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Nickel allergy is any of several
allergic Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, alle ...
conditions provoked by exposure to the chemical element
nickel Nickel is a chemical element; it has symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel is a hard and ductile transition metal. Pure nickel is chemically reactive, but large pieces are slo ...
. Nickel allergy often takes the form of nickel allergic contact dermatitis (Ni-ACD), a form of
allergic contact dermatitis Allergic contact dermatitis (ACD) is a form of contact dermatitis that is the manifestation of an allergic response caused by contact with a substance; the other type being irritant contact dermatitis (ICD). Although less common than ICD, ACD ...
(ACD). Ni-ACD typically causes a rash that is red and itchy and that may be bumpy or scaly. The main treatment for it is avoiding contact with nickel-releasing metals, such as inexpensive jewelry. Another form of nickel allergy is a systemic form: systemic nickel allergy syndrome (SNAS) can mimic some of the symptoms of
irritable bowel syndrome Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by a group of symptoms that commonly include abdominal pain, abdominal bloating, and changes in the consistency of bowel movements. These symptoms may ...
(IBS) and also has a dermatologic component.


Signs and symptoms

The most common sign of nickel allergy is inflammation of the skin at an area that comes into regular contact with nickel. This often takes the form of a reddened patch of skin with raised bumps (
papule A papule is a small, well-defined bump in the skin lesion, skin. It may have a rounded, pointed or flat top, and may have a umbilication, dip. It can appear with a Peduncle (anatomy), stalk, be thread-like or look warty. It can be soft or firm a ...
s) or small blisters ( vesicles), and
edema Edema (American English), also spelled oedema (British English), and also known as fluid retention, swelling, dropsy and hydropsy, is the build-up of fluid in the body's tissue (biology), tissue. Most commonly, the legs or arms are affected. S ...
. People with chronic dermatitis tend to have dry, scaly, and cracked skin at the site of contact. These sites of inflammation (called "primary eruptions") can occur anywhere on the skin that contacts nickel, but are most common on the hands, face, or anywhere that contacts metal objects such as jewelry or metal clothes buttons. Particularly high levels of nickel exposure can cause irritated patches of skin to appear at other sites on the body (called "secondary eruptions"). These typically occur as blistering rashes on the hands, eyelids, and at the inside of flexing joints (inside the elbow, back of the knee, etc.). Ingestion of nickel may cause a systemic reaction, which can result in generalized inflammation of the skin across the body, small blisters in the hands, irritation inside the flexing joints (flexural eczema), and redness and irritation of both buttocks. Systemic contact dermatitis (SCD) is defined as a
dermatitis Dermatitis is a term used for different types of skin inflammation, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened ...
occurring in an epi-cutaneously contact-sensitized person when exposed to haptens systemically such as orally, per rectum, intravesically, transcutaneously, intrauterinely,
intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...
ly, or by
inhalation Inhalation (or inspiration) happens when air or other gases enter the lungs. Inhalation of air Inhalation of air, as part of the cycle of breathing, is a vital process for all human life. The process is autonomic (though there are exceptions ...
. The
pathophysiology Pathophysiology (or physiopathology) is a branch of study, at the intersection of pathology and physiology, concerning disordered physiological processes that cause, result from, or are otherwise associated with a disease or injury. Pathology is ...
of systemic nickel allergy syndrome (SNAS) is not well understood. The clinical course is determined by an immunological interplay between two types of
T cells T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their ce ...
(Th1 and Th2 responses). SCD is often considered a subset of SNAS, but with only skin manifestations. SNAS presents with an array of symptoms ranging from respiratory to generalized skin rash to gastrointestinal symptoms. The gastrointestinal symptoms may mimic those of
irritable bowel syndrome Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by a group of symptoms that commonly include abdominal pain, abdominal bloating, and changes in the consistency of bowel movements. These symptoms may ...
. A meta review evaluating SNAS found that 1% of patients sensitized to nickel reacted to the nickel content of a 'normal' diet, and with increasing doses of nickel more individuals reacted SNAS is a multilayered immunological response demonstrating variance between individuals and doses of nickel exposure.


Causes


Nickel exposure

Nickel is both naturally abundant – it is the fifth most common element on earth – and widely used in industry and commercial goods. Workplace nickel exposure is common in many industries, and the performance of normal work tasks can result in nickel skin levels sufficient to elicit dermatitis. Within the workplace, individuals may be exposed to significant amounts of nickel, airborne from the combustion of
fossil fuel A fossil fuel is a flammable carbon compound- or hydrocarbon-containing material formed naturally in the Earth's crust from the buried remains of prehistoric organisms (animals, plants or microplanktons), a process that occurs within geolog ...
s or from contact with tools that are nickel plated. Historically, workplaces where prolonged contact with soluble nickel has been high have shown high risks for allergic contact nickel dermatitis. For example, nickel dermatitis was common in the past among nickel platers. Outbreaks of nickel allergy from consumer goods have been documented throughout the 20th century, with jewelry, stocking suspenders, and metallic buttons on blue jeans each resulting in dermatitis at the point of contact. Nickel can also be present in food and drinking water; ingestion of increased nickel is not associated with systemic allergic disease, but is associated with flare-ups of dermatitis or aggravation of vesicular hand eczema. Similarly, aggravation of dermatitis has been reported in response to nickel-containing surgical implants or dental gear. The risk of an object eliciting nickel allergy is linked to the amount of nickel released by its surface (and not to its total nickel content). Suspected objects can be screened by wiping the surface with a 1% dimethylglyoxime solution that turns pink if more than 0.5 μg/cm2 per week is released by the surface. Various methods exist to test the skin or nails for nickel exposure, typically relying on wiping the skin, then quantifying the nickel on the wipe via
mass spectrometry Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a ''mass spectrum'', a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is used ...
. Dietary nickel exposure may come from high-nickel foods, possibly canned food (via the packaging), possibly stainless steel cookware (whereas some grades of stainless steel contain more nickel than others), or plumbing (especially the first water run from the tap in the morning).


Physiology

Nickel allergy results in a skin response after the skin comes in contact with an item that releases a large amount of nickel from its surface. It is commonly associated with nickel-containing belt buckles coming into prolonged contact with the skin. The skin reaction can occur at the site of contact, or sometimes spread beyond to the rest of the body. Free (released) nickel that is able to penetrate the
skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different ...
is taken up by scavenger (
dendritic Dendrite derives from the Greek word "dendron" meaning ( "tree-like"), and may refer to: Biology *Dendrite, a branched projection of a neuron *Dendrite (non-neuronal), branching projections of certain skin cells and immune cells Physical *Dendri ...
) cells and then presented to the
immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...
T-Cells. With each subsequent exposure to nickel these
T cell T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...
s become stimulated and duplicate themselves. With enough exposure to nickel, the amassing clones of T-cells reach "threshold" and the skin develops a
rash A rash is a change of the skin that affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracke ...
. The rash can appear as acute, subacute, or chronic eczema-like skin patches, primarily at the site of contact with the nickel (e.g., earlobe from nickel earrings). From the time of exposure, the rash usually appears within 12–120 hours and can last for 3–4 weeks or for the continued duration of nickel contact/exposure. Three simultaneous conditions must occur to trigger Ni-ACD: #Direct skin contact with nickel-releasing item #Prolonged skin contact with nickel-releasing item #A sufficient amount of nickel is released and absorbed into the skin to cause a reaction The
pathophysiology Pathophysiology (or physiopathology) is a branch of study, at the intersection of pathology and physiology, concerning disordered physiological processes that cause, result from, or are otherwise associated with a disease or injury. Pathology is ...
is divided into induction elicitation phases. Induction is the critical phase (immunological event) when skin contact to nickel results in antigen presentation to the T cells, and T cell duplication (cloning) occurs. The metal cation Ni++ is a low molecular weight hapten that easily penetrates the
stratum corneum The stratum corneum (Latin language, Latin for 'horny layer') is the outermost layer of the epidermis (skin), epidermis. Consisting of dead tissue, it protects underlying tissue from infection, dehydration, chemicals and mechanical stress. It is ...
(top layer of skin). Nickel then binds to skin protein carriers creating an antigenic
epitope An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that binds to the epitope is called a paratope. Although e ...
. The determining factor in
sensitization Sensitization is a non-associative learning process in which repeated administration of a stimulation, stimulus results in the progressive amplification of a response. Sensitization often is characterized by an enhancement of response to a whole ...
is exposure of significant amounts of "free nickel". This is important because different metal
alloy An alloy is a mixture of chemical elements of which in most cases at least one is a metal, metallic element, although it is also sometimes used for mixtures of elements; herein only metallic alloys are described. Metallic alloys often have prop ...
s release different amounts of free nickel. The antigenic epitope is collected by dermal dendritic cells and
Langerhans cell A Langerhans cell (LC) is a tissue-resident macrophage of the skin once thought to be a resident dendritic cell. These cells contain organelles called Birbeck granules. They are present in all layers of the epidermis and are most prominent in t ...
s, the
antigen-presenting cell An antigen-presenting cell (APC) or accessory cell is a Cell (biology), cell that displays an antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize the ...
s (APC) of the skin, and undergo maturation and migration to regional
lymph node A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...
s. The complex is predominantly expressed on
major histocompatibility complex The major histocompatibility complex (MHC) is a large Locus (genetics), locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for Cell (biology), cell surface proteins essential for the adaptive immune system. The ...
( MHC) II, which activates and clonally expands naive
CD4+ T cells The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...
. Upon re-exposure these now primed T cells will be activated and massively recruited to the skin, resulting in the elicitation phase and the clinical presentation of Ni-ACD. Although ACD has been considered a Th1 predominate process, recent studies highlight a more complex picture. In Ni-ACD other cells are involved including: Th17, Th22, Th1/ IFN and the innate immune responses consistent with toll-like receptor 4.


Prevention

Nickel has a wide utility of application in manufactured metals because it is both strong and malleable, leading to ubiquitous presence and the potential for consumers to be in contact with it daily. However, for those who have the rash of allergic contact dermatitis (ACD) due to a nickel allergy, it can be a challenge to avoid. Foods, common kitchen utensils, cell phones, jewelry, and many other items may contain nickel and be a source of irritation due to the allergic reaction caused by the absorption of free released nickel through direct and prolonged contact. The most appropriate measure for nickel-allergic persons is to prevent contact with the allergen. In 2011, researchers showed that applying a thin layer of
glycerine Glycerol () is a simple triol compound. It is a colorless, odorless, sweet-tasting, viscous liquid. The glycerol backbone is found in lipids known as glycerides. It is also widely used as a sweetener in the food industry and as a humectant in ...
emollient containing
nanoparticles A nanoparticle or ultrafine particle is a particle of matter 1 to 100 nanometres (nm) in diameter. The term is sometimes used for larger particles, up to 500 nm, or fibers and tubes that are less than 100 nm in only two directions. At ...
of either
calcium carbonate Calcium carbonate is a chemical compound with the chemical formula . It is a common substance found in Rock (geology), rocks as the minerals calcite and aragonite, most notably in chalk and limestone, eggshells, gastropod shells, shellfish skel ...
or calcium phosphate on an isolated piece of pig skin (
in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...
) and on the skin of mice (
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...
) prevents the penetration of nickel ions into the skin. The
nanoparticle A nanoparticle or ultrafine particle is a particle of matter 1 to 100 nanometres (nm) in diameter. The term is sometimes used for larger particles, up to 500 nm, or fibers and tubes that are less than 100 nm in only two directions. At ...
s capture nickel ions by cation exchange, and remain on the surface of the skin, allowing them to be removed by simple washing with water. Approximately 11-fold fewer nanoparticles by mass are required to achieve the same efficacy as the
chelating Chelation () is a type of bonding of ions and their molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a polydentate (multiple bonded) ligand and a single central metal atom. These l ...
agent ethylenediamine tetraacetic acid. Using nanoparticles with diameters smaller than 500 nm in topical creams may be an effective way to limit the exposure to
metal ions A metal () is a material that, when polished or fractured, shows a lustrous appearance, and conducts electricity and heat relatively well. These properties are all associated with having electrons available at the Fermi level, as against n ...
that can cause skin irritation'. Pre-emptive avoidance strategies (PEAS) might ultimately lower the sensitization rates of children who would develop ACD It is theorized that prevention of exposure to nickel early on could reduce the number of those that are sensitive to nickel by one-quarter to one-third. Identification of the many sources of nickel is vital to understanding the nickel sensitization story, food like chocolate and fish, zippers, buttons, cell phones and even orthodontic braces and eyeglass frames might contain nickel. Items that contain sentimental value (heirlooms, wedding rings) could be treated with an enamel or rhodium plating. The Dermatitis Academy has created an educational website to provide more information about nickel, including information about prevention, exposure, sources, and general information about nickel allergy. These resources provide guidance in a prevention initiative for children worldwide. Prevention of SNAS includes modifying dietary choices to avoid certain foods that are higher in nickel than others.


Diagnosis

Nickel allergy is typically diagnosed by patch testing – applying a patch with 2.5% (in North America) or 5% (in Europe) nickel sulfate to the upper back and looking for irritation on the skin. As with other causes of allergic contact dermatitis, patches containing several common allergens are typically applied to the back for 48 hours, removed, then the spots examined for allergic reactions 2 to 5 days later. SNAS can often mimic IBS and may be more common than is widely appreciated. It therefore should be considered as a
differential diagnosis In healthcare, a differential diagnosis (DDx) is a method of analysis that distinguishes a particular disease or condition from others that present with similar clinical features. Differential diagnostic procedures are used by clinicians to di ...
item when a doctor is considering a diagnosis of IBS, and nickel allergy testing is advisable as a means to exclude or confirm SNAS. Even before such testing, some differentiating factors in the
medical history The medical history, case history, or anamnesis (from Greek: ἀνά, ''aná'', "open", and μνήσις, ''mnesis'', "memory") of a patient is a set of information the physicians collect over medical interviews. It involves the patient, and ev ...
are if certain foods prompt the symptoms (for example, peanuts or shellfish), whereas IBS is not specific to those foods.


Treatment

Once a nickel allergy is detected, the best treatment is avoidance of nickel-releasing items. The top 13 categories that contain nickel include beauty accessories, eyeglasses, money, cigarettes, clothes, kitchen and household, electronics and office equipment, metal utensils, aliment, jewelry, batteries, orthodontic and dental appliances, and medical equipment. Other than strict avoidance of items that release free nickel, there are other treatment options for reduction of exposure. The first step is to limit friction between skin and metallic items. Susceptible people may try to limit sweating while wearing nickel items, to reduce nickel release and thus decrease chances for developing sensitization or allergy. Another option is to shield electronics, metal devices, and tools with fabric, plastic, or acrylic coverings. There are dimethylglyoxime test kits that can be very helpful to check for nickel release from items prior to purchasing. The American Contact Dermatitis Society 'find a provider' resource can help identify clinicians with training in providing guidance lists of safe items. In addition to avoidance, healthcare providers may prescribe additional creams or medications to help relieve the skin reaction.


Epidemiology

Nickel allergy is the most common contact allergy in industrialized countries, affecting around 8% to 19% of adults and 8% to 10% of children. Women are affected 4–10 times as frequently as men. Nickel allergy is estimated to affect 4% of men and 16% of women worldwide. In southern European countries, nickel allergy is more common than in northern countries, 16% versus 10%. The results are similar in the USA.


Regulation

As nickel can be harmful to skin, its use in daily products must be regulated. A safety directive has been in place in Europe since 2004.
Denmark Denmark is a Nordic countries, Nordic country in Northern Europe. It is the metropole and most populous constituent of the Kingdom of Denmark,, . also known as the Danish Realm, a constitutionally unitary state that includes the Autonomous a ...
in 1980, and then shortly after the
European Union The European Union (EU) is a supranational union, supranational political union, political and economic union of Member state of the European Union, member states that are Geography of the European Union, located primarily in Europe. The u ...
(EU), enacted legislation that limited the amount of free nickel in consumer products that come in contact with the skin. This resulted in significantly decreased rates of sensitization among Danish children 0 to 18 years of age from 24.8% to 9.2% between 1985 and 1998, with similar reductions in sensitization throughout the EU. No such directive exists in the United States, but efforts are under way to mandate safe use guidelines for nickel. In August 2015, the
American Academy of Dermatology The American Academy of Dermatology (AAD) is a non-profit professional organization of dermatologists in the United States and Canada, based in Rosemont, Illinois, near Chicago. It was founded in 1938 and has more than ''21,000'' members. The Acad ...
(AAD) adopted a nickel safety position paper. The exact prevalence of Ni-ACD in the general population in the US is largely unknown. However, current estimates gauge that roughly 2.5 million US adults and 250,000 children have a nickel allergy, which costs an estimated $5.7 billion per year for treatment of symptoms. Loma Linda University, Nickel Allergy Alliance, and Dermatitis Academy created the first open access self-reported patient registry to record nickel allergy prevalence data in the US. ef 23


History

In the 17th century, copper miners in
Saxony Saxony, officially the Free State of Saxony, is a landlocked state of Germany, bordering the states of Brandenburg, Saxony-Anhalt, Thuringia, and Bavaria, as well as the countries of Poland and the Czech Republic. Its capital is Dresden, and ...
, Germany, began to experience irritation caused by a "dark red ore". Since the substance, which would later be called nickel, led to many ailments, they believed it to be protected by "
goblin A goblin is a small, grotesque, monster, monstrous humanoid creature that appears in the folklore of multiple European cultures. First attested in stories from the Middle Ages, they are ascribed conflicting abilities, temperaments, and appearan ...
s", and called it "Goblin's Copper". Josef Jadassohn described the first case of metal
contact dermatitis Contact dermatitis is a type of acute or chronic inflammation of the skin caused by exposure to chemical or physical agents. Symptoms of contact dermatitis can include itchy or dry skin, a red rash, bumps, blisters, or swelling. These rashes ...
in 1895, to a mercury-based therapeutic cream, and confirmed the cause by epi-cutaneous patch testing. In the next century nickel began to be mass-produced for jewelry worldwide due to its cheap cost, resistance to corrosion and high supply. In 1979 a large comprehensive study of healthy US volunteers found that 9% had been unknowingly sensitized to nickel. , that number has tripled. Most importantly, nickel allergy among children is increasing, with an estimated 250,000 children sensitized to nickel. Published literature shows an exponential increase in reported nickel allergy cases. The North American Contact Dermatitis Group (NACDG) patch tested 5,085 adults, presenting with eczema-like symptoms, showing 19.5% had a positive reaction to nickel. Nickel allergy is also more prevalent in women (17.1%) than men (3%), possibly due to cultural norms related to jewelry and ear piercings and therefore increased exposure to nickel. In order to investigate the current prevalence of nickel, Loma Linda University, Nickel Allergy Alliance, and Dermatitis Academy, are conducting a self-reporting nickel allergy-dermatitis survey.forms
''Loma Linda University'' (restricted access site)


References


Further reading

* {{Elements in biology Biology and pharmacology of chemical elements Contact dermatitis Element toxicology Toxic effects of metals
Allergy Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include Allergic rhinitis, hay fever, Food allergy, food al ...