SHBG) and TRH-test.

Our study did not show significant difference of TRH test vs. normal or obese controls, even in those patients who exhibited slightly augmented basal TSH levels.

Interesting data have been observed when distinguishing the subjects with normal and altered basal TSH values, concerning in particular the intellective evaluation of the two groups: the subjects with normal TSH basal values showed higher scores in the V‐QI and T‐QI (p < 0.05, see Table [1]). However, the two groups did not show any difference in the thyroid status, as shown by TRH-test and the other metabolic indexes used, such as CoQ10, previously demonstrated to be inversely correlated with thyroid hormone levels ([Mancini et al., 1991]) and SHBG, which is decreased in hypothyroidism ([Doumoulin et al., 1995]). It can be hypothesized that the higher TSH levels can be related to the mental retardation in DS, as observed by Bhaumik et al. ([Bhaumik et al., 1991]); however, the thyroid status does not seem to be involved in this phenomenon, since it is not different in DS patients and normal controls, even in presence of higher TSH values. An altered neural control of TSH, as observed in Alzheimer's dementia, can be considered ([Bhaumik et al, 1991]). The alteration of TSH in such a subgroup of patients was not related to obesity (as assumed according to experimented data on leptin and α‐MSH in obesity, with an augmented effect on TRH release, antagonized by Agouti-related peptides) ([Kim, 2000]), since peak TSH had a trend toward higher levels BMI-matched obese controls, although not significant; on the other hand, obese controls did not differ from normal controls in this respect.

In conclusion DS could represent another condition in which the evaluation of metabolic indexes, such as CoQ10 and SHBG, could fournish reliable indications on the metabolic status of the patients, since basal TSH values, even when clearly altered, do not allow to focus a hypothyroidism when considered alone. These considerations should be kept in mind when a thyroid dysfunction is suspected in DS, and the metabolic assessment should be carefully evaluated before starting a thyroid replacement therapy in such a condition.

References

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