Importance of Zinc in Cystic Fibrosis Patients

Current Pediatric Reviews, 2009, 5, 65-70

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Importance of Zinc in Cystic Fibrosis Patients Stephanie Van Biervliet*,2, Jean-Pierre Van Biervliet1, Eddy Robberech1 and Chris Taylor1 1

Cystic Fibrosis Centre, Ghent University Hospital, Ghent, Belgium

2

Department of Paediatric, Sheffield University Hospital, Ghent, Belgium Abstract: Zinc (Zn) is a multipurpose trace element, sufficiency of which is difficult to assess. However, Zn deficiency could negatively influence this disease in different aspects. The symptoms of Zn deficiency as taste disturbances, decreased appetite and impaired growth but also disturbed fatty acid profiles and disturbances in immunity, inflammation and oxidative stress defence are discussed and applied to what is known in cystic fibrosis (CF) (Table 1).

Keywords: Zinc, cystic fibrosis, fatty acids, growth, immunity, oxidative stress. ZINC SOURCE, ABSORPTION AND HOMEOSTASIS Dietary Zn is mainly found in meat. Animal protein increases the absolute amount of Zn and promotes its absorption [1]. A high dietary phytic acid and fiber content [1] will decrease the Zn absorption. Fat malabsorption will also increase the Zn losses [2]. The interactions with other dietary minerals remain an unsolved concern with a probable negative interaction with iron and a possible negative interaction with calcium [1]. Zn and copper (Cu) negatively influence the absorption of each; hence Zn is used to decrease Cu absorption in Wilson’s disease [3, 4].

Acrodermatitis enteropathica is an autosomal recessive disease, caused by a mutation in the SLC39A4 gene located on 8q24 [11]. This gene encodes the ZIP4 transporter. Patients will have difficulties with intestinal Zn absorption resulting in Zn deficiency [12]. Table 1.

Symptoms and Signs of Zn Deficiency

•

Decreased growth velocity

•

Hypogeusia

•

Glossitis

•

Impaired appetite, decreased food intake

•

Diarrhoea

•

Increased infection susceptibility

•

Skin lesions: acro-orificial localisation, alopecia, hair loss

Due to its important functions, Zn concentrations are highly regulated [7] by different Zn transporting transmembrane proteins. The Zip-family transporters increase the intracellular concentrations by promoting Zn influx into the cells or release from the intracellular vesicles [8], while the cation diffusion facilitator- family (ZnT transporters) mobilises Zn in the opposite direction [8].

•

Delayed sexual maturation

•

Eye lesions: keratopathy, decreased dark adaptation

•

Delayed wound healing

•

Mood changes, irritability, lethargy

It has been suggested that the intestinal absorption of Zn is mediated by a pancreatic ligand, enhancing jejunal Zn uptake [9, 10]. ZIP4, localised in the apical membrane of the enterocyte, is the main importer of dietary Zn [11]. ZIP1 may function as a back-up system in regulating dietary Zn uptake [8]. ZnT-1 is the only member of the ZnT family localised in the basolateral membrane of enterocytes and renal tubular cells suggesting a Zn efflux role for the protein [12]. Potential sources of endogenous Zn are pancreatic, biliary and gastrointestinal secretions besides transepithelial flux or sloughing of mucosal cells. Excretion is directly related to the total amount of Zn absorbed.

Pancreatic insufficiency, frequently present in CF, causes a major problem for Zn absorption. Krebs et al. demonstrated a decreased fractional absorption and no ability to minimise the endogenous Zn loss in CF infants [13]. Untreated pancreatic insufficiency also increases Zn losses [13, 14]. The fractional Zn absorption is improved by pancreatic enzyme replacement therapy (PERT) [14]. However, some CF patients continue to have steatorrhoea despite correct PERT [15] and might therefore be at risk for developing Zn deficiency.

The exact absorption mechanisms have not yet been completely characterised in humans. The Zn homeostasis is primarily regulated in the intestine [2, 5] by the excretion and reabsorption of endogenous Zn. The urinary Zn losses are low [6].

*Address correspondence to this author at the Department of Paediatrics, Sheffield University Hospital, De Pintelaan 185, 9000 Ghent, Belgium; Tel: 0032/9/3325514; Fax: 0032/9/3323875; E-mail: [email protected]

1573-3963/09 $55.00+.00

EVALUATION OF THE ZINC STATUS Most of the body Zn is located in the fat-free intracellular mass; only 0.2% circulates in the plasma associated with albumin and 2-macroglobulin [16]. Serum Zn concentrations are maintained within strict values even if Zn intake differs dramatically. Decrease of serum Zn will, therefore, only be seen if the Zn depletion is prolonged and severe [17]. © 2009 Bentham Science Publishers Ltd.

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Current Pediatric Reviews, 2009, Vol. 5, No. 2

Serum Zn concentrations decrease after meals [18]. Age related and gender differences have been observed in some studies [19]. Infection and inflammation cause a decrease of serum Zn [20].

Table 2. 1.

Interactions of Zinc

Disturbed nucleic acid metabolism a. Zinc finger motifs: Gene expression i. Hormonal receptor sites ii. Vitamin A receptors b. Zinc dependant enzymes in nucleic acid synthesis i. DNA and RNA polymerases

2.

Disturbed protein synthesis a. Impaired utilisation of dietary nitrogen b. Increased amino acid oxidation

3.

Disturbed fatty acid profile a. Desaturase activity b. Fatty acid absorption, oxidation c. Fatty acid incorporation

4.

Immune dysfunction a. T-cell dysfunction b. B-lymphocyte antibody production c. Innate immunity: i. chemotaxis and recruitement of granulocytes ii. phagocytosis of NK cells

5.

Anti-oxidative properties

6.

Membrane electrolyte transports

7.

Co-factor of many enzymes a. Alkaline phosphatase b. Retinol reductase

Although serum Zn has its limitations, it remains a useful indicator of Zn status [17]. Belgian children have been shown to be at risk for the development of Zn deficiency, since 13% of the population [21] has a serum Zn below the 2 standard deviation of the American NHANES II study [19]. Literature on serum Zn status in CF is conflicting. Most of the studies do not find a significant difference between CF and control populations [22-26]. However, an acrodermatitis enteropathica-like eruption is reported as a presenting symptom of CF [26-29]. Moreover, young CF patients, detected by newborn screening, have very low serum Zn values [30]. We confirmed comparable Zn concentrations in young newly diagnosed CF patients. However, no significant difference was found when compared to a local age matched control group [24].

Van Biervliet et al.

IMPORTANCE ASPECTS

OF

ZINC

IN

NUTRITIONAL

Zinc in Relation to Caloric Intake, Growth and Nutritional Status Within one week, anorexia and decreasing growth velocity emerge in rats fed a low Zn diet [31]. The growth reduction is correlated with decreased cell proliferation and DNA synthesis [32]. Zn deficient cell cultures produce less growth hormone (GH) m-RNA and insulin-like growth factor-1 (IGF-1) m-RNA [33]. A meta-analysis concluded that Zn supplementation should be considered for children at risk of Zn deficiency, as it improved growth [34]. The effects were most prominent for children being under weight and of restricted height with respect to their age. To obtain a normal growth and weight gain, sufficient caloric intakes are needed. Krebs et al. observed an improved energy intake in young healthy children during Zn supplementation [35]. CF patients are advised to increase energy intake, aiming for 120% of recommended daily allowance [36] to compensate for their persistent malabsorption [15] and increased energy expenditure [37]. Many CF patients have a suboptimal nutritional status despite the nutritional advice and PERT. Up to now, no studies have been able to demonstrate a relation between serum Zn and growth parameters [23, 25]. However, decreased IGF-1 concentrations correlate to the nutritional status of CF patients [38]. Zn supplements could theoretically have beneficial effects on energy expenditure, appetite, nutritional status as well as growth. Only one retrospective study looked at and demonstrated an improved caloric intake during Zn supplementation in CF patients with a low serum Zn [39]. Zinc in Relation to Essential Fatty Acid (EFA) Status The deficiency symptoms of Zn and EFA show remarkable similarities. They include growth retardation, delayed sexual maturation, infertility, dermal lesions, alopecia and decreased rate of wound healing. This evoked the possibility of a mutual interaction between Zn and EFA. The presence of fatty acid (FA) abnormalities in acrodermatitis enteropathica and in transient Zn deficiencies, sustains this theory [40-42]. However, the specific function of Zn in FA metabolism is still not fully understood. It is probably the result of a direct modulation of the desaturase activities involved in the FA metabolism [43] and an indirect effect by influencing absorption [44], oxidation [45] and incorporation of the FAs in the phospholipids [46,47]. In CF patients, shifts in polyunsaturated FA composition have been described [48-50]. They are attributed to an abnormal functioning phospholipase A2 [51-53] and are related to genotype [48, 50]. Hamilton reports a positive relation between serum Zn and plasma phospholipid arachidonic acid and the ratio of arachidonic acid over linoleic acid in CF [54]. FA research in CF has gained more interest, since Freedman et al. described a clinical improvement of the CFTR-/- mouse model with docosahexaenoic acid supple-

Importance of Zinc in Cystic Fibrosis Patients

ments [55]. It could, therefore, be useful to examine whether optimalisation of Zn status also improves the FA profiles of the CF patients and decreases the inflammatory state.


3

[79]. Extremely high Zn concentrations (> 30mol/l) may also decrease T-cell function [80]. Zinc and Anti-Oxidative Properties

Zinc and Intestinal Alkaline Phosphatase Activity Alkaline phosphatase (ALP) is a known metalloprotein containing Zn or magnesium, necessary for its catalytic function [56]. This enzyme plays a key role in the detoxification of bacterial lipopolysaccharides and prevents bacterial invasion [57]. Intestinal ALP gene expression is activated by a Zn binding protein [58]. The enzyme has shown to be very sensitive to oxygen free radicals [59]. Zn deficiency will, therefore, result in a decreased ALP transcription, decreased intestinal ALP activity due to an absence of Zn in its catalytic site and increased inactivation as a result of increased presence of oxygen free radicals. In CF patients, we described a decreased intestinal ALP activity at diagnosis [60, 61]. Improving the Zn status in CF patients could therefore have an influence on the frequently encountered intestinal bacterial overgrowth [62]. IMPORTANCE OF ZINC IN THE AIRWAY Zinc in Relation to Immunity and Inflammation Zn deficiency decreases the serum thymulin activity [63], required for T-helper (Th) 1 maturation and activation. CF patients who are chronically infected with Pseudomonas aeruginosa have also an imbalance between Th1 and Th2 function [64]. B-lymphocyte antibody production is disturbed during Zn depletion [65]. In CF patients transient IgG2 deficiencies have been described under the age of 6 [66], coinciding with the low serum Zn concentrations [30]. The binding affinity and concentration of serum proteins will determine which proteins are saturated with Zn. Therefore, thymulin with middle binding affinity, may remain Zn-unbound when high concentrations of 2-macroglobulin with a higher binding affinity, are present [67]. Increased 2-macroglobulin concentrations have been demonstrated in CF patients [68, 69]. Zn deficiency will also affect the innate immunity or first line defence. Recruitment and chemotaxis of granulocytes depend on a normal availability of Zn [70, 71]. The natural killer (NK) function, phagocytosis and generation of oxidative burst are impaired by decreased Zn levels [72]. Reduction of T-helper, T-suppressor and NK cell functions has been observed in advanced CF disease [68, 73, 74]. In several patient groups immune reactions improved with Zn supplements [75-77] resulting in decreased upper [75] and lower respiratory infections [77] as well as diarrhoea episodes [76]. In CF patient’s one retrospective study on Zn supplementation revealed a decreased number of antibiotic treated infections [39] and a prospective double blind pilot study demonstrated decreased days of antibiotic treatment [78]. Although there are several potential positive effects of Zn supplementation, we should also be aware of possible risk since pathogens also need Zn for proliferation. Decrease in plasma Zn during infection could be a defence mechanism

Zn forms together with Cu and selenium a triad of trace elements involved in cytosolic antioxidant defence. A number of in vivo and in vitro studies have shown increased oxidative stress in lung and airway following Zn deprivation [81, 82]. Zn acts as a protective agent for thiols in enzymes and proteins and protects their function. Zn deficiency is known to increase lipid peroxidation [83]. Long term Zn deprivation renders an organism more susceptible to injury induced by a variety of oxidative stresses. Increased oxidative stress is a well known feature in CF patients [83-85]. However, the reports on the Cu-Zn superoxide dismutase activity and gluthathion dismutase activity are contradictory [86-89]. Zinc and Chloride Transport Zn applied to the mucosal surface of airway epithelium is able to restore chloride excretion both in vitro and in vivo [90]. Zn triggers a sustained increase in cytosolic calcium via P2X purinergic receptor channels. Activation of a calciumdependent chloride secretory response followed. This finding could lead to new therapeutic options. The best way to deliver Zn to the airway epithelium surface needs, however, to be established. CONCLUSION CF patients may theoretically benefit from Zn supplements in several different aspects of their disease. A retrospective analysis of clinical data suggests improved appetite, caloric intake, nutritional status as well as pulmonary function with Zn supplements [39]. However, there have only been two small double blind prospective studies; one confirming the decrease in antibiotic needs, while the other showed no clinical changes [91]. Larger double blind studies are needed to answer the question whether or not, all or only a part of CF patients benefit from Zn supplements. Different responses including FA status, immune function and oxidative stress resistance should be followed during the study. ABBREVIATIONS AA

= Arachidonic acid

ALP = Alkaline phosphatase Cu

= Copper

CF

= Cystic fibrosis

CFTR = Cystic fibrosis transmembrane conductance regulator EFA = Essential fatty acid FA

= Fatty acid

GH

= Growth hormone

IL-10 = Interleukine 10 IGF-1 = Insulin-like growth factor-1

4


LA

= Linoleic acid

NK

= Natural killer

PERT = Pancreatic enzyme replacement therapy Zn

Van Biervliet et al. [25]

[26]

= Zinc [27]

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