For Doctors: Reactions to Ingested Nickel
By Matthew Zirwas, MD
Numerous double-blind, placebo-controlled studies have shown that ingestion of nickel leads to cutaneous symptoms in a significant number of people who have positive patch test reactions to nickel but not in those with a negative patch test to nickel.
For clarity, Systemic Contact Dermatitis to Nickel (SCDN) will refer to dermatitis (eczema) induced by nickel ingestion, while Systemic Nickel Allergy Syndrome (SNAS) will refer to individuals who have associated systemic symptoms, primarily of the gastrointestinal (GI) tract, but possibly being multi-system. Relevant to SNAS, a recent study showed that at least 40% of individuals diagnosed with irritable bowel syndrome (IBS) had a positive patch test to nickel, and those with a positive nickel patch test had dramatic improvements in IBS symptoms when they followed a rudimentary low nickel diet for three months.1
There can no longer be a question of whether this phenomenon exists, based on two lines of evidence: (1) double-blind, placebo controlled nickel challenges (DBPCNC) and (2) improvement of symptoms with dietary nickel restriction (DNR). The percentage of patients who react in DBPCNC increases with the dose of nickel administered.2–14 A meta-analysis showed a clear dose response relationship, with a substantial number of people reacting at or below doses easily obtained in the diet.5
The intensity of the patch test reactions does predict the likelihood of a positive reaction to a nickel challenge.6 In addition, the likelihood of improving with DNR is higher in those with a 1+ or 2+ patch test reactions than those with a 3+, suggesting that those with a 3+ reaction needed to reduce dietary nickel consumption to such a high degree that the low nickel diet instructions available at the time were inadequate to allow a great enough reduction.16 Taken together, these studies indicate that people with a stronger patch test reaction to nickel are more likely to have symptoms from nickel in their diet and need to follow a more strict low nickel diet to see improvement.
In one study that used a high nickel diet, rather than a challenge with a single dose of nickel, 12 nickel allergic patients were blinded to receiving a high nickel diet (containing almost 500 ug/d—which is well within the range consumed in a normal western diet).57 Urinary nickel excretion went up by 4x while on the diet and at day 4, 50% of the patients flared based on the assessment of both the patient and investigator, while by day 11 (7 days after the dietary nickel challenge had ended), 100% had flared according to both patient and investigator assessment.17
Several studies have shown that about 40% of patients with a positive patch test to nickel and cutaneous symptoms improve on a low nickel diet.11, 16, 18, 19, 20 However, with more effective information about DNR, clinical experience suggests this number is much higher.
Pathophysiology of Systemic Contact Dermatitis to Nickel
Estimates of daily intake of nickel vary, being up to 4 mg per day in some Scandinavian diets.24 In the United States, our best estimate, based on known content of commonly consumed foods, is that a normal diet leads to an average daily nickel intake 0.5 mg. Certain foods are generally high in nickel, but essentially any plant can be high in nickel if it is grown in high nickel soil.23 Dairy and meat are generally low in nickel, while legumes and whole grains are generally and reliably high in nickel. Between 10 and 40% of the consumed nickel is absorbed and that level may be higher in patients over age 30.24–26 Dietary supplements, vitamins and drinking “regular” water can also be major sources of nickel.25
What is co-ingested with nickel also affects absorption, but by exactly how much is difficult to estimate.24 For example, co-ingestion with vitamin C has been shown to reduce nickel absorption, as has co-ingestion with disodium-EDTA, a common food preservative.24 If nickel is ingested on an empty stomach, nickel blood levels peak at around 1.5 to 4 hours after nickel ingestion and remain elevated for up to 4 days.24, 26
Nickel is primarily excreted in the urine.26–27 It is also excreted in the sweat, although the relative contribution of sweat excretion is thought to be substantially less than urinary excretion.28, 29
Immunologic Response to Ingested Nickel
In individuals who react to an oral nickel challenge, blood monocytes drop around 4 hours later and then B-cell and T-cell counts drop at around 24 hours.7, 30, 37 IL-5 goes up significantly, while IL-6 and IL-10 increase, but not to statistically significant levels.7 IL-2, IL-4, TNF-alpha, and IFN-gamma are not affected.7 Duodenal biopsies done 2 days after the nickel challenge show impressive inflammation, primarily with CD45RO+ T-cells, in patients with clinical symptoms.37 In summary, it appears that in patients who react to an oral challenge, circulating lymphocytes are activated in response to nickel in the blood, migrating into the gut mucosa and skin and producing IL-4, IL-5, and IL-10.
Reduction of the Amount of Nickel Ingested
About 40% of people with a positive patch test to nickel and suspected SCDN or SNAS have been shown to improve on a low nickel diet, with that number increasing to 80% if limited to those who also have a positive challenge to oral nickel.11, 12, 16, 18–21 However, two basic questions beg answers: (1) why don’t all nickel allergic patients react to a nickel challenge, and (2) why don’t all patients who react to an oral challenge improve on a low nickel diet.
Put simply, we aren’t sure. But, we have some hypotheses: In one study, the patients with positive oral challenges had larger increases in urinary nickel excretion than those who didn’t, suggesting that those who don’t react simply didn’t absorb the nickel.14 In another study, urinary nickel levels fell more in those who improved on the diet than in those who did not (this did not reach statistical significance, likely due to small sample size).9 So, we believe that the amount of nickel absorbed is the crucial factor in determining if someone will react (which, of course, is related to the amount of nickel ingested, but is also related to other factors) and that in those in whom the diet doesn’t work it is likely because they weren’t able to reduce how much nickel they ingested to a low enough level, likely due to inadequate information being available about how to reduce dietary nickel ingestion.12
One way to supplement the diet is to co-ingest supplements that will decrease how much of the ingested nickel is absorbed. Vitamin C (ascorbic acid), 1 g, taken with every meal, may have this effect.24 Since vitamin C is cheap, widely available, and safe, this seems like something everyone following a low nickel diet should do. We specifically recommend a 1000 mg, chewable vitamin C taken mid-meal.
There are other reports of chelating nickel out of the body or desensitizing to nickel, but we have not found these methods to be safe enough to recommend widely or outside of the care of a physician who specializes in treating SCDN and SNAS.
For more tips on how to approach the low nickel diet, check out the cookbook, The 3 tenets of Low Nickel Diet Success, and the Low Nickel Food Lists
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