Is there a relationship between zinc and the peculiar comorbidities of Down syndrome?
Corrado Romano, Rosa Pettinato, Letizia Ragusa, Concetta Barone, Antonino Alberti and Pinella Failla
Zinc plays a central role in the immune system and has been found to be significantly reduced in people with Down syndrome. The effectiveness of zinc supplementation in people with Down syndrome has been reported with discordant results. A comparison was made between a range of clinical and biochemical variables and zinc levels in 120 individuals with Down syndrome. Two groups of participants, one with normal zinc levels and the second with low zinc levels, were compared on the following measures: growth hormone secretion, IgA and IgG antigliadin antibodies, presence of coeliac disease, T3, T4, fT3, fT4, TSH, hypothyroidism, hyperthyroidism, CD4/CD8 ratio, total immunoglobulins G and subclasses. No significant difference was found between the two groups, except for IgG4 which was, unexpectedly, significantly decreased in the group with normal zinc levels. In conclusion, an impairment of zinc blood level in individuals with Down syndrome does not necessarily impact on the organs and systems evaluated here.
Romano C, Pettinato R, Ragusa L, Barone C, Alberti A, Failla P. Is there a relationship between zinc and the peculiar comorbidities of Down syndrome?. Down Syndrome Research and Practice. 2002;8(1);25-28.
doi:10.3104/reports.126
Introduction
The need of zinc for the growth and survival of animals has been known since 1934
(Todd, Elvejheim & Hart, 1934), but its necessity in human
beings was only shown thirty years later (Georges, 1963).
Prasad (1991) published a review of the evidence supporting
the existence of zinc deficiency as a disease in medicine. A range of clinical features
has been observed in association with zinc deficiency. The mild type appears with
minor impairments of the immune system, taste and smell, night blindness, memory
deficiency and decreased spermatogenesis (Walsh, Sandstead, Prasad,
Newberne & Fraker, 1994; Zalewski, 1996). The
severe type shows severe immune impairment, frequent infections, pustular-bullous
dermatitis, diarrhoea, alopecia and mental disturbances (Walsh et al., 1994; Kay
& Tasman-Jones, 1975). Similar effects are found in animals with zinc deficiency
(Walsh et al., 1994; Zalewski, 1996;
Clegg, Keen & Hurley, 1989). Acrodermatitis enteropatica
is the prototype of a disease due to zinc deficiency. It is a rare genetic disease
due to the decreased absorption of zinc which has an autosomal recessive mode of
inheritance. Its clinical features are acral hyperpigmented skin lesions, bullous
dermatitis, alopecia, lack of eyelashes and eyebrows, poor growth, pancreatic islet
cell hyperplasia, lack of thymus, intermittent diarrhoea, lymphoid and splenic plasmocytosis,
low zinc in blood and urine, and low alkaline phosphatase in the serum. The main
functions of zinc can be inferred from the symptoms of zinc deficiency. Zinc plays
a central role in the immune system and, consequently, in resistance to the infections.
Severe zinc deficiency is associated with damage of epidermal cells (Aggett,
1989), which is seen in the skin lesions of acrodermatitis enteropatica
(Hambidge, Walravens & Neldner, 1977). Damage of gastrointestinal
and respiratory mucosa (Walsh et al., 1994;
Solomons, 1988), involvement of specific immune cells, such as polymorphonuclear
cells (Weston, et al., 1977; Briggs et al.,
1982; Singh, Failla & Deuster, 1994), natural killer
cells (Allen, Perri, McClain & Kay, 1983;
Salas & Kirchner, 1987) and the complement cascade (Jepsen,
Teisner & Svehag, 1990) also occurs.
Zinc and Down syndrome
Bjorksten et al. (1980) reported low zinc serum levels in 12 people with Down syndrome,
with impaired neutrophil chemotaxis and lymphocyte response to phytohemagglutinin.
Two months after supplementation with zinc sulphate, zinc serum levels increased,
neutrophil chemotaxis normalised in 11 out of 12 patients and the lymphocyte response
to phytohemagglutinin improved. Tukiainen, Tuomisto, Westermarck
and Kupiainen (1980) demonstrated that zinc causes a dose-dependent inhibition
of 5-hydroxytryptamine uptake in vitro, but zinc supplementation does not lead to
significant effects in vivo. Zinc, copper and selenium are essential microelements
of the enzymes superoxide dismutase and glutathione peroxidase, whose activities
have been reported to be increased in the erythrocytes of people with Down syndrome.
In a study (Neve, Sinet, Molle & Nicole, 1983) aiming to
define the relationships between these three microelements and both enzymes, zinc
plasma levels were found to be normal in people with Down syndrome. Subsequently,
Annerén reported, through microprobe nuclear analysis and atomic absorption spectrometry,
that zinc levels in the erythrocytes (Annerén, Johansson & Lindh,
1985) and serum (Annerén & Gebre-Medhin, 1987)
were significantly reduced in people with Down syndrome compared with a control
group. The relationship between circulating thymic hormone (FTS) and zinc has been
studied by Fabris et al. (1984). These authors, starting from the baseline of the
decreased concentration of FTS and the presence of factors inhibiting the biological
activity of FTS in vitro in the plasma of normal individuals aged over 50 years
and in the majority of young people with Down syndrome, reported that the use of
zinc sulphate in people with Down syndrome produces hormone levels of FTS and fully
prevents FTS-inhibiting activity. Such results suggest that the biologically active
FTS is the component bound with zinc and that the increasing FTS activity in the
elderly and in people with Down syndrome could be the result of modifications in
the pathway of zinc-dependent activation of FTS, probably associated with zinc-deficiency.
Subsequently, Fabris, Mocchegiani, Muzzioli and Provinciali (1988,
1991) suggested that there were correlations between the thymus, zinc and
neuroendocrine system. Franceschi et al. (1988) gave 1mg/kg/day
of Zn++ as zinc sulphate, in two trials of 2 months with a gap of 10 months, to
18 children with Down syndrome and a clinical history of respiratory, ear and skin
infections, low plasma levels of FTS, high plasma levels of unbound molecules of
FTS and a decreased absolute number of circulating T lymphocytes. After each trial
a dramatic increase of plasma levels of FTS, a near complete disappearance of the
inactive molecules of FTS, and a significant increase of the absolute number of
circulating T lymphocytes occurred, the zinc levels were corrected, the infections
decreased and school attendance increased. The decreased number of circulating B
lymphocytes and the impaired lymphocyte response to concanavalin A and phytohemagglutinin
were not modified. These positive effects were present also in those children with
Down syndrome without apparent zinc deficiency. These results were not confirmed
by Lockitch et al. (1989), who administered zinc gluconate
or placebo alternately for periods of 6 months to a group of 64 children with Down
syndrome and obtained an increase up to 150% of the mean concentrations of zinc
in the first group, a tendency towards a decrease of days or episodes of cough and
fever, but without any effect on other clinical items, or on copper, immunoglobulins
and complement serum levels, on the number of lymphocytes, nor on the in vitro response
to mitogens. Napolitano, Palka, Grimaldi, et al. (1990)
used a therapeutic trial with 1mg/kg/day of zinc sulphate on 22 people with Down
syndrome for times ranging from 6 to 9 months. Fifteen out of 22 people reached
a higher centile on their growth charts. The mean rate of height growth increased
from 23.84 mm/6 months to 40.80 7.68 mm/6 months. Growth hormone (GH) and serum
somatomedins increased. Napolitano, Palka, Lio, et al. (1990)
showed a decrease of free T3 in 17 people with Down syndrome and subclinical hypothyroidism
treated with zinc sulphate, and found 9 people with Down syndrome and low zinc levels
whose thyroid function improved with zinc supplementation. Stabile
et al. (1991) used zinc sulphate at a dosage of 20 mg/kg/day for 2 months
in 38 home-reared children with Down syndrome, 24 of whom had low zinc levels and
14 normal zinc levels. No correlation was found between low zinc levels and the
recurrence and/or the intensity of infections. Participants with low zinc levels
showed a decreased response to the phytohemagglutinin of peripheral mononuclear
blood cells compared with those with normal zinc levels. A significant increase
in the synthesis of DNA was obtained after the administration of zinc sulphate orally.
Indeed, the lymphocyte response to phytohemagglutinin was normal in all participants
up to 6 months since the end of treatment with zinc and decreased in half of the
participants 22 months after the end of the treatment. Licastro
et al. (1992) reported that 25 children with Down syndrome and low zinc
blood levels, high TSH levels and low levels of rT3, reached, after 4 months of
treatment with zinc sulphate, normalisation of zinc levels, thymulin, TSH and a
significant increase of plasma levels of rT3. After treatment with zinc no difference
was found between children with Down syndrome and the 14 control children. Supplementation
with zinc was also associated with a decreased incidence of infectious diseases
and an increase in school attendance. Licastro, Mocchegiani,
Masi and Fabris (1993) and Licastro et al. (1994)
subsequently confirmed such data. It has been shown that zinc supplementation enables
DNA repair in lymphocytes of people with Down syndrome (Chiricolo,
Musa, Monti, Zannotti & Franceschi, 1993). Recently, Bucci
et al. (1999) examined a group of individuals with Down syndrome who
had a reverse correlation between plasma levels of zinc and TSH levels. The TSH
high levels of people with low zinc levels were normalised, after six months of
zinc sulphate supplementation. Such discordant results in the literature induced
us to carry out a project which compared zinc levels with some clinical and biochemical
values during a follow-up study of people with Down syndrome in our Institute.
Materials and Methods
A sample of 120 people with Down syndrome (mean age 13 years, age range 0.4 - 48.1
years) were submitted to colorimetric assay of zinc levels. Ninety-six (80%) of
them showed levels within the normal range, whereas the remaining 24 (20%) had levels
below the normal range. Both groups were compared with regard to the following items:
growth hormone secretion, IgA and IgG antigliadin antibodies, presence of coeliac
disease, T3, T4, fT3, fT4, TSH, hypothyroidism, hyperthyroidism, CD4/CD8 ratio,
total immunoglobulins G and subclasses. Each sample distribution was tested for
normality, using three tests (Kolmogorov-Smirnov and Lilliefors tests for normality,
Shapiro-Wilk's W test). Where normal distributions were found Student's t test was
used, while Wald-Wolfowitz Runs test, Mann-Whitney U test and Kolmogorov-Smirnov
test were used when parametric assumptions were not met.
Results
No significant differences were found between the two groups with regard to growth
hormone secretion, IgA and IgG antigliadin antibodies, coeliac disease, thyroid
dysfunction, T3, T4, fT3, fT4, and TSH values, CD4/CD8 ratio and total IgG. The
subclass IgG4 was significantly lower in the group of participants with normal zinc
levels. The distribution in this case differed significantly from normality (Kolmogorov-Smirnov
one-sample test: D = .19615, p < .01; Lilliefors test: p < .01; Shapiro-Wilk's
W test: W = 0.75116, p < .0001), therefore non parametric tests were conducted.
The Wald-Wolfowitz Runs test (Z = -2.52320; p < .02), the Mann-Whitney U test
(U = 370.5; Z = -2.08633; p < .05) and the Kolmogorov-Smirnov two-sample test
(p < .05) all indicated a significant difference between the two groups.
Conclusion
Our results do not identify any statistically significant difference between low
zinc levels and normal zinc levels with regard to the evaluated items. The state
of zinc deficiency, in the sample of people with Down syndrome examined, does not
appear to be associated with any dysfunction in growth hormone secretion, proneness
to coeliac disease, thyroid function or immune function.
Correspondence
Dr. Corrado Romano • Unità Operativa Autonoma di Pediatria, Oasi Institute (IRCCS),
Via Conte Ruggero, 73, 94018 Troina (EN), Italy. • Phone: +39-0935-936111 • Fax:
+39-0935-653327 • E-mail: cromano@oasi.en.it
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