Argyria (ISV from Greek: αργύρος argyros silver + -ia) is a disease caused by the ingestion of elemental silver, silver dust or silver compounds. The most dramatic effect of argyria is that the skin is colored blue or bluish-grey. Argyria may be found as generalized argyria or local argyria. Argyrosis is the corresponding condition related to the eye. The condition is believed to be permanent. Most recent cases are due to the over consumption of home made colloidal silver as an alternative medicine.

Since at least the early part of the 20th century, doctors have known that silver or silver compounds can cause some areas of the skin and other body tissues to turn gray or blue-gray. Argyria occurs in people who eat or breathe in silver over a long period (several months to many years). A single exposure to a silver compound may also cause silver to be deposited in the skin and in other parts of the body; however, this is not known to be harmful. It is likely that many exposures to silver are necessary to develop argyria. Once argyria develops, it is believed to be permanent. However, the condition is thought to be only a "cosmetic problem". Most doctors and scientists believe that the discoloration of the skin seen in argyria is the most serious health effect of silver (in small doses).

Reports of cases of argyria suggest that gram amounts (from 2 to 4 grams) of silver or a silver compound taken in medication in small doses over several months may cause argyria in some humans. People who work in factories that manufacture silver can also breathe in silver or its compounds. In the past, some of these workers have become argyric. However, the level of silver in the air and the length of exposure that caused argyria in these workers is not known. It is also not known what level of silver causes breathing problems, lung and throat irritation, or stomach pain in people. Studies in rats show that drinking water containing very large amounts of silver (9.8 grams of silver per U.S. gallon water or 2.6 grams per liter) is likely to be life-threatening.

There is very little information about health effects following skin contact with silver compounds. Argyria that covers the entire body is not seen following skin contact with silver compounds, although the skin may change color where it touches the silver. However, many people who have used skin creams containing silver compounds such as silver nitrate and silver sulfadiazine have not reported health problems from the silver in the medicine. In one animal study, a strong solution of silver nitrate (81 milligrams silver nitrate per liter of water) applied to the skin of guinea pigs for 28 days did not cause the animals to die; however, it did cause the guinea pigs to stop gaining weight normally. It is not known if this would happen to people if they were exposed the same way.

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BASICS OF COMPOUNDING for Skin Discolorations
From International Journal of Pharmaceutical Compounding, 9/1/04 by Allen, Loyd V Jr

Introduction

Having clear, smooth, evenly colored skin is desired by many; some are fortunate to have it, but most are not. Skin color can be altered by disease or exposure to miscellaneous agents. Some patients have a change in pigment coloration as a result of inflammatory disease, including acne or atopic dermatitis.

Skin cells contain melanocytes that produce melanosomes, which are pigment granules containing the complex protein, or brown skin-coloring pigment, melanin. The pituitary hormone produces melanocyte-stimulating hormone (MSH), which stimulates melanin production. The rate of production of the pigment varies, but in both light- and dark-skinned individuals there are approximately 800 to 1000 melanocytes per square millimeter of human epidermis. A number of conditions can cause the melanocytes to become either abnormal or abnormally distributed in the skin.

Most skin conditions that cause discoloration are actually harmless, causing more cosmetic and emotional discomfort than medical problems.1,2 Skin hyperpigmentation and photoaging are considered by many to be cosmetically unacceptable, and those who find it unacceptable search for treatment methods to minimize the conditions. This article will only address hyperpigmentation treatment.

Background

Examples of pigments that can be problematic include carotene, which can result in carotenemia; iron, which can cause hemodiserin; and silver, which can cause argyria. Other pigmentation problems can be caused by the gold used in rheumatoid arthritis treatments, by tattooing, by the homogentisic acid in ochronosis and by bile pigments.

Changes in skin color may be from hyperpigmentation or hypopigmentation; both can be primary or secondary to other disorders in the body. Table 1 lists common causes of pigmentation disorders.

Primary hyperpigmentation disorders include those that are nevoid, congenital or acquired. Disorders include pigmented nevi, ephelides (juvenile freckles, an inherited characteristic; age spots; and café-au-lait spots) and lentigines (solar lentigines, senile lentigines, senile freckles, liver-spots). Other hyperpigmentation disorders include arsenical melanosis and disorders associated with Addison's disease. Neurofibromatosis may produce axillary freckling and café-au-lait spots. A patterned hyperpigmentation of the face, usually as a result of estrogen therapy, is melasma (chloasma), a problem that occurs in about 30% to 50% of women taking oral contraceptives.1

Primary hypopigmentation and depigmentation disorders include vitiligo, albinism and piebaldism. Pigment cells, or melanocytes, are destroyed in vitiligo, which occurs in about 1% of the population and may be associated with hyperthyroidism, hypothyroidism, pernicious anemia, diabetes mellitus and Addison's disease. Albinism is a collection of genetically determined traits. Piebaldism is a localized hypomelanosis producing a white forelock. Tuberous sclerosis may produce hypopigmented ash leaf spots, and hypopigmented halos can often be seen around nevi and may occur around melanomas.1

Secondary hyperpigmentation disorders include those occurring after a separate dermatologic condition, including acne; such disorders are most commonly seen in dark-skinned individuals and are called postinflammatory hyperpigmentation. Another disorder is called Berloque hyperpigmentation, which is due to phototoxicity from chemicals in the rinds of limes and other citrus fruits, and to celery. Pigmentation disorders can also be caused by some drugs, including chloroquine, chlorpromazine, minocycline and amiodarone. Benzoyl peroxide, fluorouracil and tretinoin can cause hyperpigmentation; fixed drug eruptions can result from phenolphthalein in laxatives, trimethoprim-sulfamethoxazole, nonsteroidal anti-inflammatory drugs (NSAIDs) and tetracyclincs.1

Secondary hypopigmentation (leukoderma) may result as a complication of atopic dermatitis, lichen planus, psoriasis, discoid lupus erythrematosus and lichen simplex chronicus. Liquid nitrogen used on patients with olive or darker complexions may result in hypopigmentation or depigmentation. High concentrations of corticosteroid injected intralesionally or intra-articularly may also cause localized temporary hypopigmentation.1

Some body chemicals, such as bilirubin, can be deposited in the skin and cause a discoloration. Heavy metals such as silver, gold and iron each have a characteristic color when they can be seen within the skin. Table 2 lists a number of these agents, as well as some drugs that can cause pigmentation disorders.

Symptoms

Questions for the medical history of the patient may include:

1. Family: Does anyone else in your family have a similar problem?

2. Timing: When did the discoloration begin? Was it sudden? Is it getting worse, and, if so, how quickly?

3. Quality: Describe the change. Is the skin getting darker or lighter?

4. Location: Where is the discoloration? Is there a pattern to it?

5. Aggravating factors: What medications are you using? Are you often exposed to the sun or a sun lamp? What is your diet?

6. Miscellaneous questions can involve other symptoms, as well as any rashes or skin lesions.

A trained dermatologist can generally recognize the pattern of discoloration immediately and name and characterize the discoloration. Some of these pigment changes reflect internal diseases that must be identified and treated.

Table 3 lists some symptoms, diseases and causative factors related to hyperpigmentation disorders.

Treatment

The goal of therapy in hyperpigmentation disorders is to lighten the skin so it blends into the normal skin in the area. Most products used to lighten the skin contain hydroquinone. Other drugs commonly used in the treatment of hyperpigmentation disorders include axelaic acid, glycolic acid, hydrocortisone, kojic acid, tretinoin and triamcinolone. Information on these drugs is shown within this article, and antioxidants and adjuvants used in their formulations are listed in Table 4. Normally, these agents are somewhat irritating to sensitive skin. Treatments may take 3 to 6 months to produce improvement. Laser treatments are also available. For treatment of freckles, age spots and other discolorations, using a sunscreen with a sun protection factor (SPF) of at least 1$ is a must.

Active Ingredients Used in the Treatment of Skin Hyperpigmentation

Azelaicacid (C^sub 9^H^sub 16^O^sub 4^ MW 188.22, nonanedioic acid) is marketed as an anti-acne product in Germany. It is prepared by disruptive oxidation of ricinoleic acid. It also occurs in rancid oleic acid. It is soluble 2.4 mg/mL in water at room temperature; it is freely soluble in boiling water and in alcohol.3 Azelaic acid is used in 5% to 20% concentrations.

Glycolic acid (C^sub 2^H^sub 4^O^sub 3^, MW 76.05, hydroxyacetic acid) occurs as odorless, somewhat hygroscopic crystals. It is a constituent of sugar cane and is soluble in water and alcohol.3 Alpha hydroxy acids are often combined with hydroquinone and provide an exfoliant effect to enhance the removal of the darkened cells. They are used in 1 % to 20% concentrations.

Hydrocortisone (C^sub 21^H^sub 30^O^sub 5^, MW 362.46, cortisol, Compound F) is a corticosteroid secreted by the adrenal cortex. It occurs as a white to practically white, odorless, crystalline powder. It is very slightly soluble in water and sparingly soluble in alcohol. Generally, hydrocortisone is used topically in 0.5% to 1% concentrations.4

Hydroquinone (C^sub 6^H^sub 6^O^sub 2^, MW 110.11) occurs as fine white needles. It darkens upon exposure to light and air. It is freely soluble in water, alcohol and ether. It bleaches or lightens the skin by slowing the production of melanin so the dark spots gradually fade to match the normal skin coloration. Prescription products contain more of the hydroquinone than over-the-counter bleaching agents (generally 1.5% to 2.0%). Generally applied twice daily, hydroquinone is often used at a 2% to 5% or higher concentration (up to 15%), as a cream, gel or solution and is effective in decreasing cutaneous hyperpigmentation. Once the desired results are achieved, a reduction to once-daily application is recommended.5 In more severe cases, the prescription creams also contain tretinoin and/ or a corticosteroid, such as hydrocortisone or triamcinolone.

Kojic acid (C^sub 6^H^sub 6^O^sub 4^ MW 142.11) is an antibiotic substance produced aerobically by a variety of microorganisms. It occurs as prismatic needles and is freely soluble in water, ethanol and acetone. It is a natural agent that is capable of blocking melanin production. It is also obtained from either Japanese mushrooms or asafetida extracted.3 Kojic acid is used in concentrations ranging from 2% to 10%.

Tretinoin (C^sub 20^H^sub 28^O^sub 2^, MW 300.44, retinoic acid) occurs as a yellow to light-orange, crystalline powder that is insoluble in water and slightly soluble in alcohol. It is often used at concentrations of 0.025% to 0.05%.5

Triamcinolone (C^sub 21^H^sub 27^FO^sub 6^, MW 394.43) occurs as a white, or practically white, odorless, crystalline powder. It is very slightly soluble in water and ether and slightly soluble in alcohol.5 Triamcinolone is commonly used in concentrations of between 0.025% and 0.5%.

References

1. Berger TG. Skin, Hair, and Nails. In: Tierney LM Jr, McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis & Treatment 2003. New York, NY: Lange Medical Books/McGraw-Hill; 2003: 138-140.

2. Esterly JS, West LE, West DP. Skin hyperpigmentation and photoaging. In: Berardi RR, ed. Handbook of Nonprescription Drugs. 14th ed. Washington, DC: American Pharmaceutical Association; 2004: 955-967.

3. O'Neil MJ Sr, ed. The Merck Index. 13th ed. Whitehouse Station, NJ: Merck & Co., Inc.; 2001: 158, 801, 951.

4. McEvoy GK. AHFS Drug Information-2004. Bethesda, MD: American Society of Health-System Pharmacists; 2004: 2674-2675.

5. US Pharmacopeial Convention, Inc. United States Pharmacopeia 27-National Formulary 22. Rockville, MD: US Pharmacopeial Convention, Inc.; 2004: 2765-2786.

6. Allen LVJr. Featured excipient: Antioxidants. IJPC 1999; 3(1): 52-55.

Loyd V. Allen, Jr., PhD, RPh

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