Are Down’s Syndrome Subjects Zinc Deficient?
Logic would suggest that the first step towards determining whether zinc is important in DS would be to establish whether DS people are zinc deficient. However, this simple fact, at the time of writing, has yet to be agreed on. Graham and Odent (1986) suggest six methods for measuring zinc status:
Plasma concentration; this is not an accurate reflection of zinc status as results can vary according to the time of day, how recently the subject ate and stress levels, amongst other variables.
Hair analysis; a controversial measure, this is clinically significant but complicated by other factors. Both elevated and depressed zinc levels can be present in deficiency states (Passwater and Cranton 1983).
Urine test; this do not show how much zinc is in the body but how much is being lost. The results are no indication of zinc status but may provide useful extra information.
Leucocyte concentration; this is a useful reflection of zinc status in tissues generally. The measurement does not require much blood and is not technically difficult. Brigino et al (1996) state that assays of zinc concentration in all blood cells have proved to be more accurate and sensitive than plasma assays for indicating functional zinc status.
Sweat test; this is the best indicator of zinc status, but is not widely used and is expensive to administer.
Taste test; this gives a reliable indication of zinc status within broad categories but is not refined in the data it provides.
This author has not been able to locate research measuring the zinc status of DS using urine, sweat, or taste tests. It is understandable that the latter has not been used given that the majority of DS people exhibit some degree of mental retardation and the taste test requires following complex instructions, complex vocabulary, and analysis on the part of the subject. This author believes that measurement of the zinc levels in urine and in sweat would yield useful new information to help resolve the question of DS people’s zinc status.
By far the most common method used for measuring zinc status is that of measuring plasma concentration, or serum concentration (serum is plasma minus the clotting proteins, and this paper does not concern itself with the difference as it was not found to be relevant). As an equal proportion of serum assays to plasma assays fall into the hypozincaemic findings group as into the normal values group, indicating that neither method is more likely to produce one result than the other, they shall be considered together. The majority of research shows that DS subjects have low zinc status (Milunsky, 1970; Halstead and Smith, 1970; Björkstén et al, 1980; Fabris et al, 1984; Annerén and Gebre-Medhin, 1987; Bruhl et al, 1987; Kanavin et al, 1988; Purice et al, 1988; Stabile et al, 1991; Licastro et al, 1992, 1993, 1994; Kadrabová, 1996). A notable minority of papers find no signs of deficiency (Matin, 1981; Nève et al, 1983, 1984; Noble and Warren, 1988; Laires et al, 1994). Results of both types have been found using both hospitalised subjects and those living at home. Research comparing DS patients with other mentally retarded patients showed normal values (Matin et al, 1981) and low values (Kanavin, 1988), as did research comparing DS patients with normal subjects. Controls were generally age-matched, though apparently not always matched by sex. Every paper analysed for zinc by atomic absorption spectrophotometry, but the method of preparation varied between researchers and was not always fully explained. It is possible that a method of preparing the plasma/serum for atomic absorption spectrophotometry may differently affect plasma from DS subjects than normal plasma samples but this consideration falls outside the scope of this paper. The question of whether or not DS people have low concentrations of plasma zinc remains to be answered conclusively, but it appears likely at present.
Sustrová and Strbák (1994) found that the average serum levels of zinc in DS subjects increased with age: from 66% of control levels for those aged 1 to 6 years to 88% of control levels when aged 15 to 35 years. This is a very interesting finding which prompts many questions about why and how this would be true. Is the survival rate higher amongst DS children with higher zinc levels, leading to a higher average as the population ages? Possibilities based on an improvement in zinc absorption or transport within the body seem unlikely because of the characteristic early senescence of DS people.
A few assays have been made of zinc concentration in the erythrocytes of DS. Most found the values to be significantly higher than in the controls (Milunsky et al, 1970; Nève et al, 1983, 1984; Purice et al, 1988), but Annerén et al found the values to be lower than the controls (1985). The suggestion by the latter author was that previous investigations had used a coagulant that contaminated the samples with zinc. This author does not believe that such contamination would result in the relative values of the DS samples and the control samples swapping places. Rather, each value would measure extremely high but would still retain the same relationship to the others. This author believes it more likely that DS erythrocytes have high levels of zinc — a fact also suggested by the high levels of SOD-1, a zinc-containing enzyme, found in DS erythrocytes. The role of SOD-1 in DS will be discussed later in this paper.
The most unusual piece of research was the measurement of zinc concentration in tongue muscles (Yarom et al, 1987), a rather leftfield piece of research which compared the results of samples obtained from partial glossectomies of DS patients with control samples taken from current autopsies. The finding was that the zinc levels were the same in both groups. However the average age of the 15 DS subjects was 10 years and the average age of the 8 controls was 37 years and 9 months. The control group contained a newborn baby and a 1 year old, bringing down the average considerably; with the two youngest removed the average age rises to 50 years. Given that zinc status decreases with age (Passwater and Cranton, 1983) this is not a very useful comparison, a fact compounded by the cause of death in 2 cases being cancer, in 3 cases being heart disease, and in 1 case being sepsis. These are all states associated with zinc deficiency (Passwater and Cranton, 1983). Considering these two criticisms of the control group this author feels that the research paper shows no more than that the DS children investigated had the same zinc levels as sick, old people.
Two pieces of research were found which used hair mineral analysis. Barlow et al (1981) compared the concentrations of zinc found in samples taken from DS patients with three sets of controls: other mentally retarded patients in the same hospital, hospital staff, and students in the locality. This broad range of controls is interesting. Barlow found that the concentration of zinc in DS subjects was not significantly different from that in the normal controls, but was significantly higher than that in the control patients. As both the DS patients and the control patients ate the same diet, the question that presents itself is whether the lower values found in these controls is representative of the dietary supply, and the DS subjects had high values because of retarded growth concentrating the zinc levels in their hair; or the DS patients’ values reflected dietary intake and the control patients’ values were low because of low zinc status. As zinc status is linked with mental health, this comparison needs further clarification before it is useful. The comparison with normal controls is more immediately accessible and does show a normal zinc status.
The second piece of research opens up the picture in an intriguing manner. Björkstén et al (1980) found values for hair mineral analysis and serum for both DS subjects and controls. The finding was that hair values were the same as the controls and the serum values were lower the normal. Can DS people have normal hair levels of zinc while their serum zinc levels are low? Why? Or is this data a reflection of the unsuitability of one or other of these methods for assessing zinc status? Unfortunately there is no information given about the controls, apart from them being healthy, which decreases the usefulness of the data. Björkstén et al also found elevated concentrations of zinc in DS blood clots, but this is a poorly validated index of zinc nutriture (Clinical Nutrition, 1980).
Zinc status in Down's syndrome
It is this author’s opinion that taken as a whole the research to date indicates that it is likely that DS individuals have a low zinc status. Several papers reported normalisation of low zinc levels following zinc supplementation (Björkstén et al, 1980; Franceschi et al, 1988; Lockitch et al, 1989; Napolitano et al, 1990; Stabile et al, 1991; Licastro et al, 1992, 1993, 1994; Brigino et al, 1996; Trubiani et al, 1996; Bucci et al, 1999). This indicates a prevalence of zinc deficiency. If zinc status were already at an optimum level it is unlikely that homeostatic mechanisms would allow supplementation to raise zinc levels.
Assessing concentrations of zinc in body tissues is only one way of gathering evidence about the zinc status of DS people. Björkstén et al argue that “The presence of true zinc deficiency in Down Syndrome was supported by the clinical effects of therapy since the response to therapy with zinc is probably one of the most reliable indices for making a diagnosis of zinc deficiency in man” (1980). An example is Franceschi et al’s work, which found a significant improvement in certain immune parameters in DS subjects even if their serum zinc levels were normal. In order to assess the effect of zinc supplementation it is necessary to define what responses are being measured, and these would be selected from recognised clinical conditions more often observed in DS people than in the normal population. Those conditions that have also been linked with zinc deficiency are the obvious place to start.