Systemic argyria associated with ingestion of colloidal silverDepartment of Dermatology, University of California Davis
Akhil Wadhera MD and Max Fung MD
Dermatology Online Journal 11 (1): 12
Humans have been exposed to silver and its compounds for centuries via the natural environment, industry, and through the use of silver-containing medication. Silver is a rare basic element that occurs naturally in our environment as a soft metal. Silver also occurs in the environment as a white powder (silver nitrate and silver chloride), and as a gray-to-black powder (silver oxide or silver sulfide) that is used in photography and medication. Weathering of silver-bearing rocks and soil by wind and rain releases large amounts of silver to the environment. This released silver is fairly stable; it may be taken up by plants or animals. In the metallic form it has been used for making jewelry, silverware, electronic equipment, and dental fillings.
The first recorded use of silver for medicinal purposes dates back to eighth century. In 980 AD Avicenna used silver filings as a blood purifier, for offensive breath, and for palpitations of the heart. His pathology text describes a patient with bluish discoloration of the eyes associated with ingestion of silver; this mention is probably the first recorded case of argyria. The term argyria was first used by Fuchs in 1840. In the Middle Ages silver nitrate was used for the treatment of nervous system disorders such as epilepsy and tabes dorsalis. After observing Dr. Halstead of Johns Hopkins University apply silver foil and gauze to wounds to prevent infection in 1897, Crede popularized the use of silver as an anti-infective measure . In the pre-antibiotic era, silver was used in nose drops (Argyrol, a silver proteinate), in sinusitis and common-cold remedies, and for the treatment of syphilis (Neo-Silvol, a silver arsphenamine). More recently silver arsphenamine has been used in topical astringent preparations. Silver sulfadiazine (1 %) was formulated in 1967 by substituting a portion of the sulfonamide with an atom of silver; it is the most frequently used topical agent for burn treatment .
Over the last few decades, there have been several reported problems associated with silver ingestion, including intestinal ulcers and argyria. With the availability of more effective pharmacologic alternatives, physician-directed use of silver-containing products has significantly declined. However, recently many health-food manufacturers have promoted colloidal-silver-based products as cure-alls. With the proliferation of the Internet, it has become much easier for these manufacturers to market their products to unsuspecting consumers using unsubstantiated claims of effectiveness against major illnesses such as AIDS, cancer, arthritis, and infectious diseases.
We describe a patient who used oral silver to treat his arthritis, a remedy he was introduced to through the Internet. We also review the different forms of silver present in the environment, and the physio-pharmacology and cutaneous manifestations of silver exposure.
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A 38-year-old Caucasian man presents to our clinic concerned about gray discoloration of the skin. The patient began noticing changes in his complexion approximately 5 months prior to presentation during a time when he was ingesting colloidal silver to treat his arthritis. His skin has a generalized silvery sheen, most pronounced on the sun-exposed areas of his head, neck, and hands. The affected skin appears blue-gray and slightly hyperpigmented. His nailbeds are also blue-gray.
While researching arthritis on the Internet, the patient had downloaded detailed information on the preparation of colloidal silver (colloidal silver is a suspension of submicroscopic metallic silver particles suspended in a liquid base) for a variety of indications including joint aches. He was able to obtain plans for a simple battery-operated chamber designed to leach silver from pure silver wire. He ingested approximately 16 ounces (~ 450 ml) of 450 ppm colloidal silver three times a day for 10 months. He reported improvement in his arthritis; however, he discontinued the treatment when his skin began to turn gray.
The patient's medical history includes seronegative arthritis and post-traumatic stress disorder (PTSD). He takes no medications other than the colloidal silver that he has stopped taking several weeks prior to presenting to the clinic. A review of systems reveals spells of lightheadedness without loss of consciousness that have been intermittent for 2 years prior to ingestion of silver. After extensive workup the spells ave been attributed to PTSD. The patient has a negative or normal Holter monitor evaluation and normal laboratory values: EKG, CT of the head, chem 20 panel, CBC, testosterone, CPK, PSA, ferritin, iron, iron saturation, alkaline phosphatase, albumin, vitamin A, calcium, TSH, free T4, sedimentation rate, and urinalysis. He has a negative rheumatoid factor and ANA, and he has tested negative for hepatitis B and C. Because he had a gray complexion he has been evaluated for cyanosis at multiple occasions.
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A punch biopsy of the skin of the neck is performed to confirm the diagnosis of argyria. The biopsy reveals tiny, gray-brown to brown-black granules, measuring approximately 1 mm, scattered extracellularly in the dermis but especially concentrated in the adventitia of eccrine glands.
The relatively profuse vascular networks in these regions can account for this distribution of silver. Silver granules are absent in the epidermis; however, increased melanization of the epidermis and dermal melanophages is seen. This absence of any silver deposits in the epithelium in generalized argyria is documented in many studies . Although not seen on our sections, silver particles in high concentrations are demonstrated in the perifollicular sheaths, nerves, capillary walls, elastic fibers, macrophages, and fibroblasts. Darkfield microscopy usually reveals brilliantly refractile granules that are very easy to see against a dark background. This technique is especially useful when the silver particles are not seen under light microscopy in a patient suspected to have argyria. The granules have also been seen along the basal lamina of the epidermis and blood vessels. The composition of the granules can be confirmed to be silver by X-ray microanalysis .
Physical, chemical, andbiological properties
Silver is the forty-seventh element of the periodic table and has an atomic weight of 107.87. The term silver originates from the Anglo-Saxon word siolfur. (The symbol Ag comes from the Latin word for silver, argentum). Pure silver is a brilliant white metal with a melting point of 961.78° C and a boiling point of 2162° C. It is a little harder than gold and is very ductile and malleable. Pure silver has the highest electrical and thermal conductivity of all metals and possesses the lowest contact resistance. Silver is stable in normal air and water but tarnishes when exposed to ozone, hydrogen sulphide, or air that contains sulphur. Silver occurs in ores including argentite, lead, lead-zinc, copper, and gold . It is a soft metal that is used medically in surgical instruments, dental prostheses, and in alloys. Inorganic silver compounds are germicidal and hence have been used extensively in the field of medicine. These compounds denature proteins by binding to the reactive groups of proteins resulting in their precipitation. They inactivate enzymes by reacting with the sulfhydryl groups to form hemisilver sulfides. They also react with the amino-, carboxyl-, phosphate-, and imidazole-groups and diminish the activities of lactate dehydrogenase and glutathione peroxidase .
Silver absorption, transportation, deposition and excretion
A major portion of ingested silver is absorbed in the small intestine . On the basis of animal and human experiments it is considered that up to 10 percent of ingested silver salt is initially absorbed. This percentage may be much higher if the mucous membranes of the oral cavity are disrupted. Some soluble silver salts corrode the gastrointestinal mucosa and increase the amount of silver absorbed.
Most of the absorbed silver is transported through blood as a soluble colloid with plasma protein. The plasma protein that is most commonly bound with silver is albumin, forming silver albuminate. The blood level of silver in argyremic patients is reported to vary from nondetectable to 0.005 mg Ag/l . However, Blumberg and Carey report a single patient whose spectrographic analysis of blood reveals blood silver levels of 0.5 mg/l, approximately 1 week after discontinuing the use of silver nitrate capsules .
Some of the silver in plasma is carried as a salt and may be deposited in various tissues after being reduced to its metallic form. The highest concentrations of silver are found in the skin, liver, spleen, and adrenals. Although originally believed to not penetrate the blood-brain barrier, it has been shown now that parenterally administered silver salts can accumulate in neurons and glial cells of the brain and spinal cord. The amount of silver deposited in the various tissues is directly proportional to the blood supply of the respective organ.
Animal studies demonstrate that most of the absorbed silver is eliminated through the gastrointestinal system. Even subcutaneously administered silver is excreted in the stool. Renal excretion of silver also occurs and has been shown for one patient to occur up to 3 months after administration of silver .
Toxicology of silver
Adverse health effects of silver depend on the dose and form of exposure, the duration of exposure, the route of exposure (i.e., ingestion, inhalation, or skin contact), and also on the exposed individual's characteristics (age, sex, nutritional status, and state of health). The general population is exposed to silver mostly through very low levels of silver present in food and drinking water and sometimes in the air. The silver in these sources is a result of the naturally occurring silver in water and soil. Naturally occurring silver can contribute to up to 1 × 10-6 mg silver/m3 of air, 0.2-2.0 parts of silver per billion parts of water (ppb) in lakes and river waters and 0.2-0.3 parts of silver per million parts of soil (ppm). Although the Environmental Protection Agency (EPA) recommends that the silver level in drinking water not exceed 50 ppb, drinking water supplies in the United States have been found to contain silver levels up to 80 ppb . Studies conducted by Hamilton in 1972 found the daily oral intake of silver from a typical diet to be 27-88 µg per day .
Th EPA publishes an oral reference dose (RfD) that is based on the assumption that thresholds exist for certain toxic effects such as cellular necrosis. This dose is expressed in units of micrograms per kg per day and is an estimate of the maximum amount of daily silver exposure to the human population that is not associated with any appreciable deleterious effects over a lifetime. Current RfD for oral silver exposure is 5 micrograms per kg per day. When consumed in relatively smaller quantities, no pathologic changes or inflammatory reactions other than argyria have been shown to result from silver deposition . However, if silver is administered in high doses, whether orally or intravenously, there is ample evidence of adverse effects including death. On the basis of animal experiments, many authors in the late nineteenth century determined that intravenous administration of inorganic silver has the most significant impact on the central nervous system (manifested as weakness and rigidity of the legs, loss of voluntary movements) and on the cardiac conduction system (abnormal conduction) .
Consumption of large doses of colloidal silver can result in coma, pleural edema, and hemolysis. Colloidal silver is also toxic to the bone marrow and may be associated with agranulocytosis. The toxic effects of inorganic silver ingested orally in large doses are very similar to any corrosive solution. Such ingestion can result in burning of the throat and epigastrium, leading to abdominal pain, vomiting, and diarrhea. The patient often suffers convulsions and goes into shock. The single lethal dose of silver nitrate has been estimated to be 10 gm. Silver salts are more toxic than silver proteins or colloidal silver.
Furst and Schlauder studied the carcinogenic potential of silver and gold; they concluded that finely divided silver powder injected intramuscularly did not induce any form of cancer .
Cutaneous manifestations of silver exposure
Argyria is a rare condition associated with chronic exposure to silver-containing products; it involves the deposition of silver granules in the skin, mucous membranes, and internal organs including the central nervous system. In skin, silver is mostly deposited around adnexal structures in the dermis; it is associated with a bluish-gray to slate-gray hue. This discoloration is thought to result from the presence of silver and a silver-induced increase in melanin concentration. The effect is most pronounced in sun-exposed areas such as the face, neck, arms, and dorsum of the hands, but it can also be seen in fingernails (azure lunulae), conjunctival membranes, and oral mucosa. The pigment that is deposited is usually silver sulfide, formed by the conversion of silver salts in the presence of light and sulfur-containing organic matrix (in the form of amino acids) . The silver sulfides thus formed may have a stimulatory effect on melanin synthesis . Discoloration is more proportional to the total metal dose than to the amount of sun exposure. The route of administration may determine the generalized or localized nature of argyria. Based on a biospectrometric analysis of ten of the seventy cases of generalized argyria, Gaul and Staud were able to show that the degree of discoloration of patients directly correlated with the amount of silver present .
The differential diagnosis for argyria includes methemoglobinemia, polycythemia, Addison disease, Wilson disease, carcinoid syndrome, hemochromatosis, and ingestion of certain compounds (antimalarials, minocycline, amiodorone, chlorpromazine) or other metals (gold, mercury, and bismuth). With the exception of a case report associating argyria with a convulsive seizure disorder , no physiologic alteration or organ damage has been reported in cases of tissue deposition of silver. Argyria is a rare condition, and unfamiliarity with this disorder has resulted in the clinical presentation being misdiagnosed as cyanosis, leading to invasive, expensive, and unnecessary diagnostic procedures. Silver deposition and hyperpigmentation of the skin in argyria is permanent and primarily of cosmetic significance, and it has no effective treatment.
Ocular argyrosis is the most common type of local argyria; it is manifested as a permanent dirty-gray to brownish discoloration limited to the eye and its contiguous parts; it is associated with a deposition of silver salts. These silver salts can either be from external sources, such as silver containing eye drops or cosmetic makeup, or through systemic silver deposition. Most structures of the eye are involved other than the optic nerve, retina, lens, and the vitreous. Finding of argyrosis on a careful ophthalmic exam may be the first objective sign of generalized argyria . There have been few reports of ocular argyrosis developing from occupational exposures of silver nitrate in an industrial plant and corneal argyrosis from an explosion injury [13, 14].
Although the adverse effects of silver exposure have been known to man for almost 10 centuries, the dosage necessary to produce argyria is still not completely understood. Gaul and Staud reported data on seventy cases of generalized argyria following organic and colloidal-silver medication treatment over a period of 2 years for syphilis . In a subset of twelve patients treated with 4-20 gm IV arsphenamine, argyria becomes clinically apparent after the patient has been exposed to a total IV arsphenamine dose of 8 gm. This dose converts to a total silver dose of 1.84 gm (8 × 0.23 where 0.23 is the fraction of silver in silver arsphenamine) that can cause clinical argyria. However, this number does not take into account the silver exposure a patient may have had from other sources throughout life. Gaul and Staud used their extensive database of patients with argyria and estimated that a person aged 50 would have an average retention of 0.23-0.48 gm of silver, the equivalent to 1-2 gm of silver arsphenamine . If the patient has been exposed to silver nitrate instead, the cumulative dosage needed to produce argyria has been reported to be around 6 gm . The patient reported here consumed 16 ounces of 450 ppm (450 mg/l) colloidal silver TID for 10 months, which translates to approximately 648 mg/day, a cumulative dose of 200 gm over 10 months.
In the early 1900s argyria was seen more commonly because it was associated with silver being used in various medications. However, with an increasing number of reports of problems associated with silver ingestion (including intestinal ulcers and argyria) and with the development of more effective pharmacologic alternatives, physician-directed use of silver-containing products declined. The official drug guidebooks (United States Pharmacopeia and National Formulary) have not listed colloidal silver products since 1975. On the basis of its studies, the FDA concluded that the risk of using silver products exceeds any currently understood benefits; in August 1999 FDA issued its final ruling to ban the use of colloidal silver or silver salts in over-the-counter products .
As we begin a new century with the increased interest in food supplements, alternative medicine, and the availability of information over the Internet, argyria may again be seen more frequently. Also, the FDA ruling did not apply to products being marketed as dietary supplements, and some health-food manufacturers promote colloidal-silver products as a cure-alls. With the proliferation of the Internet, it has become much easier for these manufacturers to market their products to consumers using claims of effectiveness against major illnesses such as AIDS, cancer, arthritis, and infectious diseases.
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