eMedicine Specialties > Dermatology > Diseases of Pigmentation
Argyria
Updated: Mar 13, 2009
Introduction
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.
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.
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
Frequency
United States
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.
Clinical
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.10
- Scar-localized argyria may occur secondary to silver sulfadiazine cream.11
Physical
- 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.
Causes
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.12 Others contend that silver plus light stimulates melanogenesis, which results in the blue-gray color.
Differential Diagnoses
Ochronosis
Other Problems to Be Considered
Medications (ie, phenothiazines, antimalarials, amiodarone, minocycline)
Hemochromatosis
Polycythemia vera
Addison disease
Diffuse melanosis in metastatic melanoma
Heavy metals (ie, mercury, bismuth, arsenic, gold, lead)
Central cyanosis (impaired pulmonary function, anatomic shunt, hemoglobin abnormalities, methemoglobinemia)
Peripheral cyanosis (reduced cardiac output)
Workup
Imaging Studies
In vivo silver concentrations can be measured using x-ray fluorescence.13
Procedures
The diagnosis of argyria is established by skin biopsy with formaldehyde-fixed paraffin-embedded sections stained with hematoxylin-eosin.
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.14,15,16 A simpler option is to decolorize the silver by placing histologic sections into 1% potassium ferricyanide in 20% sodium thiosulfate.
Treatment
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.
Surgical Care
- Rhee et al reported on the treatment of argyria caused by colloidal silver ingestion using the Q-switched 1064-nm Nd:YAG laser.17
Medication
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.
Pigment agents
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.
Hydroquinone (Eldopaque-Forte, Solaquin Forte, Lustra)
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 melanocyte metabolic process.
Dosing
Adult
Apply to affected areas bid, in the morning and before bedtime
Pediatric
<12 years: Not established
Interactions
None reported
Contraindications
Documented hypersensitivity; sunburns
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Avoid solar exposure; not for ophthalmic, nasal, or otic use; application area should not exceed that of face, neck, hands, or arms; long-term use in dark-skinned individuals may lead to a localized form of ochronosis
Follow-up
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.
Prognosis
A permanent and irreversible metallic tinge occurs in the skin of patients with argyria.
References
Bouts BA. Images in clinical medicine. Argyria. N Engl J Med. May 20 1999;340(20):1554. [Medline].
Fung MC, Bowen DL. Silver products for medical indications: risk-benefit assessment. J Toxicol Clin Toxicol. 1996;34(1):119-26. [Medline].
Gulbranson SH, Hud JA, Hansen RC. Argyria following the use of dietary supplements containing colloidal silver protein. Cutis. Nov 2000;66(5):373-4. [Medline].
Brandt D, Park B, Hoang M, Jacobe HT. Argyria secondary to ingestion of homemade silver solution. J Am Acad Dermatol. Aug 2005;53(2 Suppl 1):S105-7. [Medline].
Gaslin MT, Rubin C, Pribitkin EA. Silver nasal sprays: misleading Internet marketing. Ear Nose Throat J. Apr 2008;87(4):217-20. [Medline].
Legat FJ, Goessler W, Schlagenhaufen C, Soyer HP. Argyria after short-contact acupuncture. Lancet. Jul 18 1998;352(9123):241. [Medline].
Rackoff EM, Benbenisty KM, Maize JC, Maize JC Jr. Localized cutaneous argyria from an acupuncture needle clinically concerning for metastatic melanoma. Cutis. Nov 2007;80(5):423-6. [Medline].
Prescott RJ, Wells S. Systemic argyria. J Clin Pathol. Jun 1994;47(6):556-7. [Medline].
Bianchi L, Orlandi A, Di Stefani A, Ricci R, Chimenti S. "Familial" generalized argyria. Arch Dermatol. Jun 2006;142(6):789-90. [Medline].
Menaguale G, Fazio R, Fazio M. Argyria: a case following the prolonged use of a rhinologic drug. Esper Dermatol (Roma). 2003;4:299-303.
Fisher NM, Marsh E, Lazova R. Scar-localized argyria secondary to silver sulfadiazine cream. J Am Acad Dermatol. Oct 2003;49(4):730-2. [Medline].
Shelley WB, Shelley ED, Burmeister V. Argyria: the intradermal "photograph," a manifestation of passive photosensitivity. J Am Acad Dermatol. Jan 1987;16(1 Pt 2):211-7. [Medline].
Graham SA, O'Meara JM. The feasibility of measuring silver concentrations in vivo with x-ray fluorescence. Phys Med Biol. Aug 7 2004;49(15):N259-66. [Medline].
Lee SM, Lee SH. Generalized argyria after habitual use of AgNO3. J Dermatol. Jan 1994;21(1):50-3. [Medline].
Robinson-Bostom L, Pomerantz D, Wilkel C, et al. Localized argyria with pseudo-ochronosis. J Am Acad Dermatol. Feb 2002;46(2):222-7. [Medline].
Sato S, Sueki H, Nishijima A. Two unusual cases of argyria: the application of an improved tissue processing method for X-ray microanalysis of selenium and sulphur in silver-laden granules. Br J Dermatol. Jan 1999;140(1):158-63. [Medline].
Rhee DY, Chang SE, Lee MW, Choi JH, Moon KC, Koh JK. Treatment of argyria after colloidal silver ingestion using Q-switched 1,064-nm Nd:YAG laser. Dermatol Surg. Oct 2008;34(10):1427-30. [Medline].
Keywords
argyria, universal argyria, localized argyria, ingestion of silver salts, contact with silver salts, staining of skin, silver staining
Contributor Information and Disclosures
Author
Kamila K Padlewska, MD, PhD, Professor, Warsaw Academy of Cosmetics and Health Care; Chief Executive, Cosmetic-Medical Cooperative, Poland
Kamila K Padlewska, MD, PhD is a member of the following medical societies: Academy of Medical Royal Colleges
Disclosure: Nothing to disclose.
Coauthor(s)
Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.
Medical Editor
Smeena Khan, MD, Private Practice, Adult and Pediatric Dermatology Associates
Smeena Khan, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.
Pharmacy Editor
Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA
Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association
Disclosure: Nothing to disclose.
Managing Editor
Jeffrey J Miller, MD, Associate Professor of Dermatology, Penn State University College of Medicine; Staff Dermatologist, Penn State Milton S Hershey Medical Center
Jeffrey J Miller, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, Association of Professors of Dermatology, North American Hair Research Society, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.
CME Editor
Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania
Joel M Gelfand, MD, MSCE is a member of the following medical societies: Society for Investigative Dermatology
Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds None; Genentech Consulting fee Consulting; Centocor Consulting fee Consulting; Centocor Grant/research funds None; Covance Consulting fee Consulting; Shire Consulting
Chief Editor
Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.