ACMT Toxicology Visual Pearl: Skin Lesions

1. Inorganic Arsenic

Chronic inorganic arsenic exposure, most commonly reported after drinking contaminated ground water, produces skin lesions on the hands, feet, and body which are typically irreversible.

Background

The discovery of elemental arsenic is attributed to Albertus Magnus in the mid-1200s; however, the use of naturally occurring arsenic compounds dates back as far as 2000 BC, and some arsenical compounds are used in modern medicine [2]. Ancient Egyptians, Greeks, and Chinese have all commented on arsenic and its properties [3].

Today, the most common route of exposure to inorganic arsenic is through drinking contaminated groundwater [4,5]. Additional exposures include consuming crops grown in contaminated soil as well as industrial exposures from manufacturing metals, computer components, and pesticides. The current recommended limit for arsenic in drinking water is 10 μg/L; however, it is estimated that 140 million people worldwide are chronically exposed to arsenic levels >10 μg/L in their drinking water [5].

How does chronic inorganic arsenic exposure produce toxicity?[4, 6-9]

• Arsenic is naturally occurring in both organic and inorganic forms, with the inorganic forms arsenite (As3+) and arsenate (As5+) considered most toxic.
• Arsenite inhibits pyruvate dehydrogenase and binds dihydrolipoamide resulting in disruption of oxidative phosphorylation and decreased ATP production.
• Arsenate resembles phosphate and competes for binding sites in the glycolysis pathway which inhibits ATP production and uncouples oxidative phosphorylation in the mitochondria.
• Inorganic arsenic is metabolized in the liver and its metabolites are excreted in the urine along with non-metabolized inorganic forms.
• Inorganic arsenic is a known carcinogen, and the mechanisms are thought to be related to impaired DNA repair, oxidative stress, and direct genotoxicity.

What are the symptoms of chronic inorganic arsenic exposure? [4,5,10,11]

• Skin lesions are the first finding and are characterized by pigmentation changes primarily on the face, neck, and back, followed by hyperkeratosis, primarily on the palms and soles.
• Peripheral sensory and motor neuropathy, hearing loss, encephalopathy
• Hypertension and peripheral vascular disease
• Restrictive lung disease
• Diabetes mellitus
• Hepatomegaly and hepatic fibrosis
• Anemia, leukopenia, thrombocytopenia, and overall bone marrow suppression
• Cancers of the skin, lung, bladder, kidney, liver, uterus, and GI tract

What diagnostic testing is helpful? [4, 10]

• A 24-hour urine sample is the gold standard with greater than 50 μg/L considered elevated when compared to population levels.
• A spot urine can be used for surveillance, along with urine creatinine, with results measured as micrograms of arsenic per gram of creatinine.
• Urine arsenic testing can be misinterpreted by the presence of organic (relatively non-toxic) arsenic (arsenobetaine) found in seafood; therefore, it is best to request speciation for any results found to be elevated.
• Serum or blood arsenic is rapidly cleared therefore serum arsenic levels are less helpful in identifying chronic exposures.
• Hair and nail testing can be considered however this testing is more error-prone compared to urine testing, as external contamination may cause an elevated result.

How is chronic arsenic poisoning treated? [4]

• Once present, symptoms of chronic arsenic exposure are often irreversible.
• Chelation does not benefit patients with chronic arsenic exposure with symptoms or disease progression.
• Persons with chronic toxicity should be removed from the source of exposure.
• Understanding complications of chronic arsenic exposure can guide overall preventive care and screening for patients on a case-by-case basis.

Bedside Pearls

• Skin findings are the first physical manifestation of chronic arsenic toxicity.
• For diagnosis, a history of exposure is paramount.
• 24-hour urine arsenic measurement, or a spot sample with creatinine correction, plus speciation to identify inorganic arsenic, is the best way to confirm current inorganic arsenic exposure.
• Chelation is not beneficial for chronic arsenic toxicity.
• Those exposed to chronic arsenic are at higher risk for skin, lung, and bladder cancer, among other chronic health conditions.