Zinc and Wound Healing

A Review of Zinc Physiology and Clinical Applications

Samuel Kogan, BA; Aditya Sood, MD, MBA; Mark S. Granick, MD

Disclosures

Wounds. 2017;29(4):102-106. 

In This Article

Abstract and Introduction

Abstract

Our understanding of the role of zinc in normal human physiology is constantly expanding, yet there are major gaps in our knowledge with regard to the function of zinc in wound healing. This review aims to provide the clinician with sufficient understanding of zinc biology and an up-to-date perspective on the role of zinc in wound healing. Zinc is an essential ion that is crucial for maintenance of normal physiology, and zinc deficiency has many manifestations ranging from delayed wound healing to immune dysfunction and impairment of multiple sensory systems. While consensus has been reached regarding the detrimental effects of zinc deficiency on wound healing, there is considerable discord in the literature on the optimal methods and true benefits of zinc supplementation.

Introduction

Zinc, a trace element, is the most abundant intracellular metal and the second most abundant in the body overall after iron. The essential role of zinc in growth was first discovered in 1869 in the fungus Aspergillus niger.[1] In 1926 zinc was found to be endogenously present in human tissues and it was suggested that it possibly served crucial biological roles.[2,3] A significant zinc-biochemistry discovery occurred in 1939 when erythrocyte carbonic anhydrase, the enzyme responsible for the rapid and reversible conversion of carbon dioxide and water to bicarbonate and protons, was shown to require zinc for enzymatic activity.[4] Another landmark discovery was of the "zinc finger domain" in proteins, a highly conversed sequence allowing for the interaction of proteins with nucleic acids.[5] Using a bioinformatics approach encompassing genomics, proteomics, and zinc-protein interactions, researchers have identified more than 3000 unique human zinc proteins, suggesting that more than 10% of the human genome encodes zinc proteins.[6–8]

Transport, storage, and sensing zinc. The 3000 known zinc proteins are essential in enzymatic and structural roles, transport and storage, DNA repair, replication, and translation.[8] Given the overwhelming importance of zinc in innumerable physiologic processes, there must be specific mechanisms in place to ensure sufficient intracellular zinc concentrations. More than 3 dozen proteins regulate intracellular zinc concentrations, including the 14 members of the ZRT/IRT-like protein (ZIP) family (SLC39A) that function to increase intracellular zinc concentrations and the 10 members of the zinc transporter (ZnT) family (SLC30A) that decrease intracellular zinc concentrations.[9] These transporters are responsible for the movement of zinc into the cytosol via the plasma membrane and to various intracellular compartments. In addition, the metallothionein (MT) family of proteins is a class of cytosolic proteins responsible for binding free zinc. The expression of ZIP and ZnT transporters is heavily regulated transcriptionally, translationally, and posttranslationally.[10–12]

While there is a fairly comprehensive understanding of zinc transport, far less is understood about cellular zinc sensing. The only known eukaryotic zinc (II) ion sensor is metal-responsive element binding transcription factor-1 (MTF-1). It is believed to sense zinc levels through a pair of 6 zinc fingers with an affinity for zinc lower than that of other zinc fingers — thus allowing it to determine elevated zinc levels.[13] Metal-responsive element binding transcription factor-1 has been established as an essential gene, as deletion is embryonically lethal.[14]

Storage and cellular release of zinc is regulated by the MT family of proteins, of which humans have more than 12 types. Metal-responsive element binding transcription factor-1 controls the expression of the majority of the MTs. Under conditions of increased cellular zinc concentrations, the expression of MTs is increased, and as a result, the cell is capable of binding more zinc, thus decreasing total free zinc.[15]

Zinc physiology and role in health. Zinc is ubiquitously found in the body, with 85% stored in muscle and bone, 11% in the skin and liver, and the rest in other tissues.[16] Given the 3000 proteins requiring zinc, it should come as no surprise that zinc is crucial in countless physiologic processes; it is essential in growth, immune function, tissue maintenance, and wound healing.[17] Zinc absorption occurs in the duodenum and proximal jejunum and is taken into enterocytes by transporters found on the apical membrane.[18] Citric acid enhances absorption, while iron, fiber, and phytic acid inhibit absorption.[19,20] The greatest physiological requirement of zinc occurs during puberty, coinciding with the period of rapid bone growth. In addition, infants and children, pregnant and lactating women, and the elderly also require increased zinc.[21]

Zinc deficiency and excess. Unlike many essential vitamins and minerals, there are no dedicated stores of zinc. When deficiency, defined by a plasmic zinc level below 60 μg/dL, exceeds the regulatory capacity of homeostatic mechanisms, clinical symptoms may arise. Zinc deficiency can occur due to inadequate intake, reduced absorption, increased losses, or increased demand.[21] It can also occur after the use of penicillamine for Wilson's disease and due to genetic disorders such as Acrodermatitis enteropathica and sickle cell disease.[22] Inadequate intake as a result of a zinc-deficient diet or a phytate-rich diet is the most common worldwide cause of zinc deficiency. Individuals most susceptible to zinc deficiency caused by inadequate intake are those with the greatest physiological demand. Elderly populations are also at risk due to age-related decline in absorption and poor diet.[21] A randomized controlled trial of more than 600 elderly residents of nursing homes found that approximately half of the individuals studied had serum zinc concentrations below normozincemic levels.[23] Much of the literature on zinc deficiency and supplementation has been focused on the geriatric population, specifically because of the high prevalence of morbidities predisposing them to hypozincemia including malignancy, tuberculosis, dermatological disorders, chronic wounds such as arterial and venous ulcers, and chronic renal insufficiency.[24,25]

Severe zinc deficiency manifests as bullous-pustular dermatitis, alopecia, diarrhea, weight loss, intercurrent infections, and hypogonadism in males. Unrecognized severe zinc deficiency is fatal.[22] The presentation of moderate zinc deficiency includes growth retardation, delayed puberty, hypogonadism in males, rough skin, poor appetite, delayed wound healing, and abnormalities in gustation, olfaction, and night vision. Mild zinc deficiency may present with oligospermia, weight loss, and hyperammonemia.[22]

Zinc toxicity is exceedingly rare, as zinc is considered relatively nontoxic, especially via oral administration. Nonetheless, excessive intake may produce symptoms including nausea, vomiting, epigastric pain, lethargy, and fatigue. Zinc intake exceeding 10x to 20x the Recommended Dietary Allowance of 15 mg per day may induce copper deficiency and symptoms of anemia and neutropenia.[26]

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