Are You Confident of the Diagnosis?
What you should be alert for in the history
The history should reveal an exposure to topical or ingested silver. While acute cases are reported, usually the exposure occurs years later or after years of repeated exposure.
Characteristic findings on physical examination
Focal argyria may present as blue, gray or black amalgam tattoos on buccal or labial mucosa. Necessarily this will occur on mucosa in direct contact with silver containing fillings. Focal argyria may also present with slate gray patches or punctate blue gray macules in areas of skin that were at one time open wounds and treated with silver containing dressings.
Systemic argyria may show a diffuse blue gray color (blue man syndrome) with or without brownish staining in sun-exposed areas, such as the face and hands (Figure 1). Nailbeds, gingival mucosa, and the sclera may also take on a bluish-gray hue (Figure 2, Figure 3). Internally, viscera such as the liver, spleen and gut may be hyperpigmented. Melanodacryorrhea (black tears) has been reported in argyria patients.
Expected results of diagnostic studies
The genetics of susceptibility to argyria have not been definitively defined. Serum silver levels are not always available and would usually be elevated only in those still ingesting large amounts of the metal. Despite this, elevated serum and urinary silver levels have been reported in those treating open wounds with large amounts of silver sulfadiazine.
X-ray fluorescence has demonstrated in vivo silver concentrations and electron microscopy will show electron dense granules. Histologically, brown and black granules are evident on hematoxylin-eosin, formalin-fixed specimens with or without special stains (Figure 4). Sweat glands, pilosebaceous structures, nerves, and the basement membrane zone show the highest concentrations. Typically, the epidermis itself is spared.
Differential diagnosis would include other types of medication-induced hyperpigmentation, such as minocycline, amiodarone, phenothiazines, antimalarials, and zidovudine. As many of these may have similar histologic findings, unless spectrophotometry is performed to specifically identify the offending agent, a careful medication history will reveal the cause.
Erythema dyschromicum perstans (ashy dermatosis, EDP) may have a similar clinical presentation and may even show similar histopathology. The lack of mucosal involvement in EDP is an important distinction. Addison’s disease may present with a generalized hyperpigmentation including palmar creases, but this is due to increased melanogenesis rather than pigment deposition. Diffuse melanosis due to overwhelming melanoma tumor load may appear similar clinically but, by history, such patients generally have known unresponsive metastatic disease.
Who is at Risk for Developing this Disease?
Argyria requires either topical or systemic exposure to silver. Those at risk in the former case are those with open wounds treated either with silver-containing ointments such as silver sulfadiazine (Silvadene, Thermazene, SSD) or silver impregnated dressings (Aquacel, Aquacel Ag, Acticoate, Urgotul, Polymem Silver or Contreet antibacterial foam).
Patients with chronic conditions such epidermolysis bullosa and more acute denuding injuries such as thermal burns or toxic epidermal necrolysis have experienced both localized and systemic argyria. Ingested silver through nasal drops and naturopathic remedies employing colloidal silver may cause systemic argyria. There is also an occupational risk for those who prepare artificial pearls, use silver in photographic processing or who are exposed to silver dust through silver cutting, electroplating, and polishing procedures.
Silver-containing eyedrops and nasal drops are still widely available as naturopathic treatments for a variety of disorders. There may be a genetic predisposition to acquire the disease.
What is the Cause of the Disease?
Ingestion or contact through mucosa or open wounds with silver or silver containing compounds is the etiology of argyria. Respiratory exposure may occur in those exposed to silver solders, silver dust from cutting and polishing, or silver containing fumes from silver plating.
Silver is deposited in the skin and viscera which may lead to bluish discoloration (especially skin, liver and gut) and the so called “blue man syndrome.” Sun-exposed areas of the arms and face will often become the most hyperpigmented and while some of this is caused by the silver itself, others suggest that silver-protein complexes will create the equivalent of an old black and white photograph negative whereby the light causes fixation and precipitation of the silver compound, or that the silver in sun-exposed skin stimulates melanogenesis.
Systemic Implications and Complications
Systemic complications are rare and, when present, generally involve the kidneys or nervous system. In the former case, uremia, albuminuria, and fatty degeneration of kidney, liver, and heart may occur. In the latter case, seizures, paralysis, vertigo, taste abnormalities, decreased night vision and uncoordination may occur.
Also reported with argyria are neutropenia, idiopathic thrombocytopenic purpura and other coagulation disorders. Beyond the recommended skin biopsy, appropriate laboratory would include complete blood count with platelet count, complete metabolic profile to include renal and liver function tests, and a urinalysis with particular attention to albuminuria screening. Difficulties with vision, balance, or other neurologic systems should be evaluated by a neurologist and/or ophthalmologist.
The primary therapy is to remove and/or discontinue the source of the exogenous silver. Patients using colloidal silver need to be convinced to stop drinking their concoctions and patients using silver-impregnated dressings or ointments should use alternative wound dressings. Resolution of pigmentary changes without specific treatment is reported but is not usual and, when it does occur, takes months.
Chelation therapy (systemic and locally injected) has been tried without significant benefit. Hydroquinone based bleaching creams are generally ineffective. Dermabrasion has mixed results – it is not a treatment of choice. Most recently use of the Nd:YAG laser has demonstrated relatively immediate results in some patients. Benefits in such cases are limited to areas actually subjected to laser energy.
Focal argyria may be excised or ignored. If argyria is due to implanted silver acupuncture needles, they should be removed to prevent worsening of the pigmentation.
Optimal Therapeutic Approach for this Disease
Discontinue the source of exogenous silver. Avoid exposure to sun as this may worsen affected areas. Consider Nd:YAG laser treatment for cosmetically sensitive areas
Focal argyria, while unsightly, does not present any risk to the patient. Stopping the ongoing ingestion of silver-containing concoctions may not reverse the existing disease but may prevent it from getting worse. Some patients, however, are so convinced of the “health benefits” of their colloidal silver ingestion that they will ignore their worsening appearance and may prove quite resistant to suggestions that they need to discontinue it.
Unusual Clinical Scenarios to Consider in Patient Management
Generalized argyria without an identified source for exogenous silver was reported in two patients on chronic hemodialysis. This was felt to be due to unprocessed water used in the hemodialysis, an unusual case when one considers most patients have a readily identifiable topical or systemic source.
What is the Evidence?
Baker, CD, Federico, MJ, Accurso, FJ. “Case report: skin discoloration following administration of colloidal silver in cystic fibrosis”. Curr Opin Pediatr. vol. 19. 2007. pp. 733-5. (Colloidal silver is taken by patients for many conditions ranging from an immune system tonic to prophylaxis against anthrax infection. The use of alternative medicine treatments in patients must always be considered in presentations of both common and rare disorder. In this case an 11-year-old boy with cystic fibrosis developed argyria from such a treatment and, remarkably, cleared when his silver levels returned to normal after discontinuation of the colloidal silver treatment.)
Browning, JC, Levy, ML. “Argyria attributed to Silvadene application in a patient with dystrophic epidermolysis bullosa”. Dermatol Online J. vol. 14. 2008. pp. 9(While thermal burns are perhaps the main injury treated with silver-coated dressings, other chronic open wounds that a dermatologist might care for are also at risk.)
Drake, PL, Hazelwood, KJ. “Exposure-related health effects of silver and silver compounds: a review”. Ann Occup Hyg. vol. 49. 2005. pp. 575-85. (This article reviews some of the occupational exposure routes, current OSHA standards, and the consideration that there may be significantly different risks between exposures to metallic versus soluble silver compounds. Soluble compounds, especially by way of systemic absorbtion, are felt to be more toxic than metallic silver and there should probably be different exposure limits assigned.)
Lansdown, AB. “Critical observations on the neurotoxicity of silver”. Crit Rev Toxicol. vol. 37. 2007. pp. 237-50. (This article reviews the findings of silver sulfide deposits in neural tissues and suggests that the neurologic health risks associated with elevated serum silver levels and argyria may not be as conclusively established as some other articles report. This is an extension of the 2006 article by Lansdown (Lansdown AB. Silver in health care: antimicrobial effects and safety in use. Curr Probl Dermatol 2006:33:17-34), which also argued that the health risks of silver may be overstated.)
Mirsattari, SM, Hammond, RR, Sharpe, MD, Leung, FY, Young, GB. “Myoclonic status epilepticus following repeated oral ingestion of colloidal silver”. Neurology. vol. 62. 2004. pp. 1408-10. (In contrast to the Lansford articles, this case describes catastrophic neurologic injuries to a 71-year-old user of colloidal silver.)
Griffith, RD, Simmons, BJ, Bray, FN, Falto-Aipurua, LA, Yazdani Abyaneh, MA, Nouri, K. “1064 nm Q-switched Nd:YAG laser for the treatment of Argyria: a systematic review”. J Eur Acad Dermatol Venereol. vol. 29. 2015 Nov. pp. 2100-3. (Treatment for argyria is generally ineffective and chelating therapy, while theoretically promising, has not proven useful. Treating the silver deposits like a tattoo, the authors demonstrated remarkable pigment clearance clinically and confirmed significant decrease in tissue silver deposition histologically. Sometimes even a single pass may show some clearance)
Han, TY, Chang, HS, Lee, HK, Son, S-J. “Successful treatment of argyria using a low fluence Q-switched 1064-nm Nd:YAG laser”. Int J Dermatol. vol. 50. 2011. pp. 751-3. (A 49 year-old man who developed argyria after ingesting colloidal silver solution as a traditional remedy was successfully treated with seven treatment sessions.
Trop, M., Novak, M., Rodi, S., Hellbom, B., Kroel, W., Goessler, W.. “Silver-coated dressing Acticoat caused raised liver enzymes and argyria-like symptoms in burn patient”. J Trauma. vol. 60. 2006. pp. 648-52. (The authors report on a 17-year-old burn victim with 30% surface area involvement who developed elevated liver enzymes and argyria after only a week of therapy with a silver impregnated dressing. Elevated transaminases, as well as serum and urine silver levels, returned to normal quickly after discontinuation of the dressings.)
Walker, M, Cochrane, CA, Bowler, PG, Parsons, D, Bradshaw, P. “Silver deposition and tissue staining associated with wound dressings containing silver”. Ostomy Wound Manage. vol. 52. 2006. pp. 42-4. (Two silver containing dressings (hydrofiber and nanocrystalline) showed significantly more silver released and deposited in the tissues when the dressings were hydrated with water than when they were hydrated with saline.)
Wang, XQ, Chang, HE, Francis, R, Olsaowy, H, Liu, PY, Kempf, M. “Silver deposits in cutaneous burn scar tissue is a common phenomenon following the application of a silver dressing”. J Cutan Pathol. vol. 36. 2009. pp. 788-92. (Using porcine burns as a model, the authors studied the histologic characteristics of silver deposition in scars after treatment with Acticoat.)
Karakasli, A, Hapa, O, Akdeniz, O, Havitcioglu, H. “Dermal argyria; Cutaneous manifestation of a megaprosthesis for distal femoral osteosarcoma”. Indian J Orthop. vol. 48. 2014 May. pp. 326-8. (Silver is not a metal normally thought of in orthopedic prostheses but silver coated units are used. In this case silver deposition was confirmed histologically and through electron microscopy in a patient who had such a prosthesis.)
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