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Agency for Toxic Substances and Disease Registry
Case Studies in Environmental Medicine (CSEM)
Arsenic Toxicity
Clinical Evaluation
- In many cases, the source of arsenic exposure cannot be identified.
The source of exposure is identified in fewer than 50% of arsenic poisonings; however, a careful history and physical examination may improve these statistics. Because arsenic intoxication may affect multiple organ systems, a complete physical examination is imperative. In chronic ingestion, particular clues to arsenic poisoning may be provided by dermatologic and neurologic findings. The medical history should include: occupational history, diet, residential history (proximity to smelters, other industry, and hazardous waste sites), smoking history, condition of household, pets, hobbies (including use of pesticides or herbicides in farming or gardening), medications (including folk or naturopathic medications), source of drinking water, and home heating methods (wood-burning stoves and fireplaces).
Acute arsenic poisoning rarely occurs in the workplace today; it usually results from unintentional ingestion, suicide, or homicide. The fatal dose of ingested arsenic in humans is difficult to determine from case reports and depends upon many factors (e.g., solubility, valence state, etc.). The minimal lethal dose is in the range of 50 to 300 mg. The signs and symptoms of acute arsenic poisoning include the following:
- Gastrointestinal: severe abdominal pain, nausea and vomiting, and bloody or rice-water diarrhea
- Cardiovascular and respiratory: hypotension, shock; ventricular arrhythmia; congestive heart failure; and pulmonary edema
- Neurologic: light-headedness; headache; weakness, lethargy; delirium; encephalopathy; convulsions; coma; and sensorimotor peripheral neuropathy
- Hepatic and renal: elevated liver enzymes; hematuria, oliguria, proteinuria; and acute tubular necrosis, renal cortical necrosis
- Hematologic: anemia, leukopenia, thrombocytopenia, and disseminated intravascular coagulation
- Other: rhabdomyalysis, garlic odor on the breath, and delayed appearance of Mees lines.
As a result of inorganic arsenic's direct toxicity to the epithelial cells of the gastrointestinal tract and its systemic enzyme inhibition, profound gastroenteritis, sometimes with hemorrhage, can occur within minutes to hours after acute ingestion. Symptoms may last for several days. Difficulty in swallowing, abdominal pain, vomiting, diarrhea, and dehydration may result. In subacute poisoning, however, the onset of milder GI symptoms may be so insidious that the possibility of arsenic intoxication is overlooked.
Arsenic has deleterious effects on the heart and peripheral vascular system. Capillary dilation with fluid leakage and third spacing may cause severe hypovolemia and hypotension. Cardiac manifestations have included cardiomyopathy, ventricular dysrhythmias (atypical ventricular tachycardia and ventricular fibrillation), and congestive heart failure.
- Onset of peripheral neuropathy may be delayed several weeks after the initial toxic insult.
A delayed sensorimotor peripheral neuropathy may occur after acute arsenic poisoning. Symptoms are initially sensory and may begin 2 to 4 weeks after resolution of the first signs of intoxication resulting from ingestion (shock or gastroenteritis). Commonly reported initial symptoms include numbness, tingling and "pins and needles" sensations in the hands and feet in a symmetrical "stocking-glove" distribution, and muscular tenderness in the extremities. Clinical involvement spans the spectrum from mild paresthesia with preserved ambulation to distal weakness, quadriplegia, and, in rare instances, respiratory muscle insufficiency.
- Mees lines may be visible in the fingernails several months after acute arsenic exposure.
Other findings in acute arsenic poisoning may include fever and facial edema. Several months after poisoning, transverse white striae (pale bands) on the nails called Mees lines (or Aldrich-Mees lines) may be seen, reflecting transient disruption of nail plate growth during acute poisoning. In episodes of multiple acute exposures, several Mees lines may occur within a single nail. In some cases, the distance of the lines from the nail bed may be used to roughly gauge the date of the poisoning episode. However, Mees lines are not commonly seen; of 74 patients with acute and chronic arsenic poisoning, Mees lines occurred in only 5% of the patients.
Respiratory tract irritation (cough, laryngitis, mild bronchitis, and dyspnea) may result from acute exposure to airborne arsenic dust. Nasal septum perforation, as well as conjunctivitis and dermatitis, has also been reported.
The toxicity of arsine gas is quite different from the toxicity of other arsenicals, requiring different emphases in the medical history, physical examination, and patient management. Arsine is a powerful hemolytic poison in both acute and chronic exposures. The clinical signs of hemolysis may not appear for up to 24 hours after acute exposure, thereby obscuring the relationship between exposure and effect. Initial symptoms of arsine poisoning may include headache, nausea, abdominal pain, and hematuria.
- Neuropathy may be the first sign of chronic arsenic toxicity.
Skin lesions and peripheral neuropathy are the hallmarks of arsenic ingestion, and their presence should result in an aggressive search for this etiology. Neuropathy can occur insidiously in chronic toxicity without other apparent symptoms. However, careful evaluation usually reveals signs of multiorgan and multisystem involvement such as anemia, leukopenia, skin changes, or elevated liver function tests.
- Hyperpigmentation and hyperkeratosis are delayed hallmarks of chronic arsenic exposure.
- Anemia often accompanies skin lesions in patients chronically poisoned by arsenic.
Manifestations of chronic arsenic ingestion depend on both the intensity and duration of exposure. An intense exposure of several milligrams a day results in anemia, neuropathy, and hepatotoxicity within a few weeks to months. Hematologic and neurologic signs may occur after a similar latency period. Skin lesions, however, take longer to manifest (3 to 7 years for pigmentation changes and keratoses; up to 40 years for skin cancer) and may occur after lower doses than those causing neuropathy or anemia.
- Lung cancer and skin cancer are serious long-term concerns in cases of chronic arsenic exposure.
Chronic arsenic dust inhalation may be accompanied by upper respiratory symptoms, nasal perforation, and lung cancer; however, since permissible workplace arsenic levels have been lowered, these conditions are rarely encountered in workers.
- Early clinical diagnosis of arsenic toxicity is often difficult; a key laboratory test in recent exposures is urinary arsenic excretion.
Clinical diagnosis of arsenic intoxication is often difficult because both acute and chronic poisoning present a wide spectrum of signs and symptoms, which are largely dependent upon route of exposure, chemical form, dose, and time elapsed since exposure. In many cases, the patient or person providing the history might not have all of the information, or the source of exposure might not be apparent. By integrating laboratory results with history and clinical findings, it is often possible to confirm a diagnosis.
Immediately after patient stabilization, laboratory tests should be performed to obtain baseline values, with periodic monitoring as indicated. Because urinary levels of arsenic may drop rapidly in the first 24 to 48 hours after acute exposure, a urine specimen for arsenic analysis should be obtained promptly. Depending on the patient's clinical state, tests may include the following:
- General tests: CBC with peripheral smear, electrolyte panel with BUN and creatinine, urinalysis, liver function tests, nerve conduction velocity (if peripheral neurologic symptoms are present), electrocardiogram (ECG), chest radiograph, dermatologic consultation, and neurologic consultation.
- Specific tests: urine arsenic concentration.
Some arsenic compounds, particularly those of low solubility, are radiopaque, and if ingested may be visible on an abdominal radiograph.
- When total urinary arsenic is measured, it is important to inquire about recent diet.
The key diagnostic laboratory test for recent exposure is urinary arsenic measurement. The best specimen is a 24-hour urine collection, although spot urine specimens can be helpful in an emergency. Normal total urinary arsenic values are <50 µg arsenic per liter (As/L) in the absence of consumption of seafood in the past 48 hours; values in excess of 200 µg As/L are considered abnormal (ATSDR 2000a). Test results may be reported in micrograms arsenic per gram creatinine to avoid effects due to variation in urine output. Fish arsenic can significantly increase total urinary arsenic levels; therefore, it may be prudent to take a dietary history of the previous 48 hours or repeat the urinary arsenic test in 2 or 3 days. Human volunteers with an average pretest urinary arsenic level of 30 µg/L were given lobster tail for lunch. Four hours after eating, they had an average urinary level of 1,300 µg As/L. These values decreased to pretest levels within 48 hours after ingestion. Request for speciation of arsenic (i.e., analysis of organoarsenicals or different inorganic species, rather than total arsenic) may be considered. Speciated tests are more widely available than in the past; you may want to consult your local Poison Control Center for more information.
Arsenic blood levels, normally <7 µg per deciliter (µg/dL), are less useful than urinary arsenic measurements in following the clinical course of an acute poisoning case, because of the rapid clearance of arsenic from the blood.
Long after urine levels have returned to baseline, the arsenic content of hair and nails may be the only clue of arsenic exposure. However, because the arsenic content of hair and nails may be increased by external contamination, caution must be exercised in using the arsenic content of these specimens to diagnose arsenic intoxication.
- If arsenic toxicity is suspected, several tests can be performed to help confirm clinical suspicion.
The standard tests listed above will aid in evaluating the status of an arsenic-exposed patient. The CBC can provide evidence of arsenic-induced anemia, leukopenia, thrombocytopenia, or eosinophilia. Although basophilic stippling on the peripheral smear does not confirm arsenic poisoning, it is consistent with the diagnosis. Liver transaminases are frequently elevated in acute and chronic arsenic exposure and can help confirm clinical suspicion. If arsenic neuropathy is suspected, nerve conduction velocity tests should be performed. Such tests may initially show a decrease in amplitude, as well as slowed conduction. Skin lesions in patients with chronic arsenic exposure may require biopsy to rule out skin cancer.
- What findings are suggestive of arsenic intoxication in the patient described in the case study?
- What conditions other than arsenic intoxication should be considered in the differential diagnosis of the patient's neurological complaints?
- What further medical workup is indicated for the patient described in the case study?
- What does the presence of palmar-plantar keratosis suggest about the time course of the patient's arsenic exposure?
- Who else in the case study is at risk for exposure to arsenic?
- A urine specimen from the wife of the patient was found to contain total arsenic at a concentration of 300 µg/L, and a sample of the wife's hair contained 150 parts per million (ppm) arsenic. Compare this to the patient's 6,000 µg/L urinary arsenic level and 100 ppm arsenic in the hair. The wife has no signs or symptoms of chronic arsenic intoxication. How might these findings be explained?
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