CHAPTER 93

copper binding to amyloid fibers in the brain of patients with

Alzheimer’s disease may lead to local oxidative damage and cause the
characteristic neurodegeneration.**? Copper is also similarly impli-

COPPER cated in the pathogenesis of both Parkinson’s disease and autism.”*"*!

Acute or chronic copper poisoning may occur when the metal is
leached from copper pipes or copper containers. This occurs frequently
Lewis S. Nelson when carbon dioxide gas, used for postmix soft drink carbonation,
backflows into the tubing transporting water to the soda dispensers,
creating an acidic solution of carbonic acid that leaches copper from
the equipment pipes.'?’ Similarly, storage of acidic potable substances,
Copper (Cu)
such as orange or lemon juice, in copper vessels may cause copper
Atomic number = 29 poisoning. A particularly dangerous situation occurs when acidic
Atomic weight = 63.5 daltons water is inadvertently used for hemodialysis.“°* In this circumstance,

Normal concentrations the leached copper avoids the normal GI barrier and is delivered
parenterally to the patient’s circulation. In one reported series, the
Whole blood = 70-140 ug/dL (11-22 mol/L) copper concentration in the dialysis water was 650 [1g/L, causing sev-
Total serum = 120-145 g/dL (18.8-22.8 umol/L) eral poisonings and the death of a patient with a whole-blood copper
Free serum = 4-7 ug/dL (0.63-1.1 umol/L) concentration of 2095 |1g/L.*° Similarly, stagnant water or hot water,'””
even if not highly acidic,'" can accumulate copper ions from pipes and
Ceruloplasmin = 25-50 ug/dL (3.9-7.8 umol/L)
cause poisoning.”*!
Urine = 5-25 ug/24 h (.078-3.9 nmol/L) Although most natural water contains a small quantity of copper
(4-10 ug/L), it is tightly bound to organic matter and therefore not
Copper is a widely available metal that is associated with both acute orally bioavailable. Copper pipes typically add about 1 mg of copper
and chronic poisoning. Although essential to life, acute overdose with to the daily intake of an adult. The Environmental Protection Agency
copper salts produces severe gastrointestinal (GI) and systemic effects guidelines permit up to 1.3 mg/L of copper in drinking water,”
that may be life threatening. This clinical syndrome and the underlying although in some areas, intermittent concentrations may rise as high
mechanism is similar to that noted with iron poisoning. Regardless of as 60 mg/L. Copper in water may be tasted at concentrations of 1 to
the means of exposure, patients with acute copper poisoning require 5 mg/L, and a blue-green discoloration is imparted when the concen-
expeditious identification and empiric therapy. trations are greater than 5 mg/L.” Acute GI symptoms occur when
drinking water contains more than 25 mg/L,® although concentrations
as low as 3 mg/L are associated with abdominal pain and vomiting in
HISTORY AND EPIDEMIOLOGY many, without an increase in the serum copper concentration.'” In one
blinded, randomized study comparing copper-adulterated water with
Copper is available naturally, either as native copper (elemental copper)
pure water, women appeared more sensitive than men to copper, but
or as one of its sulfide or oxide ores. Important ores include malachite
both groups were symptomatic when the copper concentration in the
(CuCO,-(OH),), chalcocite (Cu,S), cuprite (Cu,O), and chalcopyrite
water was 6 mg/L.°
(CuFeS, or Cu,S-Fe,S,). Chalcopyrite, a yellow sulfide ore, is the source
Metallic copper is ideal for electrical wiring because it is highly mal-
of 80% of the world’s copper production. The smelting, or separation,
leable and can be drawn into fine wire. Its electrical conductivity is only
of copper ores began about 7000 years ago; copper gradually assumed
exceeded by silver. Similarly, its excellent heat conductivity accounts
its current level of importance at the start of the Bronze Age, around
for its widespread use in cookware. Although the metal is reactive with
3000 B.c. Smelting begins with roasting to dry the ore concentrate,
air, it forms a resistant layer of insoluble copper carbonate on its sur-
which, in more modern times, is further purified by electrolysis to a
face. It is this water- and air-resistant compound that accounts for the
99.5% level of purity. The sulfide ores have a naturally high arsenic green coloration of ornamental roofing and statues. Because copper is a
content, which is released during the extraction process, posing a risk
soft metal, it must be strengthened before use in structural applications
to those who perform copper smelting.
or as a coinage metal. This is most commonly done by the creation of
Although acute copper poisoning is uncommon in the United States,
copper alloys. Brass is an alloy of copper compounded with as much
the historical role of copper as a therapeutic agent remains noteworthy.
as 35% zinc. Similarly, bronze contains copper combined with up to
Copper sulfate was used in burn wound debridement until cases of
14% tin. Gun metal is an alloy that contains 88% copper, 10% tin, and
systemic copper poisoning were reported.® Interestingly, in one report,
2% zinc. Sterling silver and white gold also contain copper.
each wound debridement procedure was associated with an 8% to
10% decrease in the hematocrit. In the 1960s, copper sulfate (250-mg
dose containing 100 mg copper ion) ironically was recommended as an CHEMICAL PRINCIPLES
emetic agent, typically for use in children after potentially toxic expo-
sures.” It was recognized for its rapidity of onset and effectiveness, and Metallic copper (Cu°), although not in itself poisonous, may react in
it compared favorably with syrup of ipecac. However, copper-induced acidic environments to release copper ions. The metallic copper con-
emesis was rapidly identified to be a highly dangerous practice, and traceptive intrauterine device (IUD) derives its efficacy from the local
this use was generally discontinued,”*"'’ although fatal cases from this release of copper ions.’° Metallic copper bracelets worn by patients with
use still occur.”* Copper salts are administered in religious rituals as a rheumatoid arthritis and other ailments purportedly derive their far-
green-colored “spiritual water” containing 100 to 150 g/L of copper reaching antiinflammatory effect through dermal copper ion absorp-
sulfate as an emetic to “expel one’s sins.””"!” tion and distribution to affected tissues.'*> Local copper ion release is
A growing body of knowledge links copper to the promotion of both responsible for the occasional case of dermatitis that occurs after skin
physiologic and malignant angiogenesis.” In this latter case, copper exposure to copper metal.“ Ingestion of large amounts of metallic
may enable tumor expansion, invasion, and metastasis. Additionally, copper—for example, as coins—may rarely produce acute copper

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 Chapter 93 Copper

poisoning.'**!°° Poisoning under these circumstances is a result of the

release of large amounts of copper ion from copper alloy by the acidic
PHARMACOLOGY AND PHYSIOLOGY
gastric contents. Also, inhalation of finely divided metallic copper Copper is an essential metal that our body stores in milligram amounts
dust or bronze powder, which is used in industry and for gilding, may (100-150 mg). Daily requirements of copper are approximately 50 g/kg
produce life-threatening bronchopulmonary irritation, presumably as in infants and 30 ug/kg in adults. The average daily intake of copper
a consequence of the local release of ions.**** in the United States noted in the Third National Health and Nutrition
The majority of patients with acute copper poisoning have been Examination Survey (NHANES III) is about 1.2 mg.”
exposed to ionic copper. In copper sulfate, also known as cupric sul- The daily requirement of copper is satisfied by nuts, fish, and green
fate, the copper atom is in the +2 oxidation state. Copper sulfate is vegetables such as legumes, although our largest source is generally
used as a fungicide and algicide and to eradicate tree roots that invade from drinking water. Copper deficiency is exceedingly rare even in
septic, sewage, and drinking water systems.'' Copper sulfate is the the poorest communities and is most frequently caused by excessive
most readily available form and is the form involved in the majority zinc intake®! or by a genetic aberration such as Menkes “kinky-hair”
of nonindustrial copper salt exposures. Copper sulfate was a favorite syndrome, in which intestinal copper uptake is impaired. Menkes
ingredient in many home chemistry sets because of its brilliant blue syndrome is characterized by mental retardation, thermoregulatory
color when dissolved in water. Although serious poisoning, particularly dysfunction, hypopigmentation, connective tissue abnormalities, and
in children,!” led regulatory agencies in the United States to restrict its pili torti (kinky hair). Interestingly, with the increased focus on the role
use, it still accounts for the most consequential chemistry set-related of copper in neurodegenerative disorders and cancer, some authors
toxic exposures reported in other countries.** Similarly, homegrown suggest intentionally depleting patients of their copper stores with
copper sulfate crystals from kits are occasionally responsible for fatal tetrathiomolybdate, an experimental copper chelator.”
poisonings.** Copper is absorbed by an active process involving a copper adenos-
Cuprous salts, containing copper in the +1 oxidation state, are unsta- ine triphosphatase (CuATPase) in the small intestinal mucosal cell
ble in water and readily oxidize to the cupric form. There are numerous membrane, also known as the Menkes ATPase (see below). The GI
copper salts with varying oxidation states used in industry and agri- absorption varies with the copper intake and the food source® and is
culture (Table 93-1), many of which are not poisonous. Because those as low as 12% in patients with high copper intake. In the presence of
salts that are water soluble are more likely to be toxic, it is important to damaged mucosa, such as after acute overdose, the fractional absorp-
determine the nature of the copper product implicated in an exposure. tion is likely to be significantly higher.” After it has been absorbed,
Analogously, when examining the medical literature, it is critical to copper is rapidly bound to high-affinity carriers such as ceruloplasmin
discern which form of copper is involved in the scientific experiment and low-affinity carriers such as albumin for transport to the liver and
or case report before applying the results to clinical practice. other tissues. The amount of unbound copper in the blood under

a
TABLE 93-1. Important Copper Products

Chemical Name Chemical Structure Common Name Notes

Chalcopyrite CuFeS, Copper iron sulfide Copper ore; source of 80% of world’s copper
Chromated cupric arsenate 35% CuO CCA Wood preservative
20% CrO,
450% As,O,
Copper octanoate Cu[CH,(CH,),COO], Copper soap Fungicide in home garden products, paint,
rot-proof rope and roofing
Copper triethanolamine complex Cu ((HOCH,CH,),NN), Chelated copper Algicide
Cupric acetoarsenite Cu(C,H,0,), - 3Cu(AsO,), Paris or Vienna green Insecticide, wood preservative, pigment?
Cupric arsenite CuHAsO, Swedish or Scheele’s green Wood preservative, insecticide?
Cupric hydroxide Cu(OH), Copper hydroxide Fungicide
Cupric chloride cul, Catalyst in petrochemical industry
Cupric chloride, basic CuCl, - 3Cu(OH), Basic copper chloride; copper Fungicide
oxychloride
Cupric oxide CuO Black copper oxide; tenorite Glass pigment, flux, polishing agent
Cupric sulfate CuSO, Roman vitriol, blue vitriol, Fungicide, plant growth regulator,
bluestone, hydrocyanite whitewash, homegrown crystals
Cupric sulfate, basic CuSO, -3Cu(OH), - 3CaSO, Bordeaux solution Fungicide
Cuprous cyanide CuCN Cupricin Electroplating solutions
Cuprous oxide Cu,O Red copper oxide, cuprite Antifouling paint

*No longer used in the United States.

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 Part C_ The Clinical Basis of Medical Toxicology

normal circumstances is well below 1%. After being released locally in

the reduced form from its carrier, copper uptake by the hepatic cells
TOXICOLOGY AND PATHOPHYSIOLOGY
occurs via a specific uptake pump.' This process, which is facilitated
by the reducing agent ascorbic acid, provides a potential window,
REDOX CHEMISTRY
however brief, for detoxification of the ion by chelating agents. In acute Because copper is a transition metal, it is capable of assuming one of
overdose, a high fraction of the plasma copper remains bound to low- several different oxidation (or valence) states, and it is an active par-
affinity proteins, such as albumin, and thus is biologically active. ticipant in redox reactions. In particular, participation in the Fenton
In the hepatocyte, complex trafficking systems exist (involving reaction and Haber-Weiss cycle explains the toxicologic effects of
ceruloplasmin, metallothionein, and other metallochaperones within copper as a generator of oxidative stress and inhibitor of several key
the cytoplasm) to prevent copper toxicity and to aid delivery to the metabolic enzymes (see Fig. 11-2).***” In the presence of sulfhydryl-
appropriate enzymes.**! A distinct Cu-ATPase located on certain rich cell membranes, such as those on erythrocytes, cupric ions are
subcellular organelles such as the trans-Golgi network or pericanali- reduced to cuprous ions, which are capable of generating superoxide
cular lysosomes assists in the appropriate localization and elimina- radicals in the presence of oxygen.” This one-electron reduction of
tion, respectively, of the metal.”° By this mechanism, copper is either oxygen regenerates the cupric ion, allowing redox cycling and continu-
incorporated into enzymes or released, as a metallothionein-copper ous generation of reactive oxygen species (Fig. 93-1). In particular, the
complex, directly into the biliary system for fecal elimination. mitochondrial electron transport chain and lipid membranes serve as
Some copper released from the liver is bound primarily to cerulo- ready sources of electrons for copper reduction, establishing a chain of
plasmin, an o,-sialoglycoprotein with a molecular weight of 132,000 events that ultimately leads to mitochondrial or membrane dysfunc-
Daltons. Ceruloplasmin-bound copper accounts for approximately tion, respectively.*°
90% to 95% of serum copper. Ceruloplasmin is a multifunctional pro-
tein that binds six atoms of copper per molecule. Copper bound to this ERYTHROCYTES
carrier has a plasma half-life of approximately 24 hours. Ceruloplasmin
is also involved in the mobilization of iron from its storage sites, and
Cupric ion inhibits sulfhydryl groups on enzymes in important anti-
oxidant systems, including glucose-6-phosphate dehydrogenase and
it serves an analogous role as a ferroxidase during the ferrous-ferric
conversion. Cu’ is oxidized directly by ceruloplasmin, thereby avoiding
glutathione (GSH) reductase.’** However, although support for these
effects is only indirect, intraerythrocyte concentrations of reduced
the generation of reactive oxygen species.
GSH decrease demonstrably after copper exposure.** This effect is pre-
There are several important copper-containing enzymes in humans
sumably part of the protective role that GSH, a nucleophile or reduc-
(Table 93-2). The common link among these enzymes is their par-
ing agent, normally has on oxidants, such as either cupric ions or the
ticipation in redox (reduction-oxidation) reactions in which a mol-
ecule, typically oxygen, donates or shares its electrons with another reactive oxygen species they generate.*** Thus, in the setting of copper
poisoning, in which excessive quantities of oxidants are produced,
compound. In this respect, the physiology, chemistry, and toxicology
the depletion of GSH presumably augments peroxidative membrane
of copper are most similar to those of iron. In fact, “blue-blooded”
animals, such as octopi and spiders, use copper in hemocyanin, a blue
damage.
The importance of hemoglobin-derived reactive oxygen species is
pigment, in an analogous manner that “red-blooded” animals use iron
demonstrated by the lack of hemolysis in the presence of copper under
in hemoglobin.
anaerobic conditions or in an environment saturated with carbon
The volume of distribution of copper is 2 L/kg, and the half-life
of erythrocyte copper is 26 days. The elimination of copper occurs
monoxide.” The in vitro hemolytic activity of copper sulfate is reduced
by albumin and several sulfhydryl-containing compounds, including
predominantly through biliary excretion after complexation with
ceruloplasmin. Biliary excretion approximates GI absorption and aver-
ages 2000 ug/24 h.>!°!?? Renal elimination under normal conditions is
trivial, accounting for approximately 5 to 25 g/24 h.°

GSH
—_GSSG
EEE
or or
TABLE 93-2. Important Copper-Containing DMPS Ox-DMPS
Enzymes and Proteins and Their Functions
Cu2+ \/ . Cut + 2Ht
Enzyme or Protein Function
Cut + HgO2 ——> Cu?+ + OH~ + OH”
Alcohol dehydrogenase Metabolism of alcohols Fenton reaction
Catalase Detoxifies peroxide
Cut + HpOo + Oo* ——> Cu?* + Oo + OH~ + OH"
Ceruloplasmin enzymes Copper transport, ferroxidase
Haber-Weiss reaction
Cytochrome C oxidase Electron transport chain
Dopamine B-hydroxylase Converts dopamine to norepinephrine FIGURE 93-1. Copper in the cupric or Cu?* state is reduced by sulfhydryl containing
compounds such as glutathione (GSH) or dimercaptopropane sulfonate (DMPS) to its
Factor V Coagulation cascade
cuprous form (Cut), forming disulfide links in the process. Oxidized glutathione (GSSG)
Lysyl oxidase Cross-links collagen and elastin is subsequently enzymatically reduced by glutathione reductase to regenerate GSH.
Monoamine oxidase Deamination of primary amines Superoxide anions, formed when molecular oxygen (O,) acquires an additional electron,
Superoxide dismutase Detoxifies free radicals are continually generated by mitochondria. Both the Fenton and the Haber-Weiss reac-
Tyrosinase Melanin production tions use the cuprous form of copper as a catalyst to convert hydrogen peroxide or
superoxide radical into the more biologically consequential hydroxyl radical (OH*).'*”

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 Chapter 93 Copper

p-penicillamine and succimer.’ Interestingly, dimercaptopropane sul- Thus, reactive oxygen species are probably also responsible for the
fonate (DMPS), another sulfhydryl-containing compound often used nephrotoxic effects of copper. Pathologic analyses of the kidneys of
as a chelator, exacerbates copper-induced hemolysis. This paradoxic oliguric or anuric patients typically reveal acute tubular necrosis that
effect is variably attributed to concomitant inhibition of superoxide may demonstrate hemoglobin casts. These findings suggests that renal
dismutase, an important antioxidant enzyme, or to the ability of DMPS failure may result indirectly from the hemoglobinuria induced by the
to efficiently reduce either membrane dithiols or cupric ions, in either massive release of free extracellular hemoglobin. The urinary hemo-
case increasing the generation of superoxide.’ globin, similar to myoglobin, may undergo conversion to ferriheme or
Hemolysis frequently occurs within the first 24 hours after with release its iron, either of which results in oxidative stress on the renal
acute copper poisoning.**"!”!”? This rapidity of hemolysis differs mark- tubular epithelial cell. Additionally, free extracellular hemoglobin may
edly from most other oxidant stressors, which may take several days, cause renal vasoconstriction through the local scavenging of nitric
and is likely a result of the differing nature of the erythrocyte insult. oxide within the renal arterioles.
That is, the hemolysis that occurs after most oxidant exposures is
caused by precipitation of hemoglobin as Heinz bodies and subsequent
erythrocyte destruction by the reticuloendothelial system. Hemoglobin CENTRAL NERVOUS SYSTEM
precipitation may also occur in the setting of acute copper poisoning, Although charged entities such as copper ions do not readily cross the
particularly after less substantial exposure. Additionally, and account- blood-brain barrier, elevated cerebrospinal fluid copper concentra-
ing for the early hemolysis, copper also directly oxidizes the erythro- tions are characteristic of chronic copper overload conditions such as
cyte membrane, thereby initiating red cell lysis independently of the Wilson disease.'”? This accumulation is accomplished through carrier-
reticuloendothelial system.*'°° Oxidant-induced disulfide cross-links mediated transport of albumin-bound, not ceruloplasmin-bound,
in the erythrocyte membrane reduce its stability and flexibility, thereby copper into the central nervous system.
predisposing to early cell rupture.*
Copper-induced oxidation of the heme iron within the erythrocyte
produces methemoglobinemia.* Given the high incidence of hemoly- CLINICAL MANIFESTATIONS
sis, the methemoglobin is commonly released within the plasma. In this
situation, methylene blue may not reliably reduce the ferric iron. ACUTE COPPER SALT POISONING
The acutely lethal dose of ingested copper sulfate is suggested to be
LIVER 0.15 to 0.3 g/kg, but this is unverified. GI irritation is the most common
Although most of the accumulated copper in hepatocytes is rap- initial manifestation of copper salt poisoning. This syndrome includes
idly complexed with metallothionein or otherwise used, failure to the rapid onset of emesis and abdominal pain, possibly followed by
completely sequester copper ions allows their participation in redox gastroduodenal hemorrhage, ulceration, or perforation.®** Blue color-
reactions. Hepatic cells are protected from copper toxicity in vitro ation of the vomitus may occur after the ingestion of certain copper
by induction of metallothionein with zinc or cadmium salts or by the salts, particularly copper sulfate.°*!!”!”° Blue vomitus is not, however,
infusion of metallothionein before exposure. These interventions dem- pathognomonic for copper poisoning and also occurs in patients who
onstrate the toxicologic significance of free intracellular copper. These ingest boric acid, methylene blue, or food dyes. Other common symp-
findings also explain the therapeutic use of zinc acetate in patients with toms include retrosternal chest pain and a metallic taste.
Wilson disease because copper itself is not a good inducer of metal- Given its location within the GI tract, the liver receives the initial
lothionein in humans. and most substantial exposure to any ingested copper. In patients with
Copper ions also generate hydroxyl radicals, which are potent more severe acute copper sulfate poisoning, hepatotoxicity is a fre-
inducers of both lipid peroxidation, and other reactive oxygen species. quent, although rarely an isolated, manifestation. Jaundice, although
The peroxidative effect on biologic membranes is more significant in among the most common clinical and biochemical findings after over-
animals deficient in vitamin E and is prevented by vitamin E replace- dose, can be hepatocellular or hemolytic.’®
ment, presumably because of the role of vitamin E as a free radical Hemolysis is more common than hepatotoxicity and occurs invari-
scavenger.*!!° These effects are most pronounced in mitochondria, ably in patients with liver damage.**''* As noted, copper-induced
perhaps as a consequence of the reduction of cupric to cuprous ion in hemolysis often occurs rapidly after exposure and may be severe (see
these organelles.**'!* Copper also accumulates in the cellular nuclei, Pathophysiology above and Chap. 24). In most reported cases, the dis-
where localized production of hydroxyl radicals may form DNA covery of significant methemoglobinemia occurs early in the patient’s
adducts and cause apoptosis.'’” Histologically, liver damage follows a clinical course and is rapidly followed by hemolysis.*! Because free
centrilobular pattern of necrosis. methemoglobin is filterable, methemoglobinuria may occur, although
The sequelae of the potent hepatotoxic effects of copper are not it cannot be differentiated from other heme forms in the urine without
isolated to the liver. After liver necrosis occurs, typically at liver cop- specialized testing.
per concentrations greater than 50 mg/g dry weight, massive release of Renal and pulmonary toxicity occur occasionally and represent
copper into the blood occurs, which may be of sufficient magnitude to extraerythrocytic manifestations of the oxidative effects of the copper
cause hemolysis. This sequence of events is common during the crises ions. Despite massive intravascular hemolysis, hemoglobinuric renal
of Wilson disease and may allow for an understanding of the delayed failure is uncommon in patients who receive adequate volume-replace-
secondary episode of hemolysis that occurs in some copper-poisoned ment therapy.”
patients. Hypotension and cardiovascular collapse occur in patients with
the most severe poisoning and is likely multifactorial in origin.”
Undoubtedly, intravascular volume depletion from vomiting and
KIDNEYS diarrhea is involved. However, the severity and poor patient outcome
The kidneys bioaccumulate copper. Although primarily bound to despite appropriate volume repletion suggests that the direct effects of
metallothionein when available, copper is otherwise free to participate copper on vascular and cardiac cells are also involved. Sepsis, as a result
in oxidant-generating reactions in a manner analogous to that of iron. of transmucosal bacterial invasion, may also be partially responsible.”

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 Part C_ The Clinical Basis of Medical Toxicology

Depressed mental status, which ranges from lethargy to coma or in India or idiopathic copper toxicosis elsewhere, generally occurs in
seizures after acute poisoning, is likely an epiphenomenon related to the setting of excessive dietary intake of copper because of copper-
damage to other organ systems. These findings are particularly com- contaminated water from brass vessels used to store milk. These chil-
mon in patients with hepatic failure and are comparable to those of dren may have a genetic predisposition to copper accumulation because
hepatic encephalopathy from other causes. In patients with chronic signs of chronic liver disease develop by several months of age and
copper poisoning, such as Wilson disease, neurologic manifestations progress rapidly.''* Both serum copper and ceruloplasmin concen-
are prominent and typically involve movement disorders (see Chronic trations are markedly elevated, which differentiates this disease from
Copper Poisoning below). Wilson disease. The incidence of the disease has decreased dramatically,
Intravenous injection of copper sulfate reportedly produces a clinical probably as a result of improved nutrition and replacement of copper
syndrome identical to that that occurs after ingestion, although the GI utensils and storage containers with those made of steel. One family of
findings may be less pronounced.'*'*** Subcutaneous administration four developed abdominal pain, malaise, tachycardia, and anemia after
of a veterinary copper glycinate solution produced skin necrosis in the approximately 1 month of eating homegrown vegetables treated with
area of the injection."’” copper oxychloride pesticide.** Each patient had anemia and a slightly
Although not strictly a form of copper poisoning, inhalation of copper elevated (or upper limit of normal) serum copper concentration.
oxide fumes, generated during welding or other industrial processes, may “Vineyard sprayer’s lung,” first described in 1969, refers to the occu-
produce metal fume fever, a syndrome historically called “brass chills” pational pulmonary disease that occurred among Portuguese vineyard
or “foundry workers’ ague.” Patients with this syndrome present with workers applying Bordeaux solution, a 1% to 2% copper sulfate solution
cough, chills, chest pain, or fever that are most likely immunologic, not neutralized with hydrated lime (Ca(OH),).” The patients developed inter-
toxicologic, in origin (see Chap. 124). However, copper oxide formation, stitial pulmonary fibrosis and histiocytic granulomas containing copper.
unlike zinc oxide, only occurs at extremely high temperatures, account- Many of these workers also developed pulmonary adenocarcinoma, hepatic
ing for the relative infrequency of copper-induced metal fume fever. angiosarcoma, and micronodular cirrhosis, raising the possibility of a car-
cinogenic effect of chronic copper exposure.”* There is also a suggestion of
an increased incidence of pulmonary adenocarcinoma among smelters,
CHRONIC COPPER POISONING who are, however, exposed to many other xenobiotics, including arsenic,
Although hepatolenticular degeneration, known as Wilson disease, is a a known carcinogen.*° Copper is not on the list of suspected carcinogens
condition of chronic copper overload, there are qualitative similarities compiled by the International Agency of Research on Cancer (IARC).
to acute copper poisoning. Wilson disease is an inherited autosomal Ophthalmic effects of copper salts, primarily after occupational expo-
recessive disorder of copper metabolism affecting approximately one in sure, include irritation of the corneal, conjunctival, or adnexal struc-
40,000 persons. The gene implicated in this disease (ATP7B) codes for a tures. Chronic ophthalmic exposure to particulate elemental copper
hepatocyte membrane-bound, copper-binding protein that is required or one of its alloys may result in chalcosis lentis, from the Greek word
for the maturation of ceruloplasmin and the biliary excretion of copper. chalkos, or copper. This chronic exposure manifests as a green-brown
Transgenic replacement models, in which human ATP7B is expressed discoloration of the lens or cornea, similar to Kayser-Fleischer rings.
in deficient animals, demonstrate normalization of copper excretion.®
The absence of this gene and the resultant increase in hepatic copper
concentrations produce continuing oxidative stress on the hepatocyte DIAGNOSTIC TESTING
and cellular necrosis with the inevitable development of cirrhosis. Patients
undergo periodic fluctuations in the extent of their copper-induced hepa- Real-time testing for copper is impractical, and almost all management
totoxicity, and episodes of severe hepatotoxicity are frequently associated decisions must be based on clinical criteria. Copper concentrations are
with hemolysis as stored copper is released from dying hepatocytes. often obtained for confirmatory or investigative purposes. Although
The adverse effects of copper on the lenticular nucleus in the basal never adequately studied, whole-blood copper concentrations may
ganglia cause movement disorders such as ataxia, tremor, parkin- correlate better with clinical findings than do serum copper concen-
sonism, dysphagia, and dystonia.” No other form of copper poison- trations.*? The rapid movement of copper from serum into the eryth-
ing is associated with substantial or direct neurotoxicity. Psychiatric rocyte presumably explains this finding. However, although there is a
manifestations, such as behavioral changes or mood disorders, may statistical relationship between the whole-blood copper concentrations
also occur.”! Accumulation of copper within the cornea accounts and the severity of poisoning,**’” there is little correlation between
for the characteristic green-brown Kayser-Fleischer rings. Although clinical findings at any given copper concentration, regardless of which
patients’ serum copper concentrations are decreased, they typically biologic tissue is measured. Similarly, other than at extremely high or
have a reduced ceruloplasmin concentration caused by the failure of low concentrations, there is no defined concentration at which the
copper incorporation into ceruloplasmin and release from the liver prognosis may be established with certainty. Reported serum copper
and an elevated urinary copper concentration. Treatment involves concentrations in patients with hemolysis range from 96 to 747 g/dL,
lifelong therapy with p-penicillamine, trientine (triethylene tetramine), and those after severe poisoning have values of 6600°° to 8267 ug/dL.*!
or molybdenum salts if the patient is D-penicillamine sensitive. Zinc Serum copper concentrations in 11 patients with copper-induced
acetate, which has been approved by the Food and Drug Administration acute renal failure ranged from 115 to 390 ug/dL.*° The normal urinary
(FDA) as a maintenance therapy, induces the formation of intestinal copper excretion per 24 hours is up to approximately 25 lg and is
metallothionein and thereby blocks copper absorption by enhancing reportedly as high as 628 1g/24 h in patients with copper poisoning.“*
intestinal mucosal cell sequestration.” Orthotopic liver transplantation Occasionally, serum copper concentrations reveal a secondary
results in improvement in nearly all aspects of the disease, including increase, likely as a consequence of release during hepatocellular
the central nervous system and ocular manifestations. necrosis. This secondary rise typically occurs only in patients with life-
Chronic exogenous copper poisoning is uncommon in adults but threatening poisoning, and clinical evaluation is far more important
is reported after the use of copper-containing dietary supplements.” and relevant than serial copper concentrations.’
However, subacute or chronic exposure is common in children in some Elevated copper concentrations are also noted in patients with
parts of the world. This condition, commonly called childhood cirrhosis inflammatory conditions, biliary cirrhosis, pregnancy, and estrogenic

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 Chapter 93 Copper

oral contraceptive use.“ These conditions are associated with an poisoning. Studies on the efficacy of chelation therapy after acute
elevated ceruloplasmin level, and although the serum copper concen- copper salt poisoning are limited. Even when administered early and
trations increase, the fraction of bound copper in the serum remains appropriately, organ damage and death still occur. Application of
normal. Copper concentrations in the erythrocyte remain normal. the data from the existing literature is complex because of the lack of
Patients with Wilson disease have elevated hepatocyte copper content, controlled therapeutic studies of human copper poisoning. Although
but their serum copper concentrations are generally below normal experimental animal models and uncontrolled human data exist, the
unless hepatic necrosis is occurring.*! results are frequently contradictory. Three chelators are clinically
Although serum ceruloplasmin concentrations increase in patients available, and most data regarding dosing and efficacy data are derived
with acute copper poisoning,’ presumably reflecting increased hepatic either from their use in the treatment of patients with Wilson disease
synthesis, the ceruloplasmin concentration cannot be used to define or from their effects on copper elimination during chelation of patients
the patient’s prognosis. Tissue metallothionein concentrations may manifesting toxicity from other metals.
also increase after copper poisoning, but the implication of this find- Most patients with copper poisoning are initially treated with intra-
ing, which is limited by the inability to rapidly obtain tissue samples, muscular British anti-Lewisite (BAL).!°!”° Although BAL may be less
is unknown.” Ceruloplasmin concentrations are low in patients with effective, its use is appropriate in patients in whom vomiting or GI
Wilson disease, reflecting aberrant enzymatic activity. injury prevents oral p-penicillamine administration. Furthermore,
Routine laboratory testing after acute copper salt poisoning because the BAL-copper complex primarily undergoes biliary elimina-
should include an assessment for both hemolysis and hepatotoxicity. tion, whereas D-penicillamine undergoes renal elimination, BAL proves
Differentiation of these causes as a cause for jaundice is made by stan- useful in patients with renal failure. When tolerated, p-penicillamine
dard methodology, such as comparison of the bilirubin fractions and therapy should be started simultaneously or shortly after the initiation
an assessment of the hepatic enzymes and hemoglobin, that is, whereas of therapy with BAL (see Antidotes in Depth A26: Dimercaprol).
indirect bilirubin is proportionally elevated in patients with hemolysis, Calcium disodium ethylenediaminetetraacetate (CaNa,EDTA)
the direct fraction increases in patients with hepatocellular necrosis. reduces the oxidative damage induced by copper ions in experimental
An assessment of the patient’s electrolyte and hydration status is war- models.’ However, it does not greatly enhance the elimination of
ranted. The prothrombin time may be prolonged in the absence of copper when used for the chelation of other metals.'°*!?! In addition,
liver injury or disseminated intravascular coagulopathy and may be the short-term use of CaNa,EDTA inactivates dopamine B-hydroxylase
result of a direct effect of free copper ions on the coagulation cascade.” in humans, presumably by chelating the copper moiety from its active
In addition, many reports document abnormal glucose 6-phosphate site.*° However, because the in vivo activity of this enzyme is restored
dehydrogenase (G6PD) activity, suggesting for the cause of hemolysis. on the addition of exogenous copper, the potential for inhibition of
However, interpretation of this test result is difficult because copper the formation of neuronal norepinephrine during the treatment of
poisoning interferes with the measurement of G6PD. acute poisoning is unknown. Successful clinical use of CaNa,EDTA
Although copper metal embedded in the skin is clearly visible, topi- has been reported.****!” Interestingly, CuCaEDTA is used as a copper
cally applied copper salts are not visualized.'® The clinical usefulness of supplement in animals, and overdose of this formulation results in
radiographs to identify ingested copper solutions has not been studied. copper poisoning, suggesting that its chelating ability is limited” (see
Obtaining an abdominal radiograph, although probably of limited ben- Antidotes in Depth A28: Edetate Calcium Disodium).
efit, may be justified because it occasionally demonstrates the presence p-Penicillamine (Cuprimine), a structurally distinct metabolite of
of radiopaque material in the GI tract. penicillin, is an orally bioavailable monothiol chelator. It is used in the
treatment of lead, mercury, and copper toxicity, as well as in the man-
agement of rheumatoid arthritis and scleroderma. It has also recently
MANAGEMENT been investigated for its antiangiogenesis effects in cancer therapy,
which occur by chelation of copper that serves as a cofactor for certain
Supportive care is the cornerstone to the effective management of
growth factors, such as fibroblast growth factor. p-Penicillamine
patients with acute copper poisoning, emphasizing antiemetic therapy,
is effective in preventing copper-induced hemolysis in patients with
fluid and electrolyte correction, and normalization of vital signs before
Wilson disease. Its protective mechanism is primarily mediated
the consideration of chelation therapy. GI decontamination is of limited
through chelation of unbound copper ions, rendering them unable to
concern because the onset of emesis generally occurs within minutes
participate in redox reactions.” The p-penicillamine-copper complex
of ingestion and is often protracted. In patients who present early after
undergoes rapid renal clearance in patients with competent kidneys.
ingestion of a liquid copper solution and who have not yet vomited,
The use of p-penicillamine is not formally studied in the patients with
aspiration with a nasogastric tube may remove copper ion. In one case,
acute copper salt poisoning, but case studies and animal models sug-
even after extensive vomiting, nasogastric aspiration still removed blue
gest that copper elimination is enhanced.*>' The recommended dose
solution, but removing this remaining volume is unlikely to provide
is 1.0 to 1.5 g/d given orally in four divided doses. p-Penicillamine is
significant clinical benefit.!” Although oral activated charcoal is unlikely
also indicated for the treatment of chronic exogenous copper poison-
to be harmful, it is of unproved benefit, and it may hinder the ability to
ing, such as Indian childhood cirrhosis. Initiation early in the course of
perform GI endoscopy to evaluate the corrosive effects of a copper salt
disease and discontinuation of the exposure are associated with hepatic
on the mucosal surface.’ For this reason, even though activated charcoal
recovery and dramatically improved survival rates.
may adsorb the remaining copper in the proximal GI tract, it is relatively
Although p-penicillamine appears to be effective, it is associated
contraindicated in most situations. Advanced therapy for patients with
with several significant complications. In nearly 50% of patients treated
renal failure may include hemodialysis, and liver transplantation may be
with p-penicillamine for Wilson disease, there is worsening of the
needed for patients with life-threatening hepatic failure.
neurologic findings.” Subacute toxicities of D-penicillamine include
aplastic anemia, agranulocytosis, and renal and pulmonary disease.
CHELATION THERAPY Long-term use of D-penicillamine is also associated with the develop-
Chelation therapy should be initiated when hepatic or hematologic ment of cutaneous lesions and immunologic dysfunction. However, in
complications are present or there are other manifestations of severe the brief treatment necessary for acutely poisoned patients, the major

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 Part C_ The Clinical Basis of Medical Toxicology

risk is the potential for hypersensitivity reactions that occur in 25% of The molecular adsorbents recirculating system (MARS) and single-
patients who are allergic to penicillin. This hypersensitivity reaction pass albumin dialysis (SPAD), which are modified forms of hemodi-
is likely related to contamination of the pharmaceutical preparation alysis in which albumin is included in the dialysate, are reported to
with penicillin rather than immunologic cross-reactivity.°'* The use of rapidly and substantially lower the serum copper concentrations in
p-penicillamine during pregnancy is associated with congenital abnor- patients with fulminant Wilson disease, allowing a bridge to hepatic
malities in fetuses, although all of the data are derived from women transplantation.”*> One patient was treated with albumin dialysis
with Wilson disease who were receiving long-term therapy.” using a 44 g/L albumin-containing dialysate and a slow dialysate flow
Succimer is sometimes described as an ineffective copper chelator, rate (1-2 L/h) in a manner similar to routine continuous venovenous
although it is able to triple the baseline copper elimination in a murine hemodiafiltration reportedly removed 105 mg of copper and normal-
model.”’ Given its ease of use, relative safety, and benefit in experimen- ized the serum copper concentration.!””> The risk associated with
tal models,' succimer may be used in lieu of D-penicillamine in patients hemolysis likely remains, and caution should be used when extrapolat-
with mild or moderate poisoning. Under these circumstances, the use ing therapy from Wilson disease to exogenous copper poisoning.
of standard lead poisoning dosing regimens is warranted (see Chap. 93 Plasma exchange enhanced the elimination of copper in patients
and Antidote in Depth A27: Succimer [2,3-Dimercaptosuccinic Acid]) with fulminant Wilson disease.”’’”? Copper removal ranged from
DMPS, an experimental chelator that is gaining popularity for the 3 to 12 mg per treatment, but it is unclear if either of these removal
treatment of arsenic poisoning, prevents acute tubular necrosis in techniques would be beneficial after an ingestion of gram quantities of
copper-poisoned mice.*” DMPS also proved to be the most effective of a copper sulfate. The same warning as above about inadvertent red cell
panel of chelators in a murine model of copper sulfate poisoning,” and lysis applies.
it substantially increased urinary copper elimination in nonpoisoned Peritoneal dialysis is not useful in patients with fulminant Wilson
individuals.’ However, DMPS, unlike p-penicillamine, forms intra- disease.’”> Peritoneal dialysis removed less than 700 wg in a copper
molecular disulfide bridges, which, in so doing, liberates an electron. sulfate-poisoned child whose copper concentration was 207 [1g/dL.*”
This property, which accounts for its potency as a reducing agent, also However, in the same patient, the addition of albumin to the dialysate
probably explains its propensity to worsen copper-induced hemolysis removed 9 mg of copper at a time when the child’s serum copper con-
in vitro.** Because an adequate analysis of risk versus benefit is unavail- centration had already decreased substantially.
able, DMPS should not be used to chelate copper-poisoned patients at Management of hepatic toxicity requires little more than standard
this time. supportive care. The potential benefit of N-acetylcysteine has not been
Trientine, an orally bioavailable xenobiotic, is the second-line chela- studied, although it is useful in many forms of fulminant hepatic fail-
tor for patients with Wilson disease, but its use in patients with acute ure. Liver transplantation should be considered, but specific criteria for
copper poisoning is unreported. This, too, is the case with zinc therapy transfer to a specialized liver unit or for transplant, other than those
to induce metallothionine synthesis, which is also of proven efficacy that are applicable for Wilson disease or other more common, noncop-
in Wilson disease but has an unknown role in the treatment of acute per etiologies, are undefined.
copper poisoning. The need for several weeks of zinc therapy before There are no controlled data on the treatment of acute copper
realizing full efficacy makes its therapeutic use in acutely poisoned poisoning in pregnancy. The available data on pregnant women with
patients questionable. Although large oral doses of zinc salts may limit Wilson disease document that p-penicillamine is teratogenic and that
the absorption of copper ion, the concomitant GI irritant effects of zinc zinc may be the preferred therapy.
ion make this therapy impractical.**
Tetrathiomolybdate, an FDA-recognized chelating agent with
orphan drug status, although not marketed, may be available through
compounding pharmacies, typically as ammonium tetrathiomolyb-
SUMMARY
date. Tetrathiomolybdate is suggested to benefit copper-poisoned ani- Acute copper poisoning is rare in the United States but is associated
mals in uncontrolled studies,”® but its use in acute copper poisoning in with dramatic toxicologic effects, primarily hemolysis and hepatotoxic-
humans is unstudied. Tetrathiomolybdate depleted the copper stores in ity. The effects are primarily mediated by oxidative stress on the eryth-
a patient with cancer who purchased the compound over the Internet rocyte and hepatocyte, and this similarity to iron salt poisoning adds a
as an “alternative” antiangiogenesis therapy.” framework for the conceptual understanding of the disease. The infre-
quency of acute copper poisoning severely limits our ability to perform
controlled studies on its management. Chelation is most commonly
EXTRACORPOREAL ELIMINATION performed with BAL and p-penicillamine. Succimer is more familiar
There are limited data regarding the extent to which copper ion is to most clinicians and has fewer associated adverse effects and may
eliminated by various extracorporeal means. Exchange transfusion therefore be an acceptable alternative. Extracorporeal elimination is
is of undefined, but probably limited, benefit in acute copper sulfate unlikely to be of benefit. Fortunately, exhaustive research into diseases
poisoning.*’ Hemodialysis membranes undoubtedly allow copper ions of copper metabolism, particularly Wilson disease, which has periodic
to cross, based on the epidemics in which hemodialysis using copper- exacerbations similar to acute copper poisoning, has provided insight
rich water inadvertently resulted in copper poisoning.*® Although into managing patients with acute copper salt poisoning.
copper should be similarly cleared by hemodialysis, its relatively large
volume of distribution limits the potential clinical usefulness of this
technique. Furthermore, copper ions are highly protein bound, and the
dialyzable concentration is typically less than 1 pmol/L, suggesting that
REFERENCES
hemodialysis would have little clinical usefulness. This fact is supported 1. Aaseth J, Korkina LG, Afanas’ev IB. Hemolytic activity of copper sulfate as
by case reports in which serum, tissue, or dialysate concentrations of influenced by epinephrine and chelating thiols. Zhongguo Yao Li Xue Bao.
copper are assessed.°*4 Furthermore, given the propensity of hemodi- 1998;19:203-206.
2. Aaseth J, Ribarov S, Bochev P. The interaction of copper (Cut) with the
alysis to lyse erythrocytes, which may release stored copper and worsen
erythrocyte membrane and 2,3-dimercaptopropanesulphonate in vitro: a
toxicity, hemodialysis is not recommended.” source of activated oxygen species. Pharmacol Toxicol. 1987;61:250-253.

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