Dermatology

Heavy Metal Dermatoses: Arsenic

Are You Confident of the Diagnosis?

What you should be alert for in the history

Public health awareness in areas (eg, China, Bangladesh, United States, Chile) known to have problems with arsenic.

Characteristic findings on physical examination

Because of the pronounced affinity of arsenic for keratinizing structures, including hair and nails, acute intoxication becomes primarily manifest in a variety of skin eruptions, alopecia, and characteristic striation of the nails (Mee’s lines). Manifestations of prolonged arsenic exposure are hyperpigmentation, arsenical keratosis, and neoplasia.

Arsenic melanosis is viewed as the abnormal stimulation of normal melanin biosynthesis by arsenic. Extracutaneous manifestations are protean and include weakness, anemia, burning sensation of eyes, solid swelling of legs, liver fibrosis, chronic lung disease, gangrene of toes, neuropathy. The prevalence of pigmentation and keratosis, hepatomegaly, chronic respiratory disease and weakness rose significantly with increasing arsenic concentrations in drinking water. The respiratory effects were most pronounced in individuals with high arsenic water concentrations who also had skin lesions.

Blood level of arsenic should be measured and is generally used for assessing acute exposure. Renal clearance of a single high dose of arsenic is fast and highly efficient. With sensitive inductively coupled plasma mass spectrometry (ICP-MS), accurate blood level of arsenic can be measured. Besides, using blood for measurement has advantages over urine as creatinine adjustment is not necessary and blood is less affected by renal function.

Diagnosis confirmation

Hyperkeratosis and hyperpigmentation are non-specific cutaneous findings. In at-risk areas, low threshold for investigations of possible arsenic dermatosis should be considered.

Who is at Risk for Developing this Disease?

Arsenic is a ubiquitous nonessential toxic element. Arsenic exposure may result from environmental sources where high arsenic concentrations are present in the soil, including well water, foods, pesticides, sheep dips, copper and other ores, fabric dyes. Arsenic can also be present in medicinal sources such as Fowler’s solution containing arsenite, Asiatic pills, Donovan’s solution and De Valagin’s solution.

Chronic arsenic toxicity results in the development of a number of internal and cutaneous malignancies. In chronic arsenic toxicity, cutaneous dark brown hyper-pigmentation is common. Arsenical keratoses are usually multiple and typically occur at sites of friction and trauma, especially on the palms and the soles. Keratoses usually manifest as small, punctate, nontender, horny, hard, yellowish, often symmetric, cornlike papules, or as diffuse thickening or small (<2mm) sand-paper-like keratoses. Cutaneous conditions also include warty keratoses on the palms, soles and ears (http://www.dermnet.org.nz/reactions/arsenic.html).

Other skin manifestations of chronic arsenic toxicity include hyperpigmented and hypopigmented macules on the torso and limbs. The pigmented lesions often present as finely freckled macules distributed bilaterally symmetrically. Diffuse hyperpigmented patches in the intertriginous, genital, and acral areas may be an early sign of chronic arsenic toxicity.

Another type of arsenical keratosis seen in most patients with arsenical cancers (Bowen’s disease and superficial basal cell carcinomas) manifests as scaly erythematous or pigmented patches on unexposed body areas. Transverse white bands (Mee’s lines) on the fingernails are seen in acute and chronic arsenic toxicity. The occurrence of multiple skin cancers on exposed and unexposed areas at a young age should raise suspicion of arsenic toxicity.

What is the Cause of this Disease?

Etiology

Due to dose-related exposure to arsenic, either accidentally or purposefully.

Pathophysiology

Arsenic is carcinogenic in its inorganic form (arsenic trioxide), which binds preferentially to sulfhydryl groups, and inhibiting enzymes such as pyruvate oxidase. The toxicity involves the denaturation of cellular proteins and alteration of their structural integrity. Regardless of route of exposure, skin is extremely sensitive to arsenic toxicity due to the attraction of arsenic to the skin’s sulfhydryl group-containing proteins. Chronic arsenic accumulation increases the susceptibility of the skin to ultraviolet light and is associated with an increased incidence of skin tumors.

Systemic Implications and Complications

Initial systemic manifestations include anorexia, lethargy, hypotonia, irritability, and personality changes. Increased drooling and profuse perspiration, hypertension, tachycardia, and intermittent low-grade fever may be present. Death may occur.

Treatment Options

Severe acute intoxication with arsenic responds to therapy with dimercaprol or penicillamine. Successful treatment of palmoplantar arsenical keratosis with a combination of keratolytics and low-dose acitretin has been reported.

Optimal Therapeutic Approach for this Disease

Toxicology consultation is required.

BAL 3 to 5mg/kg/dose by deep intramuscularly every 4 hours for 2 days, every 4 to 6 hours for an additional 2 days, then every 4 to 12 hours for up to 7 additional days.

D-penicillamine as a second-line drug: 750mg/day for 2 to 4 weeks; no longer recommended for use in arsenic intoxication. It showed little efficacy in an animal model.

Successful treatment of palmoplantar arsenical keratosis with a combination of keratolytics and low-dose acitretin has been reported.

Patient Management

Prevention is by awareness of environmental hazards and vigilance. Adequate laws protecting the public should be enforced.747

Unusual Clinical Scenarios to Consider in Patient Management

An increased risk of internal malignancies associated with arsenic exposure. Lung, bladder, and kidney malignancies have been the most commonly reported tumors. Hepatic angiosarcoma and leukemia have also been linked to chronic arsenic exposure.

Cardiovascular disease, peripheral vascular disease, diabetes, reproductive problems and hematologic abnormalities may all result from chronic arsenic exposure.

Peripheral neuropathy may occur and present similarly to the Guillian-Barré syndrome, with an asymmetric peripheral neuropathy.

What is the Evidence?

Smith, AH, Hopenhayn-Rich, C, Bates, MN, Goeden, HM, Hertz-Picciotto, I, Duggan, HM. "Cancer risks from arsenic in drinking water". Environ Health Perspect. vol. 97. 1992. pp. 259-67.

(Ingestion of arsenic, both from water supplies and medicinal preparations, is known to cause skin cancer. The evidence assessed here indicates that arsenic can also cause liver, lung, kidney, and bladder cancer and that the population cancer risks due to arsenic in US water supplies may be comparable to those from environmental tobacco smoke and radon in homes. Large population studies in an area of Taiwan with high arsenic levels in well water [170 to 800mcg/L] were used to establish dose-response relationships between cancer risks and the concentration of inorganic arsenic naturally present in water supplies.It was estimated that at the current Environmental Protection Agency standard of 50mcg/L, the lifetime risk of dying from cancer of the liver, lung, kidney, or bladder from drinking 1L/day of water could be as high as 13 per 1000 persons. It has been estimated that more than 350,000 people in the United States may be supplied with water containing more than 50mcg/L arsenic, and more than 2.5 million people may be supplied with water with levels above 25 mcg/L. For average arsenic levels and water consumption patterns in the United States, the risk estimate was around 1/1000. Although further research is needed to validate these findings, measures to reduce arsenic levels in water supplies should be considered.)

Tondel, M, Rahman, M, Magnuson, A, Chowdhury, IA, Faruquee, MH, Ahmad, SA. "The relationship of arsenic levels in drinking water and the prevalence rate of skin lesions in Bangladesh". Environ Health Perspect. vol. 107. 1999. pp. 727-9.

(To determine the relationship of arsenic-associated skin lesions and degree of arsenic exposure, a cross-sectional study was conducted in Bangladesh, where a large part of the population is exposed through drinking water. Four villages in Bangladesh were identified as mainly dependent on wells contaminated with arsenic. We interviewed and examined 1481 subjects 30 years of age or older in these villages. A total of 430 subjects had skin lesions [keratosis, hyperpigmentation, or hypopigmentation].Individual exposure assessment could only be estimated by present levels and in terms of a dose index, ie, arsenic levels divided by individual body weight. Arsenic water concentrations ranged from 10 to 2040mcg/L, and the crude overall prevalence rate for skin lesions was 29 per 100. After age adjustment to the world population, the prevalence rate was 30.1 per 100 and 26.5 per 100 for males and females, respectively. There was a significant trend for the prevalence rate both in relation to exposure levels and to dose index (P<.05), regardless of sex.This study shows a higher prevalence rate of arsenic skin lesions in males than females, with clear dose-response relationship. The overall high prevalence rate in the studied villages is an alarming sign of arsenic exposure and requires an urgent remedy.)

Guha Mazumder, DN. "Chronic arsenic toxicity: clinical features, epidemiology, and treatment: experience in West Bengal". J Environ Sci Health Part A: Toxic/Hazardous Substances & Environmental Engineering. vol. 38. 2003. pp. 141-63.

(Chronic arsenic toxicity due to drinking arsenic-contaminated water has been one of the worst environmental health hazards affecting eight districts of West Bengal since the early 80s. Detailed clinical examination and investigation of 248 such patients revealed protean clinical manifestations of such toxicity. Over and above hyperpigmentation and keratosis, weakness, anemia, burning sensation of eyes, solid swelling of legs, liver fibrosis, chronic lung disease, gangrene of toes, neuropathy, and skin cancer are some of the other manifestations.A cross-sectional survey involving 7683 participants of all ages was conducted in an arsenic-affected region between April 1995 and March 1996. Out of a population of 7683 surveyed, 3467 and 4216 people consumed water containing As below and above 0.05mg/L, respectively. Except painful abdomen, the prevalence of all other clinical manifestations tested, eg, pigmentation, keratosis, hepatomegaly, weakness, nausea, lung disease and neuropathy, were found to be significantly higher in As-exposed people (water As > 0.05mg/L) compared with control population [water As level < 0.05mg/L].The prevalence of pigmentation and keratosis, hepatomegaly, chronic respiratory disease and weakness rose significantly with increasing arsenic concentrations in drinking water. The respiratory effects were most pronounced in individuals with high arsenic water concentrations who also had skin lesion. Therapy with chelating agent DMSA was not found to be superior to placebo effect. However, therapy with DMPS caused significant improvement of clinical condition of chronic arsenicosis patients as evidenced by significant reduction of total clinical scores from 8.90 +/- 2.84 to 3.27 +/- 1.73; P < .0001.Efficacy of specific chelation therapy for patients suffering from chronic As toxicity has further need to be fully substantiated. However, supportive treatment could help in reducing many symptoms of the patients. Treatment in hospital with good nutritious diet has been found to reduce symptom score in a subset of placebo-treated patients in West Bengal during the course of DMSA and DMPS trial. People should be advised to stop drinking As-contaminated water or exposure to As from any other source. The various clinical manifestations should be treated symptomatically.)

Stolman, LP, Kopf, AW, Garfinkel, L. "Are palmar keratoses a sign of internal malignancy". Arch Dermatol. vol. 101. 1970. pp. 52-5.

(The authors report no statistical difference in the prevalence of palmar keratoses in patients with cancer when compared to a control group of individuals who did not have overt cancer. Palmar keratoses occurred more frequently on the left than on the right hand and more frequently on the hypothenar eminences than elsewhere in both groups. They conclude that the etiology and significance of palmar keratoses is unknown, but in the New York city area these lesions cannot be considered a stigma of cancer.)

Cuzick, J, Evans, S, Gillman, M, Price Evans, DA. "Medicinal arsenic and internal malignancies". Br J Cancer. vol. 45. 1982. pp. 904-11.

(A mortality analysis has been carried out on a cohort of patients given Fowler's solution [potassium arsenite] for periods ranging from 2 weeks to 12 years between 1945 and 1969. An excess of fatal and non-fatal skin cancer was apparent, but there was no overall excess mortality from cancer. Further analyses by site of cancer, dose level, and time from first exposure are also presented.A subset of patients were examined in 1969-70 for the presence of arsenical keratoses, hyperpigmentation and skin cancer. About half the patients had one or more of these signs. Although the cancer mortality of this entire subgroup was similar to the expected value, all the cancer deaths occurred in patients with prior signs of arsenicism. These data suggest that while any excess of internal malignancy due to the use of Fowler's solution is small or nonexistent, there may be a susceptible subgroup that can be identified from dermatologic manifestations.)

Poole, S, Fenske, NA. "Cutaneous markers of internal malignancy. II. Paraneoplastic dermatoses and environmental carcinogens". J Am Acad Dermatol. vol. 28. 1993. pp. 147-64.

(A variety of cutaneous disorders may reflect the presence of an internal disease. The ability to recognize those that may indicate an underlying malignancy is of particular importance. In part I of this series malignant involvement of the skin, either direct or metastatic, and the genodermatoses with malignant potential were reviewed. In this portion, we describe the paraneoplastic dermatoses as well as the cutaneous effects of some environmental carcinogens associated with internal malignancy. In addition, several uncommon and controversial associations between benign dermatoses and internal malignant disease will be discussed.)

Smith, AH, Arroyo, AP, Mazumder, DN, Kosnett, MJ, Hernandez, AL, Beeris, M. "Arsenic-induced skin lesions among Atacameno people in Northern Chile despite good nutrition and centuries of exposure". Environ Health Perspect. vol. 108. 2000. pp. 617-20.

(It has been suggested that the indigenous Atacameño people in Northern Chile might be protected from the health effects of arsenic in drinking water because of many centuries of exposure. Here we report on the first intensive investigation of arsenic-induced skin lesions in this population. We selected 11 families [44 participants] from the village of Chiu Chiu, which is supplied with water containing between 750 and 800mcg/L inorganic arsenic. For comparison, 8 families [31 participants] were also selected from a village where the water contains approximately 10mcg/L inorganic arsenic.After being transported to the nearest city for blind assessment, participants were examined by four physicians with experience in studying arsenic-induced lesions. Four of the six men from the exposed village, who had been drinking the contaminated water for more than 20 years, were diagnosed with skin lesions due to arsenic, but none of the women had definite lesions. A 13-year-old girl had definite skin pigmentation changes due to arsenic, and a 19-year-old boy had both pigmentation changes and keratoses on the palms of his hands and the soles of his feet.Family interviews identified a wide range of fruits and vegetables consumed daily by the affected participants, as well as the weekly intake of red meat and chicken. However, the prevalence of skin lesions among men and children in the small population studied was similar to that reported with corresponding arsenic drinking water concentrations in both Taiwan and West Bengal, India--populations in which extensive malnutrition has been thought to increase susceptibility.)

Shannon, RL, Strayer, DS. "Arsenic-induced skin toxicity". Hum Toxicol. vol. 8. 1989. pp. 99-104.

(We reviewed available literature on the effects of inorganic arsenic on the skin to determine the potential hazards and to collate information regarding dosage and exposure to the incidence of skin cancer. Arsenic intake may result from occupational or medicinal exposure, or from drinking well water in areas with high arsenic levels in the soil.Arsenic causes a variety of benign skin lesions including hyperpigmentation and hyperkeratosis. Some hyperkeratotic lesions and squamous cell carcinomas in situ may progress to invasive carcinoma; other invasive squamous cell carcinomas will develop de novo. These cutaneous squamous cancers may metastasize; mortality is low, but has been reported. Locally invasive but non-metastasizing basal cell carcinomas may arise as well. These lesions occur in a characteristic pattern of distribution and are usually multiple.Observers reporting medicinally administered arsenic have described dose-response relationships between the amount of arsenic ingested and the frequency of various skin lesions. For arsenic found in drinking water, however, there is more controversy regarding the doses and exposure times necessary for cutaneous toxicity.)

Kurokawa, M, Ogata, K, Idemori, M, Tsumori, S, Miyaguni, H, Inoue, S. "Investigation of skin manifestations of arsenicism due to intake of arsenic-contaminated groundwater in residents of Samta, Jessore, Bangladesh". Arch Dermatol. vol. 137. 2001. pp. 102-3.

(The authors examined the residents in Samta Village located in southwest Bangladesh, one of the most severely arsenic-polluted districts in the world, and investigated the effects of arsenic pollution of groundwater on residents of arsenic-contaminated areas in 1998. The total number of participants was 135 [82 male, mean age, 34.8 years; 53 female, mean age, 33.1 years]. All except one, a 26-year-old man, demonstrated some skin abnormalities typical of arsenicism. Concerning malignant skin lesions, 23 residents were clinically diagnosed as having malignant disorders: 15 men [aged 24 to 65 years] and 8 women [aged 35 to 55 years]. Furthermore, 13 patients [9 men and 4 women] had multiple lesions. The authors point out that most of the arsenicism in the Ganges Delta has been caused by drinking well water contaminated with inorganic arsenic. Among 282 tube wells in Samta Village analyzed for arsenic concentration level, only 23 contained water found to have below a 0.05mg/L arsenic concentration level, the standard safety value established by the World Health Organization. They concluded that arsenic pollution in the Ganges Delta is extremely serious and that it is urgent to find ways to provide safe drinking water for the residents of this area.)

Son, SB, Song, HJ, Son, SW. "Successful treatment of palmoplantar arsenical keratosis with a combination of keratolytics and low-dose acitretin". Clin Exper Dermatol. vol. 33. 2008. pp. 202-4.

(The authors report a 62-year-old woman with an 8-year history of corn-like papules on the palms and soles. She had a history of long exposure to Korean proprietary medicines, which were suspected to contain arsenic. The palmoplantar arsenical keratosis was successfully treated with a combination of low-dose acitretin and keratolytics [Duofilm; Stiefel Laboratories, Coral Gables, FL, USA], which is composed of 16.7% salicylic acid and 16.7% lactic acid.)
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