Argyria

Background

Argyria results from prolonged contact with or ingestion of silver salts. Argyria is characterized by gray to gray-black staining of the skin and mucous membranes produced by silver deposition. Silver may be deposited in the skin either from industrial exposure or as a result of medications containing silver salts. See the image below.

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A 92-year-old asymptomatic white man with generalized argyria. For many years, this man had used nose drops containing silver. His skin biopsy showed ....

See Clues on the Skin: Acute Poisonings, a Critical Images slideshow, to help diagnose patients based on their dermatologic presentations.

The most common cause of argyria is mechanical impregnation of the skin by small silver particles in workers involved in silver mining, silver refining, silverware and metal alloy manufacturing, metallic films on glass and china, electroplating solutions, and photographic processing. Colloidal silver dietary supplements are marketed widely for cancer, AIDS, diabetes mellitus, and herpetic infections.^{[1, 2, 3]} Cases have followed the prolonged use of silver salts for the irrigation of urethral or nasal mucous membranes, in eye drops, wound dressing, and the excessive use of an oral smoking remedy containing silver acetate.^{[4, 5]}

Argyria has also been attributed to surgical and dental procedures (eg, silver amalgam-tattooing, silver sutures used in abdominal surgery). Blue macules have appeared at sites of acupuncture needles and silver earring sites.^{[6, 7]} Great individual variability exists in the length of exposure and total dose needed to result in argyria.

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Pathophysiology

Localized argyria occurs in the conjunctiva or oral mucous membrane after long-term topical treatment with silver salt solutions or short-contact acupuncture.

Universal argyria can develop after long-term systemic treatment with drugs that contain silver salts. This used to occur in patients who had taken silver protein suspension for chronic gastritis or gastric ulcer or as nose drops.^[8] Argyria also happens as an occupational disease in workers who prepare artificial pearls or who are employed in the cutting and polishing of silver (absorption of silver dust).

The normal human body contains approximately 1 mg of silver; the smallest amount of silver reported to produce generalized argyria in humans ranges from 4-5 g to 20-40 g. Silver at 50-500 mg/kg body weight is the lethal toxic dose in humans.

Bianchi et al report a possible genetic predisposition for argyria.^[9]

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Etiology

Although pigmentary changes occur primarily in sun-exposed sites, granules are evenly deposited throughout all skin. Differing theories exist as to why the blue-gray pigmentation is restricted to sun-exposed sites. Some believe that silver compounds complexed with proteins in the skin are reduced to elemental silver by light, similar to the process of photo imaging.^[10] Others contend that silver plus light stimulates melanogenesis, which results in the blue-gray color.

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Epidemiology

Argyria has become a rare dermatosis, mainly because of the avoidance of silver-containing compounds as medicinals and a decrease in occupational exposure in the silver industry. Exposure to silver was common in the early part of this century. The famous Blue Man, a member of the Barnum and Bailey Circus sideshow, had a classic case of argyria.

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Prognosis

A permanent and irreversible metallic tinge occurs in the skin of patients with argyria.

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History

A careful history is necessary. Be sure to inquire about possible occupational and environmental exposure, the use of dietary supplements in general, and colloidal silver protein dietary supplements in particular.

Habitual use of silver-based nose drops may produce pigmentation most apparent on the nose and the nail lunulae.^[11]

Scar-localized argyria may occur secondary to silver sulfadiazine cream.^[12]

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Physical Examination

Early on, a gray-brown staining of the gums develops, later progressing to involve the skin diffusely. The cutaneous pigmentation usually is a slate-gray, metallic, or blue-gray color and may be clinically apparent after a few months, but clinical appearance usually takes many years and depends on the degree of exposure.

The hyperpigmentation is most apparent in the sun-exposed areas of skin, especially the forehead, nose, and hands.

In some patients, the entire skin acquires a slate blue-gray color.

The sclerae, nail beds, and mucous membranes may become hyperpigmented.

Viscera tend to show a blue discoloration, including the spleen, liver, and gut, findings evident during abdominal surgery or at postmortem examination.

Rarely, black tears (melanodacryorrhea) can appear during argyrosis of the conjunctiva.

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Complications

The systemic toxic effects of silver may include the following:

• Gastrointestinal catarrh
• Tissue wasting
• Uremia
• Albuminuria
• Fatty degeneration of the liver, kidney, and heart
• Hemorrhage
• Idiopathic thrombocytopenia
• Fluidity of the blood
• Chronic bronchitis
• Loss of coordination
• Decreased night vision
• Gustatory disturbance
• Vestibular impairment
• Seizure of the grand mal type
• Death by paralysis of the respiratory system

Current thought holds that the substantial amounts of silver in argyria usually result in no serious effects on human health. However, a few cases have notable clinical symptoms and signs. This lack of significant systemic silver toxicity in argyria may be due to the interaction of selenium and sulfur with silver in vivo.

It was reported that argyria can be associated with unexpected and quickly developing severe radiation dermatitis during chemoradiotherapy treatment.^[13]

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Imaging Studies

In vivo silver concentrations can be measured using x-ray fluorescence.^[16]

Dermoscopy, reflectance confocal microscopy, and high-definition optical coherence tomography can be used in the diagnosis of generalized argyria.^{[17, 18]}

Corneal confocal microscopy and electrophysiological tests may help confirm the diagnosis of ocular argyrosis.^[19]

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Procedures

The diagnosis of argyria is established by skin biopsy with formaldehyde-fixed paraffin-embedded sections stained with hematoxylin-eosin.

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Histologic Findings

Small, round, brown-black granules appear singly or in clusters and are evident with routine staining. They spare both the epidermis and its appendages, appearing in greatest numbers in the basement membrane zone surrounding sweat glands. These silver granules also favor the connective-tissue sheaths around pilosebaceous structures and nerves. They have a predilection for elastic fibers and are best visualized as strikingly refractile with dark-field illumination. An increase in the amount of melanin in exposed skin also appears to occur.

Electron microscopy demonstrates electron-dense granules. In early cases, they are located within fibroblasts and macrophages, while later most are present extracellularly. Neutron activation analysis, atomic absorption spectrophotometry, or x-ray dispersive microanalysis can be used to confirm that the granules contain silver and often also sulfur and less commonly selenium.^{[20, 21, 22]} A simpler option is to decolorize the silver by placing histologic sections into 1% potassium ferricyanide in 20% sodium thiosulfate.

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Medical Care

Treatment with depigmenting preparations is not satisfactory; however, according to some reports, 5% hydroquinone treatment may reduce the number of silver granules in the upper dermis and around sweat glands and diminish the number of melanocytes.

Chelation attempts to remove silver from the body have been unsuccessful.

Sunscreens and opaque cosmetics may be helpful in preventing further pigmentary darkening and aid in masking obvious discoloration.

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Surgical Care

The treatment of argyria caused by colloidal silver ingestion using the Q-switched 1064-nm Nd:YAG laser has been reported,^{[23, 24]} and a picosecond 755-nm Q-switched alexandrite laser has also been used with success for treatment.^{[25, 26]}

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Medication Summary

Selenium and sulfur have been shown to have favorable modifying effects on the metabolism and toxicity of silver by forming complexes with silver. Silver selenide is highly insoluble in vivo, and this effectively reduces the availability of monovalent silver to interfere with normal enzymatic activities in tissues. However, the silver-sulfur complexes formed in vivo do not seem as stable as silver-selenium complexes.

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Hydroquinone (Eldopaque-Forte, Solaquin Forte, Lustra)

• Dosing, Interactions, etc.

Clinical Context:  Topical application produces a reversible depigmentation of the skin by the inhibition of the enzymatic oxidation of tyrosine to 3,4-dihydroxyphenylalanine and suppression of the melanocyte metabolic process.

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Class Summary

According to reports, a 4% hydroquinone treatment could reduce the number of silver granules in the upper dermis and around sweat glands and reduce the number of melanocytes; however, no completely satisfactory treatment modalities exist and some pigmentation remains permanently.

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