CALL US...TM
The Official Newsletter of the California Poison Control System
Volume 9, Number 3
Fall 2011
Arsenic Poisoning
INTRODUCTION
Arsenic is a naturally occurring and ubiquitous metalloid
that can result in poisoning from a variety of sources including environmental
and occupational exposures as well as more nefarious intent including homicide
and suicide. Historically, arsenic has
been referred to as the Poison of the Kings and King of Poisons secondary
to the potency and discreteness of action and historical use in the murder of
political opponents. More recently,
arsenic trioxide, has been increasingly used as
treatment for promyelocytic leukemia (PML).
Contaminated food, water, and soil are the primary sources of arsenic for the
general population. Groundwater contamination by arsenic has severely impacted
the health of various populations in certain regions of the world such as
Bangladesh and West Bengal. There are considerable challenges associated with
arsenic exposure, as many forms exist with varying degrees of toxicity. Clinical manifestations demonstrate multiple
organ system involvement and depend on the acuity of exposure and individual
variability in metabolism.
CASE PRESENTATION
A 49 year-old Central California woman has
been experiencing a several month history of non-healing vesicles and bulla
covering her hands and has been recently diagnosed with diabetes mellitus type
II and hypertension. Her
laboratory findings demonstrate a mild leukopenia (WBC 5000/mm3) and
normocytic anemia (Hemoglobin 7g/dL). An EKG demonstrates a normal sinus rhythm
with a QTc interval of 495ms. Her 24-hour urinary arsenic level is 62 mcg/L.
Is this consistent with arsenic toxicity?
What are potential sources of exposure?
What is the significance of an arsenic level of 62 mcg/L?
Physical Characteristics and Toxicity
Arsenic exists in elemental, gaseous (arsine), organic and
inorganic forms. Metallic arsenic is
generally thought to be nontoxic as it is insoluble in water or bodily
fluid. Inorganic arsenics however can be toxic dependent on valence state:
trivalent (As3+) and pentavalent (As5+)
state. Arsine gas is highly toxic
and exposure occurs in industrial settings when arsenic-containing ores or
metals come into contact with acidic solutions. Organic arsenics vary in toxicity with arsenobetaine
found in fish and shellfish and arsenosugars having
very low toxicity while melarsoprol, used in the
treatment of African trypanosomiasis having toxicity
similar to that of the inorganic arsenics.
These multiple states, individual variability in metabolism, and
differences in toxicity following acute and chronic exposures contributes
greatly to the confusion and difficulty of diagnosis and management of patients
with arsenic exposure and poisoning.
Mechanism of Toxicity
Arsenics exhibit different mechanisms of toxicity dependent
on the valence state. Trivalent
arsenicals (arsenite) are thought to inhibit multiple
enzymatic pathways through inhibition of the regeneration of lipoamide from dihydrolipoamide. Lipoamide is an
important cofactor in the conversion of pyruvate to acetylcoenzyme
A (acetyl-CoA), a central molecule involved in
metabolism. Decreased acetyl-CoA leads
to decreased citric acid cycle activity and disruption of oxidative
phosphorylation. This also leads to a deficiency of succinyl-CoA,
an important factor in red blood cell maturation. Trivalent arsenicals also inhibit thiolase with resultant inhibition of fatty acid oxidation.
They additionally inhibit glutathione synthase, and glucose-6-phosphate
dehydrogenase (G6PD) with resultant inability to prevent oxidative stress and
free radical generation and subsequent lipid peroxidation. Trivalent arsenicals also may prolong the QTc interval by inhibiting potassium channels within the
heart.
Pentavalent Arsenicals (arsenate)
produce toxicity through a different proposed mechanism. Some arsenate will be
reduced to arsenite. Arsenate may also substitute for
phosphate groups in the conversion of adenosine diphosphate
(ADP) to adenosine triphosphate (ATP).
Inorganic arsenic is odorless and tasteless and can be
absorbed by several routes including gastrointestinal, respiratory, intravenous
and mucosal routes. Inorganic arsenics
are thought to exhibit a three-phase mode of distribution and subsequent
clearance. Following an acute exposure,
up to 90% of arsenic is cleared from the blood with the majority being thought
to have redistributed to organ tissues (skin, liver, kidney, and muscle) within
a few hours of exposure. Thus, blood
testing may not be helpful except early following an acute exposure. The
remaining arsenic following phase I has a more gradual clearance from the blood
over 1-7 days. The bulk of arsenic that
has redistributed to organ tissue has a more prolonged elimination over days to
weeks with renal elimination being predominant.
Arsenobetaine and arsenosugars found in fish, shellfish, and algae are
excreted rapidly in the urine unchanged with 85% being eliminated after 6-7
days. This is in stark contrast to the
days to weeks involved with the excretion of inorganic arsenics.
Toxic manifestations vary depending on amount and form
ingested as well as the chronicity of ingestion. Following a large acute oral
exposure to inorganic arsenic (arsenite or arsenate),
patients will develop gastrointestinal symptoms including severe nausea,
vomiting, abdominal pain, and diarrhea. This diarrhea has been described as
rice-water in consistency.
Gastrointestinal symptoms are the earliest manifestation of acute oral
poisoning and occur within minutes to several hours following ingestion.
Multi-organ dysfunction may ensue with large exposures. Cardiovascular dysfunction including sinus
tachycardia, hypotension, and shock has been reported. This is secondary to multiple mechanisms
including decreased contractility of the heart, increased vascular
permeability, and diminished peripheral vascular tone. Prolongation of QTc interval may occur with resultant dysrhythmias. Encephalopathy, coma, delirium, and seizures
may occur over several days following acute exposure due to cerebral
edema. Acute lung injury (ALI), acute
respiratory distress syndrome (ARDS), frank respiratory failure, hepatitis,
hemolytic anemia, and renal failure have all been reported. Less severe exposures may result in a
prolonged gastrointestinal phase despite fluid supplementation and antiemetic therapy.
Those that survive the initial acute exposure may
subsequently develop a peripheral neuropathy in a stocking-glove distribution,
initially sensory with an often exaggerated painful response to delicate
stimuli, followed by the development of a motor neuropathy. Bone marrow
suppression, chronic respiratory syndromes including cough, dyspnea, and chest
discomfort may result. Chest imaging may
reveal a patchy infiltrative pattern.
Patchy alopecia, desquamation, herpetiform
lesions and diaphoresis and edema of the face may similarly occur.
Chronic arsenic poisoning is somewhat more insidious and
occurs most frequently from environmental or occupational exposures. Skin changes, both malignant and
nonmalignant, hypertension, diabetes mellitus, peripheral vascular disease
(Blackfoot disease), and cancers of the lung, liver, bladder, skin have all been associated with chronic arsenic exposure.
The skin is particularly susceptible to the toxic effects of arsenic and
multiple lesions have been described including alterations in pigmentation,
hyperkeratosis, squamous cell carcinoma, basal cell carcinoma and Bowen disease
(intraepidermal squamous cell carcinoma). Blackfoot
disease is an obliterative peripheral vascular
disease that occurs in areas of Taiwan where inorganic arsenics are
endemic. Pulmonary changes, hepatic
fibrosis, neuropathies, and bone marrow suppression may similarly occur.
Exposure to arsine gas can cause hemolysis, with subsequent hemoglobinuric renal failure and death.
To appropriately
interpret arsenic laboratory data, one must be aware of the large number of
potential confounders that may lead to elevation in arsenic levels. These include a large number of food products
that contain organic arsenics (nontoxic) and the accumulation of nontoxic
arsenic metabolites in patients with underlying renal disease and impaired
clearance. Similarly, an understanding
of the timing of absorption, metabolism, clearance, and elimination are
essential in the interpretation of arsenic lab data.
Diagnosis ultimately depends on an appropriate history and
physical examination with potential confirmation via blood or urinary arsenic
levels. In an acute setting, elevated
spot urine arsenic confirms exposure in a patient with characteristic history
and physical findings; however, a low concentration does not rule out
significant poisoning. Definitive
diagnosis depends on the collection of a 24-hour urine arsenic level greater
than 50 mcg/L, 100 mcg/g creatinine,
or 100 mcg total arsenic. Because seafood can transiently elevate arsenic
levels up to >1700mcg/L, collection should take place ideally after a 1-2
week abstinence from food containing arsenic (in particular, fish or shellfish)
in a metal free polyethylene container that has not been acid washed. Acid washing is thought to alter speciation
of arsenic. Elevated levels of arsenic should be speciated
using High Performance Liquid Chromatography (HPLC) separation and subsequent
Mass Spectrometry to differentiate between the various valence states of
inorganic arsenic and the presence of organic arsenics such as arsenobetaine.
Other testing should include a complete blood count where a
normocytic, normochromic, or megaloblastic anemia may
be seen. Leukocytosis acutely followed
by leukopenia and thrombocytopenia may occur.
Basophilic stippling and karyorrhexis (rupture
of a cell nucleus) may be seen following arsenic exposure. Karyorrhexis may
occur as early as 4 days following exposure and may last up to 2 weeks
following exposure. Elevated serum creatinine and aminotransferases with a low or falling haptoglobin may similarly assist in the diagnosis of
arsenic toxicity.
Acute arsenic poisoning is
life threatening and appropriate supportive care is indicated. Careful attention to fluid and electrolyte
balance and monitoring for EKG changes is indicated. Decontamination remains controversial as
arsenic binds poorly to activated charcoal, bentonite,
or cholestyramine.
Significantly poisoned patients usually have nausea and vomiting, and
administration of charcoal may lead to aspiration. Nevertheless, the benefit of a small amount
of binding may be indicated. Attention
to airway protection should be addressed if gastric decontamination is pursued. If radiopaque material is visualized on
abdominal radiograph, whole bowel irrigation should be considered and continued
until no radioopaque material is visualized on
abdominal imaging.
Following chronic exposure to arsenic, the immediate priority
is to identify the source and remove patients from continued exposure. Chelation therapy is controversial as these
products are not without potential associated risks and indications
for termination of chelation therapy is unclear. Dimercaprol (British
Anti-Lewisite or BAL) and Succimer (2,3-dimercaptosuccinic acid or DMSA) are the two chelators available in the United States that have
demonstrated some ability to remove arsenic from the body. The decision to initiate chelation should be
dependent on the severity of illness. Acutely poisoned, seriously ill patients
may benefit from chelation prior to laboratory confirmation. BAL is the chelator
of choice for seriously ill patients.
BAL is a suspension in peanut oil that can only be delivered via deep
intramuscular injections. Dosing is 3-5
mg/kg every 4-6 hours. Side effects and
limitations include hypertension, fever, diaphoresis, GI effects, hemolysis in
G6PD-deficient patients, sterile abscess development, and the chelation of
other essential elements following prolonged course. Animal studies suggest that BAL may actually
cause a shift of arsenic into the brain.
Succimer is an oral analog of BAL that may be
used in subacute or chronic exposure. Adverse effects
include transient hepatic aminotransferase elevations,
nausea/vomiting/diarrhea, thrombocytosis, eosinophilia, rash, and pruritis. Dosing is
10 mg/kg/dose every 8 hours for 5 days followed by 10 mg/kg/dose every 12
hours.
- The patient does demonstrate some findings
suggestive of arsenic poisoning, however these symptoms are also
nonspecific and may reflect other etiologies. In particular, the diagnosis of
hypertension and diabetes while associated with chronic arsenic exposure
has many other causes. Similarly, a
mild leukopenia, anemia and QTc interval
prolongation are nonspecific. The clinician must have a high index of
suspicion and consider other potential etiologies in addition to arsenic
toxicity.
- Food products and environmental or
occupational exposures are a common source of arsenic exposure. A very careful history regarding
environment, occupation, and dietary habits is essential. Arsenic containing wood preservative
(Copper Chromate Arsenic) was previously used as a means to preserve
wooden structures and many older homes may still contain wood treated in
this manner. Similarly, a
seafood-rich diet may elevate total arsenic levels. In some areas of the world, inorganic arsenic
contamination of drinking water is an important source of exposure. More recently, Dr. Oz, a television
personality, suggested that the United States is poisoning children
secondary to arsenic being found in apple juice. What he failed to mention
is that the predominant form of arsenic found in apple juice and other
consumer products is organic arsenic, with inorganic levels well below
those considered toxic.
- While elevated, this level of arsenic
and the clinical presentation does not necessitate immediate chelation
treatment. Speciating the specimen should be
considered to determine the predominant form of arsenic present. The test
should also be repeated following a two-week period of seafood,
supplement, or alternative therapy abstinence. Traditional Chinese Medicine (TCM) and
other non-regulated products have previously been demonstrated to contain
arsenic.
CONSULTATION
ASSISTANCE
Consultation
with a specialist in poison information or with a medical toxicologist can be
obtained free of charge by calling the California Poison Control System at
1-800-222-1222.
This issue of CALL US... was written by Mike Darracq, MD MPH
CALL US... is published by the California Poison
Control System. Editorial Board: Executive Director, Stuart E. Heard, PharmD;
CPCS Medical Directors: Timothy E. Albertson, MD, Richard F. Clark, MD, Richard
Geller, MD, Kent R. Olson, MD; CPCS Managing Directors: Judith Alsop, PharmD,
Thomas E. Kearney, PharmD, Lee Cantrell, PharmD. Assistant Editors: Binh
Ly, MD, Cyrus Rangan, MD, Chris Tomaszewski, MD, and Aaron Schneir, MD. Editor:
Richard F. Clark, MD.
The California
Poison Control System is operated by the School of Pharmacy, University of
California, San Francisco. (callus@calpoison.org)