Nickel is a transition metal that is present in the human body in very low concentrations (approximately 10-15mg in the whole body of an adult) but that has a range of essential biological functions, primarily as a cofactor for the function of multiple metalloenzymes including the urease enzyme (which catalyses the hydrolysis of urea to ammonia and carbon dioxide), the hydrogenase enzyme (which is involved in hydrogen metabolism in some bacteria), and possibly the superoxide dismutase enzyme (though this role is less well-established in humans than in some other species). Nickel deficiency is rare in humans (because nickel is present in a wide range of foods and because the body has efficient mechanisms for nickel absorption and homeostasis), but when it occurs (in the context of general nutritional deficiency or in people with conditions that impair nickel absorption), it produces a characteristic pattern of dermatitis, growth retardation, and impaired nitrogen metabolism that is consistent with the known functions of nickel-dependent enzymes in the body.
Nickel and Urease
Urease is the nickel-dependent enzyme that catalyses the hydrolysis of urea to ammonia and carbon dioxide, and it is present in virtually all organisms — from bacteria and fungi to plants and animals — reflecting the ancient evolutionary origin of this enzyme and its critical importance in nitrogen metabolism. In humans, urease is expressed primarily in the kidney and in the gastrointestinal tract (where it is produced by the gut microbiota), and it plays an important role in the final step of the urea cycle — the conversion of urea to ammonia and carbon dioxide, which is then excreted by the kidneys or metabolised by the gut microbiota. The nickel-dependent activity of urease is essential for normal nitrogen metabolism, and when nickel is deficient, the activity of urease is impaired and the nitrogen homeostasis of the body is compromised. The clinical significance of this nickel-urease connection is most clearly seen in the rare genetic deficiency of urease, which produces a clinical syndrome that includes hyperammonaemia, intellectual disability, and the accumulation of urea cycle intermediates that is characteristic of urease deficiency.
The gut microbiota are a major source of urease activity in the human body, and the ammonia that is generated by microbial urease in the gut is an important contributor to the total ammonia load that the liver must process through the urea cycle. The management of conditions that are associated with elevated ammonia (including hepatic encephalopathy and the urea cycle disorders) often involves the use of strategies that reduce the ammonia generated by gut microbial urease — including the use of the disaccharide lactulose (which alters the gut microbiota and acidifies the colon, converting the absorbable ammonia to the non-absorbable ammonium ion) and the use of the antibiotic rifaximin (which reduces the bacterial load in the gut and thereby reduces the microbial production of urease and of ammonia).
Nickel and the Skin
Nickel is one of the most common causes of allergic contact dermatitis worldwide — nickel allergy affects approximately 10-15% of the general population and is one of the most frequent causes of the skin rash that develops in response to jewellery, watches, belt buckles, and other metal objects that are in prolonged contact with the skin. Nickel allergy is a Type IV hypersensitivity reaction (delayed-type hypersensitivity) that is mediated by the T lymphocytes of the immune system, and it is one of the most common occupational skin diseases in people who work with nickel-containing metals (including metalworkers, jewellers, and laboratory technicians). The management of nickel allergy involves the avoidance of nickel-containing objects and the use of topical corticosteroids for the treatment of acute flare-ups.
Practical Application
For general nickel nutrition, the evidence-based approach is to ensure adequate nickel intake from a varied diet that includes nuts, seeds, whole grains, legumes, and the small amounts of nickel that are present in most foods. The estimated safe and adequate daily dietary intake for nickel is approximately 25-35mcg daily for adults, and most people in the developed world achieve this from a varied diet. Nickel supplementation is not generally recommended because nickel deficiency is rare and because the therapeutic index of nickel is narrow (nickel is a potential toxicant at higher doses, and chronic nickel exposure is associated with respiratory toxicity, carcinogenicity, and the development of the cardiovascular and renal toxicity that is associated with the systemic nickel disease). For comprehensive skin health support in people with nickel allergy, the management strategy involves avoidance of nickel-containing objects, the use of barrier creams, and the use of topical corticosteroids for acute flare-ups, along with the support of the immune system through adequate zinc, vitamin D, and the omega-3 fatty acids.
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