Arsenical Keratosis

Updated: Mar 30, 2016
  • Author: Chih-Shan Jason Chen, MD, PhD; Chief Editor: Dirk M Elston, MD  more...
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Overview

Background

Arsenic is a natural occurring metalloid, an abundant element found in many types of rocks. Weathering of rocks releases arsenic-containing dust and allows arsenic compounds to enter groundwater. Arsenical compounds are used in industrial, agricultural, and medicinal substances. Arsenic is also an environmental contaminant in drinking water (well water) and the food chain and is an occupational hazard for miners and glass workers. Higher levels of arsenic are notoriously poisonous to multicellular life. Lower levels of inorganic arsenicals are known to be chemical carcinogens.

As early as 1888, Hutchinson reported skin cancer in patients who had taken arsenical medications. Numerous reports have since confirmed that ingested arsenic can cause Bowen disease (squamous cell carcinoma in situ); invasive squamous cell carcinoma; basal cell carcinoma of the skin; and (less frequently) internal cancers of the lung, the kidney, the bladder, and the liver. [1]

Arsenic also causes pigment changes and (very frequently) hyperkeratotic lesions of the skin called arsenical keratoses. Arsenical keratoses are the most characteristic skin feature of long-term arsenic exposure.

Other Medscape articles related to arsenic include Neurological Manifestations of Arsenic Intoxication and Arsenic Toxicity in Emergency Medicine.

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Pathophysiology

The carcinogenic mechanism of arsenic is not well understood. Arsenic compounds have shown no mutagenicity in standard bacterial and mammalian test systems; however, they can increase the mutagenicity of other DNA-damaging agents. Arsenite impairs nucleotide excision repair, [2] and it may also affect gene expression by increasing or decreasing DNA methylation. [3, 4] The high affinity of arsenic for sulfhydryl groups makes keratin-rich cells (eg, epidermal keratinocytes) a sensitive target for arsenic-induced toxicity.

Arsenic has been shown to alter epidermal keratinocyte differentiation processes, [5] affect cell cycle and apoptosis, induce overexpression of growth factors such as transforming growth factor-α and epidermal growth factor receptor, [6, 7] and enhance proliferation of human keratinocytes. These in vitro findings may have revealed part of the pathogenesis of arsenical keratoses. The oncogenesis of arsenic-induced cancers still awaits elucidation. [8]

In the endemic region of West Bengal, India, only 10-30% of people exposed long term to arsenic developed characteristic skin lesions. A 2008 study suggests the individual capacity of DNA repair determines the level of chromosomal aberration, which leads to a susceptibility to develop arsenic-induced premalignant hyperkeratoses. [9]

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Epidemiology

Frequency

United States

Arsenical keratosis and arsenic-induced skin cancers are very rare in the United States. Only isolated incidences of cutaneous toxicity from environmental or medicinal exposure have been reported. Several epidemiologic studies of communities exposed to drinking water with higher arsenic levels have not shown any excess incidence of skin cancers.

Documented regions with natural groundwater arsenic contamination include Millard County, Utah; Lane County, Oregon; Lassen County, California; Fallon, Nevada; Fairbanks, Alaska; and New Hampshire. [10] One study suggests persons living in the southwestern United States are at higher risk for being exposed to elevated levels of arsenic in drinking water. [11]

International

Arsenic-induced skin lesions have been noticed in some endemic regions, mainly due to long-term exposure to high levels of arsenic in drinking water. Such regions have been reported in Southern Taiwan, Japan, Vietnam, China, New Zealand, Poland, Hungary, Spain, Canada, Mexico, Chile, Argentina, West Bengal (India), Sri Lanka, Bangladesh, and western Iran. [10, 12]

According to large epidemiologic studies conducted by Yeh et al [13] and Tseng et al [14] in 1968 in Taiwan, among a high-risk population of 40,421 people, arsenic-induced hyperpigmentation was recognized in 18.4% of patients, arsenical keratosis in 7.1%, and skin cancers in 1.5%. Of the 428 people with skin cancer, 72% also presented with arsenical keratosis and 90% had hyperpigmentation.

A study conducted by Fierz [15] in Germany of 262 patients who had been taking Fowler solution for 6-26 years revealed that 40% of these patients developed arsenical keratosis and that 8% had skin cancers.

In a large-scale study in an endemic region, 18,000 persons in Bangladesh and 86,000 persons in West Bengal (India) were clinically examined. Of them, 3695 (20.6%, including 6.11% children) in Bangladesh and 8500 (9.8%, including 1.7% children) in West Bengal had arsenical dermatological features. [16]

An epidemiologic study has been conducted in Kurdistan (western Iran), where the arsenic concentration in drinking water ranges from 42-1500 μg/L. Among 587 villagers examined, 30.7% had skin manifestations of chronic arsenic toxicity. The prevalence rates of Mee lines (transverse bands of leukonychia) on the nails, arsenic keratoses, and pigment disorders among these patients were 86.1%, 77.2%, and 67.8%, respectively. [12]

Race

Several large studies have focused in regional endemic areas. No global epidemiologic studies have been performed, and no direct predilection has been found among persons of different races.

Sex

In a study in Bangladesh, 430 out of 1481 research subjects older than 30 years who lived in villages with arsenic-contaminated wells were found to have arsenic-induced skin lesions, such as keratosis and hyperpigmentation or hypopigmentation. [17] The prevalence rate is approximately 30%, with a slightly higher prevalence in males than in females. Another study in West Bengal (India) revealed the prevalence of arsenic-induced skin lesions in men was 2- to 3-fold higher than in women. [18]

Age

Immediately consider possible arsenic exposure if skin cancer is found in a relatively young person. The presence of arsenic skin toxicity can be seen in all age groups, although a latency period does occur.

Symptoms of chronic arsenic toxicity develop insidiously after 6 months to 2 years or more of exposure. In the study by Fierz, [15] the minimal latency period from exposure to the development of arsenical keratoses was 2.5 years, and the average latency period for skin cancer was 14 years.

A Japanese study reported the appearance of Bowen disease after 10 years, squamous cell carcinoma after 20 years, and lung cancer after 30 years of apparent arsenic exposure. [19]

In Taiwanese studies, the youngest patients reported to have skin hyperpigmentation, arsenical keratoses, and skin cancer were aged 3, 4, and 24 years, respectively.

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Etiology

A dose-response relationship exists between the amount of arsenic exposure and the frequency of various skin lesions. However, several studies have shown skin lesions that have developed in persons who consumed drinking water containing arsenic concentrations of less than 50 μg/L. A detail investigation has found that arsenic exposures of greater than 100 μg/L, even 200 μg/L in drinking water, are the cause of the characteristic skin lesions. [20] Three main categories of sources from which patients might have been exposed to arsenic include medicinal, drinking water (environmental), and occupational hazards.

Medicinal arsenic

Inorganic arsenic has been used in medicine for at least 2500 years, particularly since the 18th century, when it was used to treat a great variety of illnesses (eg, acne, diarrhea, gastric ulcer, asthma, malaria, lupus, psoriasis, neurodermatitis, eczema, rheumatism). During the 19th and early 20th centuries, the most popular preparation in the Western world was called Fowler solution, which contained 1% potassium arsenite. [21] In Asia, Chinese proprietary herbal medicine has been the mainstay of remedies for thousands of years and is still popular in that area; it is also available in the United States. Some of these traditional Chinese medicines have been reported to contain high levels of arsenic. [22, 23, 24]

Drinking water

Studies from endemic areas have found that arsenic-contaminated water (mainly well water) is the source of exposure. Cases of arsenic-induced toxicity have been reported in some endemic areas of Chile, Taiwan, India, [25] Bangladesh, and Mexico. An area on the southwest coast of Taiwan has been referred to as the endemic area of Blackfoot disease (a chronic peripheral vascular disease that may progress into gangrenous changes of the lower extremities). The same area also shows a high prevalence of skin cancer. Both conditions are dose related to high arsenic levels in artesian well water that local residents consume daily. In a Taiwanese study, Morales et al [26] reported the lifetime risk of death related to arsenic toxicity is 1 in 100 from consuming 50 μg/L of arsenic in drinking water.

Occupational hazards

Legge reported skin manifestations and lung cancer in sheep dip workers exposed to arsenic as early as 1902. Other reports showed arsenic carcinogenesis in smelter workers, pesticide workers, glass manufacturers, and miners. Burning plywood may cause arsenic-containing fumes to be inhaled. High-tech industries use gallium arsenide to produce semiconductor computer chips.

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