SELECTED STUDIES


Section Editor: Prof. Talaat I. Farag

 

 

Endocrinological Deficits in Down’s Syndrome Patients
with Zinc Deficiency

 

By Rezk L. Al-Naggar1, Sadika A. Al-Awadi1 & Najat A. Al-Awadi2

 

1Kuwait Medical Genetic Center; and 2West Salmiya Health Clinic, Ministry of Health

 

 

 

Objectives:

Overt  and subclinical hypothyroidism are the most common endocrinal deficits in  patients with Down syndrome (DS). Hypozincemia  in DS patients is related to some endocrinal and immunological functions. Zinc deficiency has been found to impair immune response and growth rate. The aim of this study is to evaluate the role of zinc deficiency in subclinical hypothyroidism and growth hormone (GH) / Insulin like Growth Factor ( IGF-1 ) levels in DS patients before and after zinc supplementation. Results : An inverse correlation has been found between TSH levels and zinc values in hypozincemic patients before therapy ( P=<0.05 ). Higher TSH levels have been observed (> 4.2 mIU/L ) in 47% of cases. A statistically significant difference in GH levels between hypozincemic and normozincemic patients has been found (P = <0.001). Low GH values were recorded in hypozincemic patients with DS compaired to normozincemic patients . On the other hand IGF-1 levels have been found to be high in hypozincemic patients ( P= <0.001). There was also a significant association between the low zinc levels and impaired thyroid function and GH values (P= <0.05 ). There was an improvement of thyroid function ( TSH levels, 6.2+/-4.02 vs 2.72=/-1.64mIu/L ) after zinc supplementation of hypozincemic patients for 6 months.
Conclusion: Our present study showed that zinc deficiency has a remarkable effect on the thyroid function and the growth parameters in patients with DS. We recommend that our patients need further cycles of zinc supplementation to have more improvement in both  thyroid function and  growth parameters.

 

Introduction:

Subclinical hypothyroidism is the most endocrinal deficit inpatients with DS, as evidenced by normal level of thyroxine (T4), and elevated thyrotropine (TSH) hormones [1-4]. The raised levels of TSH have been described in up to 60 % of DS subjects. Thyroid antiperoxidase (AP) and antithyroglobulin (ATG) antibodies have been detected in 20-30% of patients, so causes other than thyroid autoimmunity could play a role in subclinical hypothyroidism in DS patients [5,6]. It has been suggested that the high TSH level has an indirect effect on growth rate observed in DS individuals [7]. The low plasma zinc level might be partially responsible for elevated TSH level. Zinc supplementation in the diet possibly restore immune function deficit, improve thyroid function and decrease TSH level [8-11]. The role of zinc deficiency in many endocrine disorders mainly related to hypofunction has been widely investigated and elucidated [12]. Growth delay, male hypogonadism and insulin secretion have been shown to improve after zinc supplementation in hypozincemic individuals [13-16]. The aim of the present work is to evaluate the effect of zinc deficiency and supplementation for 6 months on TSH, GH and IGF-1  in  patients with DS.

  

Subjects and methods:

 

Patients:

The present study include 57 cases ( 33 males & 24 females ) , age at the beginning of the study was 5.7+/-5.4 and the range 10/12 to 20 years. Fifty-six patients had regular trisomy - 21 and  a case had mosaic DS. Karyotyping was done using standard cytogenetic techniques to confirm the diagnosis using peripheral blood and GTG- banding methods. The patients were free from morphological and functional errors of thyroid gland and there was no family history of thyroid dysfunction. The DS patients divided into 3 groups regarding thyroid function : 1. Euthyroidism group (26 cases ), 2. Subclinical hypothyroidism (27 cases ) and 3. Hypothyroidism (4 cases ).  All DS patients again categorized into : whole patients category ( 57 cases ) , hypozincemic patients ( 19 cases ) and  normozincemic patients category (38 cases ) according to serum zinc levels. Forty subjects were included as control group and  all investigations used were applied to them.

 

Methods:

Physical examination was carried out at the genetic center. Blood samples were taken at the maternity hospital laboratory where the protocols of analyses were applied. Zinc in  plasma assayed by collecting blood in heparinized plastic tube and using the flame atomic absorption ( I.L. 457 spectophotometer, Thermo Jamel, Milan Italy ) after acid mineralization of 1 ml of plasma by microwave MDS 81D ( CEM corporation, Mathews NC ). Blank samples were evaluated at the same time as plasma samples for mineralization. Reference values in the normal population were taken as a comparable study. Thyroid function was tested at each examination by determining T4 / TSH levels , antithyroglobulin and antiperoxidase antibody titers. Immunoradiometric method was applied for TSH assay ( NR, 0.27 - 4.2 mIu /L ) while radioimmunoassay was used for T4 determination ( NR, 12.0 - 22.0 pmol/L ). Thyroid autoantibodies, ATG antibodies and thyroid microsomal antibodies (AP) were assayed using the radioimmunoassy.

Statistical analysis was carried out using Student's t- test for paired and unpaired data and correlation test for nonparametric data.

 

 

Results:

The total number of study patients is 57 divided into two subgroups, normozincemic 38 (67%) and hypozincemic DS subjects 19 (33%). Sex distribution was M/F(1.4:1) table 1. Hypothyroidism occurred in 1.8% of normozincemic versus 5.2 % of hypozincemic patients, while subclinical hypothyroidism occurred in 28% of normozincemic and 19.4% of hypozincemic patients. On the other hand euthyroidism occurred in 37% of normozincemic and 9% of hypozincemic individuals, table 2. Thyroid function tests and zinc values are shown in table 3. Increased levels of TSH > 4.2mIu / L, have been found in 21 cases (37%) out of 57 patients without positive thyroid autoantibody titre and 6 cases (10%) with positive titre. Significant inverse correlation has been found between zinc level and TSH value (t=2.42,P=<0.05). Low plasma zinc level (8.8+/-1.9, ranged 5.6-10.6mmol/L) has been found in 19 patients (33%), of whom 13 patients(68%) had high TSH levels. In normozincemic patients 15(39%) out of 38 subjects had high TSH values. A highly significant difference in TSH levels between hypozincemic, whole group and normozincemic patients (P=<0.01 vs P=<0.02 respectively) and TSH levels were 6.2+/-4.2 vs 5.3+/-3.8, 4.8+/-4.3mIu/L respectively). At the end of the first 6 months of therapy, the correlation became less obvious (X2=1.31, d.f.=2, P=>0.5) between zinc  and TSH values. A highly significant difference in GH levels between hypozincemic , normozincemic and whole groups of patients (P=0.001 & P= 0.01 respectively).

There was  significant low GH level in hypozincemic compared to normozincemic and whole groups of patients (2.4+/-1.9 vs 4.9+/-7.9 & 3.99+/-6.69mIu/L respectively).  On the other hand there was increased IGF-1 level in hypozincemic patients with significant difference between this group and the normozincemic group of patients (P=<0.001). There was an association between zinc levels, thyroid function and GH values ( X2 value =7.99 ,d.f.=3, P= <0.05 ), which indicated a significant association before therapy. There was also a significant association  between zinc level and GH / IGF-1 values ( X2 = 7.03 ,d.f.=2 & P= < 0.05 ). After zinc supplementation for 6 months, the association between zinc level and thyroid function became statistically insignificant  ( P= > 0.5 ), table (4). There was a remarkable decrease in hypozincemic DS patients, decline in TSH levels  and the number of subclinical DS patients,  28% instead of 47%, ( P = <0.001 ) but  there was no obvious association between the decreased TSH levels  and the increased zinc values ( X2   = 0.61, df.=2 & P= >0.5 ).

 

Table (1): Sex distribution in the DS patients study group.

 

Subgroup

Sex

Total

%

M

F

Normozincemic

21

17

38

66.7

Hypozincemic

12

7

19

33.3

Total

33

24

57

100

 

 

 

Table (2): Cases of normozincemia/hypozincemia in the three groups of thyroid dysfunction.

 

Normozincemic

 No           %

Hypozincemic No            %

Total          

No              %

Hypothyroidism

1               1.8

3              5.2

4               7

Subclinical hypothyroidism

16              28.1

11             19.3

27*              47.4

Euthyroidism

21              36.8

5                8.8

26             45.6

total

38              66.7

19               33.3

57             100

Six cases of subclinical hypothyroidism had raised TSH with high autoantibody titers (4 cases had elevated AP & 2 cases with raised ATG).

 

Table (3): Zinc and endocrine functions in whole, normozincemic and hypozincemic  groups of DS patients.

 

 

Normal values

Whole group(57 cases) M+/-SD       min  max    

Hypozincemic (19) M+/-SD    min   max   

Normozincemic (38) M+/-SD   min    max        

Zinc

11-24 mmol/L

13.6+/-6.72           4.4        53.7

8.76+/-1.94      5.6        10.6

16.22+/-7.04    12.0         53.7

T4

12-22 pmol/L

16.89+/-3.06         8.26      25.54

17.05+/-4.1       8.26      22.5

16.8+/-2.1      11.85      21.35

TSH

0.27-4.2 mIu/L

5.31+/-3.84           0.36      17.64

6.2+/-4.02          0.36      11.3

4.87+/-4.26      0.36     17.64

GH

0.15-13 mIu/L

3.99+/-6.69         0.13        36.6

2.4+/-1.9          0.13        8.0

4.9+/-7.9          0.85       36.6

IGF-1

0.5-124 pmol/L

67.5+/-60.6        1.1        312

90.6+/-65.07     30         271

55.98+/-54.98    1.1        312

 

 

Table (4): Plasmatic zinc level, endocrine functions before and after zinc supplementation
in the three groups of Down syndrome patients.

 

 

Normal values

Whole group (57 cases)

Hypozincemic (19 cases)

Normozincemic (38 cases)

Before

After

Before

After

Before

After

Zinc

11-24 mmol/L

13.6+/-6.77

14.84+/-4.3

8.76+/-1.94

13.23+/-3.55

16.22+/-7.04

18.44+/-1.32

T4

12 - 22 pmol/L

16.89+/-3.06

17.08+/-2.53

17.05+/-4.1

17.35+/-2.95

16.8+/-2.1

17.2+/-1.85

TSH

0.27 - 4.2 mIu/L

5.31+/-3.84

2.75+/-1.55

6.2+/-4.02

2.72+/-1.64

3.1+/-1.6

3.88+/-1.86

GH

0.15 - 13 mIu/L

3.99+/-6.69

3.81+/-1.8

2.4+/-1.9

2.41+/-2.3

4.9+/-7.9

5.2+/-1.35

IGF-1

0.5 - 124 pmol/L

67.5+/-60.6

75.65+/-54.8

90.6+/-65.07

89.6+/-61.3

55.98+/-54.98

61.7+/-48.3

 

  

Discussion:

In the present study we have found 21 patients with DS (37%)  having subclinical hypoyhyroidism with raised TSH levels and without thyroid autoantibodies confirming previous reports describing more DS patients with high TSH values than those with thyroid autoantibody positive titres [5,6]. We have found also an inverse correlation between the raised TSH values and zinc levels in hypozincemic individuals. There was a significantly high TSH levels in hypozincemic subjects (P = <0.05) and increased incidence of hypothyroidism in children / adolescents with DS in accord with previously reported series ( 1,3,16,32 ).

 

Zinc supplementation as zinc sulphate ( 1 ml every 5 kg / BW ) has proven to be effective in decreasing TSH levels in hypozincemic DS individuals comparable to normozincemic subjects. Before zinc sulphate supplementation there  was a significant high TSH levels in hypozincemic group comparable to the whole  and normozincemic  subjects, (P = 0.01 vs 0.02 ) respectively. At the end of 6 months of zinc sulphate supplementation , there was a statistically insignificant difference (P=>0.5)  in the TSH values between the aforementioned three groups of  patients.

 

Cautions should be considered in these results because of the relatively small number of our study subjects and only one cycle of zinc supplementation was applied.  The effect of zinc therapy on the TSH levels and improvement of thyroid function were obvious and reported in many previous series  [8-12]. It is preferable to continue zinc therapy for more than one cycle as it is postulated that 2 or more cycles can prevent the effect of zinc deficiency on the hypothalamic-pituitary-thyroid axis for approximately 2 years [17]. We have found a highly significant difference in GH levels between the whole group / normozincemic and hypozincemic patients (P= <0.01 vs P= <0.001 ) respectively. A significant low level of GH was detected in hypozincemic vs normozincemic group of patients (2.4+/-1.9mIu/L & 4.9 +/-7.9mIu/L respectively ) and hypozincemic vs whole group (2.4 +/-1.9mIu/L & 3.99 +/-6.69 mIu/L respectively ). On the other hand there was a significant increase in the  IGF-1 levels in hypozincemic patients comparable to the whole and normozincemic groups of subjects (P= <0.001).

 

We have also found a significant association between zinc levels , GH and IGF-1 values, X2 value = 7.03 and df. =2, P= <0.05. The previous reports suggested a possible correlation between zinc levels and thyroid function and it was confirmed that the zinc values were different in hypothyroid and hyperthyroid patients compared to controls [Al-Naggar etal.,19-22 ]. These studies showed also that thyroid hormones regulate zinc concentration. Zinc supplementation has been reported to normalise TSH response to TRH in hypozincemic individuals with low T3 levels [23]. Other reports suggested that an increase in TSH after zinc supplementation in DS [16[ while another series confirmed TSH decrease [8,25 ]. This controversy could be due to alteration in the zinc levels of the treated subjects.

 

In the present work we have found a decrease in TSH in hypozincemic patients while normozincemic subjects showed insignificant increase of TSH after zinc supplementation[26,27]. Follow up of DS patients showed that the frequency of attacks of infections decrease with zinc supplementation and normalization of it's plasmatic level which means that there is improvement of the immune response and school attendance. This observation means that zinc deficiency play a pivotal role in some of the pathological manifestations of the syndrome as repeated infections and thyroid malfunction. The mechanism of zinc action is not well known, nevertheless there were possible targets of action such as deiodination steps in hormonogenesis, thyroid hormone receptors and thymic-pituitary axis. The different FT3 / FT4 ratios detected in supplemented individuals during follow up could be due to the modulation of deiodination by the different zinc concentrations [26,27]. Plasmatic zinc concentration affects also on the activity of T3 receptor binding to specific target DNAs by what is called thyroid response elements [28]. It has been found that zinc+2facilitate proper folding of thyroid receptor into it's active structure. [29]. Zinc supplementation has been proved to restore the active form of thymulin which contains one zinc ion per molecule and associated with improvement of thyroid - pituitary axis function [25,31-33].

 

In conclusion: Our present study showed that zinc deficiency has a remarkable effect on thyroid and pituitary functions in hypozincemic DS patients. One cycle of zinc supplementation for 6 months improve thyroid function by decreasing TSH levels and improvement in GH/IGF-1 values. We think that if multiple cycles of zinc supplementation were carried out properly, more improvement will happen in endocrine and immune functions.

References:

  1. S. M. Puechel and J. C. Pezzullo. Thyroid dysfunction in Down Syndrome.  Am.  J. Dis. Child.1985; 39:636-639.

  2. S. Dinani and S. Carpenter. Down Syndrome and thyroid disorders. J Mental Defic. Res.1990;34:187-193.

  3. D. L. Friedman, T. Kastner, S. W. Pond and D. Rice O'brien. Thyroid dysfunction in individuals with Down syndrome. Arch. Intern. Med.1989;149:1990-1993.
  4. A. T. Cutler, R. Benezra-Obiter, and J. S. Brink. Thyroid function in young children with Down syndrome. Am. J. Dis. Child.1986;140:479-483.

  5. D. Rubello, G. B. Pozzan, D. Casara, M. E. Girelli, S. Boccato, F. Rigon et al. Natural course of subclinical hypothyroidism in Down syndrome: prospective study and therapeutic considerations. J. endocrinol. Invest.1995;17:35-40.
  6. R. T. Zori, D. A. Schatz, H. Ostrer, C. A. Williams, R. Spillar, and W. J. Riley. Relationship of autoimmunity to thyroid dysfunction in children and adults with Down syndrome. Am. J Med. Genet.1990;7(suppl):238-241.

  7. T. Sharav, R. M. Collin and P. J. Baab. Growth studies in infants and children with Down syndrome and elevated levels of thyrotropin. Am. J. Dis. Child. 1988; 142: 1302-1306.

  8. G. Napolitano, G. Palka, S. Lio S., I Bucci, P De remigis, L. Stuppia, etal. Is zinc deficiency a cause of subclinical hypothyroidism in Down syndrome?. Ann. Genet. 1990; 33 : 9-15.

  9. B. Bjorkstein, O. Back, K. H. Gustavson, G. Hallmans, B. Hagglof, and A. Tarvick. Zinc and immune function in Down syndrome. Acta Pediatr. Scand.1980; 69: 183-187.

  10. C. Franceschi, M. Chiricolo, F. Licastro, M. Zannotti, M. Masi, E. Mocchegiani etal. Oral zinc supplementation in Down syndrome: restoration of thymic endocrine activity and some immune defects. J. Ment. Defic. Res. 1988;32: 168-181.

  11. N. Fabris, E. Mocchegiani, L. Amadio, M. Zanotti, F. Licastro and Franceschi. Thymic hormone deficiency in normal aging and Down syndrome: Is there a primary failure of thymus? Lancet 1984;1: 983-986.

  12. A.S. Pasad. Clinical, endocrinological, biochemical effects of zinc deficiency. Clin. Endocrinol. Metab.1985; 14: 567-589.

  13. T. Nakamura, S. Nishiyama, Y. Futagoishi-Suginohara, I. Matsuda and A. Higashi. Mild to moderate zinc supplementation on linear growth velocity. J. Pediatr. 1993; 123:65-69.

  14. A. E. Favier. Hormonal effects of zinc on growth in children. Biol. Trac. Elements Res. 1992; 32: 383-398.

  15. S. Z. Ghavami-Maibodi, P. J. Collipp, M. Castro-Magana, C.-Stewart and aaaaaaaaaas. Y. Chen. Effects of oral zinc supplementation on growth, hormonal levels and zinc in healthy short children. Ann Nut. Metab. 1983; 27: 214-219.

  16. M. Sustrova and V. Strbak. Thyroid function and plasma immunoglobulins in subjects with Down syndrome during ontogenesis and zinc therapy. J. Endocrinol. Invest. 1994; 17: 385-390.

  17. I. Bucci, G. Napolitano, C. guilani, S. Lio, A. Minnucci, F. Di Glacomo, G. Calobrese, G. Sabatino, G. Calabrese and F. Monaaco. Zinc supplementation iproves thyroid function in hypozincemic Down syndrome. Biol. Trace Element Research.1999; 67: 257-268.

  18. J. Neve. Clinical implications of trace elements in endocrinology. Biol. Trace Element Res.1992; 32: 173-185.

  19. R. J. Mc Connell, C. E. Menendez, F. Rees Smith, R. I. Henki and R. S. Rivlin. Defect of taste and smell in patients with hypothyroidism. Am J Med.1976; 59: 354-364.

  20. K. Aihara, Y. Nishi, S. Hatano, M. Kimara, K. Yoshimitsu, N. Takeichi etal. Zinc,copper manganese and selenium metabolism in thyroid diseases. Am. J. Clin. Nutr.1984;40:26-35.

  21. K. Yoshida, J. Kiso, T. Watanabe, K. Kaise, H. Fukazawa etal. Erythrocyte zinc concentration in patients with subacute thyroiditis. J. Clin. Endocrinol Metab.1990; 70: 788-791.

  22. E. Dolev, P. A. Deuster, B. Solomon, U. H. Trostmann, L. Wartofsky and K. D. Burman. Alteration in magnisium and zinc metabolism in thyroid diseases. Metabolism.1988; 37: 61-67.

  23. S.Nishiyama, Y. Futagoishi-suginohara, M. Matsukara, T. Nakamura, A. Higoshi,, M. Shinohara etal. Zinc supplementation alters thyroid hormone metabolism in disabled patients with zinc deficiency. J. Am. Coll. Nutr.1994;13: 62-67.

  24. F. Licastro, E. Mocchegioni, M Zanotti,       g. Arena, M. Masi and N. Fabris. Zinc affects the metabolism of thyroid  hormones in children with Down syndrome : normalization of thyroid stimulating hormone and reversal of  triiodothyronone plasmatic levels by diatry zinc supplementation. Int J. Neurosci.1992; 65: 259-268.

  25. J. O. Oliver, D. S. Sachan, P. Su, and M. Applehans. Effects of zinc deficiency on thyroid function. Drug-Nutrient.Interact.1987; 5: 113-124.

  26. Essential trace elements and thyroid hormones [Editorial]. Lancet; 339: 1575-1576.

  27. I. J. ramirez, M. Halwer, L. E. Sharpio, and M. I. Surks. Zinc(II) inhibits the release of thyroid and glucocorticoid receptor from chromatin of cultured GC cells. Hor. Metab. Res.1991; 23: 155-161.

  28. T. Miyamoto, A. Sakurai,and L. J. De Groot. Effects of zinc and other divalent metals on deoxyribonucleic acid binding  and hormone-binding activity on human α1 thyroid hormone receptor expressed in Escherichia coli. Endocrinology.1991; 129: 3027-3033.

  29. N. Fabris, E. Moccheggiani, S. Mariotti, F. Pacini, and A. Pinchera. Thyroid function modulates thymic endocrine activity. J.Clin. Endocrinol. Metab. 1986; 62: 474-478.

  30. N. Fabris, E. Mocchegiani, S.Mariotti,G. Caramia,T. braccilli, F. Pacini etal. Thymulin deficiency and low 3,5,3'-triiodothyronine syndrome in infants with low birth weight syndrome. J. Clin. Endocrinol. Metab.1987; 65: 247-252.

  31. G. Napolitano, I. Bucci, C. Giuliani, G. Palka, S. Lio, E. Moccegiani et al. Thyroid function in relation to endocrine thymic  activity in Down syndrome children before and after zinc supplementation, in progress in Thyroid Research, A. Gordon, J. Gross, and G. Henneman, eds., Balkema-Brookfield, Rotterdam. 1991, 291-293.

  32.  R.L.AL-Naggar, S.A.AL-Awadi, N.M.AL-Awadi. Thyroid dysfuntion in children and adolescents with Down’s syndrome. Am J Hum Genet.2002; (abstract).

Correspondence: Dr. Rezk L. Al- Naggar, MD. Consultant Clinical Geneticist, Kuwait Medical Genetics Centre. His e-mail is: rlotfyra@netscape.net

 


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