Abstract

Zinc is an essential trace element involved in a multitude of human biological processes. Normally, zinc homeostasis is largely maintained by uptake of zinc into the enterocyte involving the brush border membrane followed by baso-lateral membrane exit into the circulation. This is accomplished by distinct gene-based protein carriers (eg., ZIP4, ZnT-1) to balance zinc loss, particularly from the intestinal and urinary tracts as well as integument. A genetically-based autosomal recessive disorder, acrodermatitis enteropathica, and other disorders leading to secondary malabsorption of zinc, such as celiac disease, may alter this balance, lead to significant dermatologic and intestinal histological effects, but may be entirely reversible with oral zinc supplements. Importantly, zinc may also attenuate transglutaminase activities and has been suggested to have the potential, hypothetically, to promote the generation of “celiac-safe” products.

1. Introduction

Zinc is an essential trace element that plays a critical role in several human biological processes as one of the most abundant micronutrients in the human body, after iron ^{1, 2}. Most zinc is present in bone and skeletal muscle, estimated to total about 2.6 g. Each day, zinc from the diet and endogenous zinc from secretions in the intestinal lumen, become available for uptake to compensate for zinc losses through different tissue sites so as to maintain zinc homeostasis ^{3, 4}. Human in vivo studies on the mechanisms involved in zinc uptake are limited and dated ^{5, 6}. As a result, much recent information on intestinal transport and absorption of zinc has been derived from from in vitro model systems, including experimental animals, tissues, cells (often from cultured conditions, eg. Caco-2) and isolated membrane vesicle preparations in the laboratory. Details of these studies have been reviewed by others elsewhere ⁷. Zinc is associated with more than 2800 proteins, required for catalytic, structural and regulatory functions, gene expression, metalloenzyme activities, cell processes including differentiation, apoptosis and proliferation as well as signalling, especially with immune function and neural modulation ⁷.

2. Human Zinc Homeostasis and Deficiency

In healthy individuals, plasma or serum zinc levels range from 12 to 16 uM. Less than 1% of total body zinc is mainly bound to albumin, macro- globulin and transferrin with only nano-molar concentrations of free zinc rapidly exchangeable between different tissues. Still, since most zinc is found in bone and skeletal muscle, turnover and availability between different compartments is slow. As a result, zinc requirements must be continuously replenished largely from dietary sources with losses from fecal and urinary excretions, sweat, menstrual losses, hair, nails and desquamated skin. Added physiological requirements occur with pregnancy, lactation and early infancy (7). Zinc homeostasis is largely maintained by intestinal uptake in the small intestine over a broad range of dietary intakes. With deficiency states, usual fecal and urinary losses are reduced and, eventually plasma zinc falls, followed by losses from less exchangeable sites including bone and muscle. Zinc deficiency is usually associated with limited food supply, especially with reduced bioavailability (eg., vegetarians, elderly and with impaired absorption, as in celiac disease). Because of the lack of a suitable biomarker for zinc deficiency, mildly deficient states may be difficult to clinically recognize even though the consequences to health may be severe. Once recognized, symptoms may be entirely reversible, solely with zinc supplementation.

3. Intestinal Absorption and the Epithelial Cell

Zinc may be absorbed along the length of the entire small intestine, but, in humans, the major sites appear to be proximal in the duodenum and jejunum ^{5, 6}. At the apical or microvillus brush border membrane of the enterocyte, zinc uptake occurs followed by excretion at the baso-lateral membrane into the portal blood with binding primarily to circulating albumin for distribution to the body. With usual dietary intake, kinetic evaluation of zinc absorption suggests a carrier-mediated and saturable process, although at high luminal zinc concentrations, uptake may be by passive diffusion. At the brush border membrane, absorption occurs through ZIP4 protein (zinc-ligand binding protein) encoded by the gene SLC39A4 on chromosome 8q24.3. This protein transports zinc from the lumen of the small intestine into the epithelial cell. An autosomal recessive mutation in this gene leads to impaired zinc absorption ^{8, 9}. ZnT-1 is a basolateral membrane protein that transports zinc from the enterocyte to the portal blood. Other transporters have been described (ZIP 5 and ZIP 14) that also import zinc from blood into enterocytes or bi-directionally between the lumen and the epithelial cell, possibly providing an added regulatory mechanism for zinc homeostasis ^{10, 11}. Within the enterocyte, zinc is present in 3 principal pools that may be regulated to maintain cellular zinc homeostasis: bound to protein (particularly metallothionein-bound zinc serving as a buffering compartment), free zinc stored in vesicles or as free cytoplasmic zinc with these latter 2 pools believed to be the biologically active forms of the zinc ion ⁷.

4. Acrodermatitis Enteropathica

This is a genetically-based zinc skin disease usually seen in infants due to differing gene mutations for the gene encoding ZIP4 with resulting impaired zinc absorption from the small intestine ^{8, 9}. A hereditary form was also described in a 33-yr old female with minimal diarrhea, but clinically responsive to oral zinc ¹² The prevalence of the disorder has been estimated at 1 to 9 in 1,000,000 with a global incidence rate of 1in 500,000 newborns ^{13, 14}. Clinical features appear after human breast-fed infants, rich in zinc, are weaned. In addition, a zinc-binding ligand in human breast milk, absent or diminished in other animal milk, increases the bioavailability of zinc, especially in the first 1 to 2 months of lactation. Early on, the skin lesion shows a decrease in the granular layer with confluent parakeratosis, but with aging, ballooning degeneration and necrosis of keratinocytes is described reflected in sharply demarcated, dry, scaly and erythematous plaques, often in the peri-oral and genital areas. Hair and nail changes may also occur, including diffuse alopecia. Systemic changes include diarrhea, irritability, lethargy, growth retardation, anemia, neuro-psychiatric changes, hypogonadism, eye and immunological changes ^{13, 14}.

Plasma zinc levels less than 65 ug per L may assist in confirming the diagnosis but zinc levels are influenced by contamination of collection tubes, time of day, co-existent inflammatory disorders and low serum albumin. Skin biopsies are not believed to be diagnostic. Other disorders may cause mimicry, including differing malabsorption syndromes, including celiac disease. Treatment involves zinc supplementation with an anticipated response of 100%. If not treated, the disorder may be fatal or associated with significant morbidities including dermatitis, alopecia, growth retardation and serious bacterial and fungal infections. With zinc, hypocupremia has been described in adults and so monitoring of serum copper (along with zinc) has been recommended ^{13, 14}. Interestingly, reversible small intestinal mucosal biopsy changes were described by some ^{15, 16}, but not all ^{17, 18} investigators with zinc therapy. Patchy inflammatory changes of variable severity with mild to moderate architectural changes in the small intestine were believed to be due to zinc deficiency in acrodermatitis enteropathica ¹⁵. For 3 infants (2 males and 1 female, aged 4 to 9 months) changes were completely reversible with each patient showing an initial partial response to di-iodohyroxy-quinoline, followed by complete small intestinal histological response to oral zinc ¹⁶. In a separate report, investigators described apparently normal small intestinal mucosal biopsies, but ultrastructural changes in Paneth cells, possibly secondary to zinc deficiency rather than as a primary defect ¹⁹.

5. Malabsorption and Celiac Disease

In adults, similar changes have been described in patients with malabsorption syndromes, including skin changes, impaired zinc uptake and deficiency ^{20, 21}, particularly in children with newly diagnosed celiac disease complicated by severe malnutrition ²⁰. A similar study evaluated zinc homeostasis in children relative to severity of biopsy changes (Marsh 3 or more). Although there was no change in the fractional absorption of zinc and calculated gut function, the exchangeable zinc pool was lower in celiac children with severe histological changes ²². Interestingly, a zinc absorption test after oral zinc sulphate administration was described to evaluate small intestinal function in celiac disease and associated small intestinal mucosal disease in dermatitis herpetiformis to evaluate gluten-free diet compliance ²³. Zinc supplementation in children with celiac disease complicated with short stature and diarrhea was also compared to zinc deficient children on a gluten-free diet ²⁴. Plasma zinc levels increased with a gluten-free diet regardless of use of zinc supplements. In addition ²⁵, children with newly diagnosed celiac disease and treated with a gluten-free diet were evaluated for levels of zinc, copper and iron. One of 2 groups also received zinc supplements, but there were no significant differences detected suggesting that a gluten-free diet alone was sufficient. These findings also support recent observations ²⁶ that iron supplements are not necessary in adults with newly diagnosed celiac disease permitting treatment of the anemia solely with a gluten-free diet. Thus, most studies in celiac disease and secondary malabsorption have been reported in children Further evaluations in adult celiac disease are needed.

6. Summary and Conclusions

Zinc absorption in human small intestine is transport-mediated with uptake into the bloodstream through brush border (eg., ZIP4) and baso-lateral (eg., ZnT-1) membrane protein carriers that are genetically-based to maintain normal zinc homeostasis. Acrodermatitis enteropathica is an autosomal recessive membrane transport protein disorder that may lead to severe clinical findings associated with zinc deficiency. Usually, the disorder appears in early infancy after weaning from human breast milk, however, adults with the disorder have been reported. Early recognition and treatment with oral zinc appears to be sufficient to reverse clinical changes in children including microscopic and ultrastructural changes in the small intestinal mucosa. Similar changes may develop in patients with malabsorption, including superimposed clinical and histopathological changes in celiac disease. In addition, however, recent information ²⁷ suggests that zinc is a key regulator of transglutaminase activity.

Zinc may modulate transglutaminase activity (specifically, TG 2) in celiac disease ²⁷. Zinc is known to inhibit transglutaminase activities and, possibly, play a very critical role in celiac disease ²⁸, dermatitis herpetiformis (with epidermal TG 3) and attenuation of transglutaminase (TG 2) activity ²⁹. Indeed, zinc could, conceivably, produce celiac-safe products ³⁰. Added studies are needed to further explore this potentially exciting role of zinc in celiac disease.

References