95: Copper

Copper exits naturally, either as native copper (elemental copper, Cu^o) or as one of its sulfide or oxide ores. Important ores include malachite (CuCO₃·(OH)₂), chalcocite (Cu₂S), cuprite (Cu₂O), and chalcopyrite (CuFeS₂or Cu₂S·Fe₂S₃). Chalcopyrite, a yellow sulfide ore, is the source of 80% of the world’s copper production. The smelting, or separation, of copper ores began about 7000 years ago; copper gradually assumed its current level of importance at the start of the Bronze Age, around 3000 bc. Smelting begins with roasting to dry the ore concentrate, which, in more modern times, is further purified by electrolysis to a 99.5% level of purity. The sulfide ores have a naturally high arsenic content, which is released during the extraction process, posing a risk to smelters.

Although acute copper poisoning is uncommon in the United States, the historical therapeutic role of copper remains noteworthy. Copper sulfate was used in burn wound débridement until cases of systemic copper poisoning were reported.⁵¹ Interestingly, in one report, each wound débridement procedure was associated with an 8% to 10% fall in the patient’s ­hematocrit. In the 1960s, copper sulfate (250-mg dose, containing 100 mg copper ion) ironically was recommended as an emetic agent, typically for use in children following potentially toxic exposures.⁶⁰ It was recognized for its rapidity of onset and effectiveness, and it compared favorably with syrup of ipecac. However, copper-induced emesis was rapidly identified as a highly dangerous practice, and this use was generally discontinued,^68,111 although fatal cases still occur. Copper salts are administered in religious rituals as a green-colored “spiritual water,” containing 100 to 150 g/L of copper sulfate as an emetic to “expel one’s sins.”^5,110

There is a growing body of knowledge linking copper to the promotion of both physiologic and malignant angiogenesis.⁴⁷ In this latter case, copper may enable tumor expansion, invasion, and metastasis. Additionally, copper binding to amyloid fibers in the brains of patients with Alzheimer disease may lead to local oxidative damage and cause the characteristic neurodegeneration.¹⁹ Copper is also similarly implicated in the pathogenesis of both Parkinson disease and autism.^22,126

Acute or chronic copper poisoning can occur when the metal is leached from copper pipes or copper containers. This occurs frequently 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.¹²² Similarly, storage of acidic potable substances, such as orange or lemon juice, in copper vessels may cause copper poisoning. A particularly dangerous situation occurs when acidic water is inadvertently used for hemodialysis.^35,74 In this circumstance, the leached copper avoids the normal gastrointestinal barrier and is delivered parenterally to the patient’s circulation. In one reported series, the copper concentration in the dialysis water was 650 μg/L, causing several poisonings and the death of a patient with a whole-blood copper concentration of 2095 μg/L.³⁶ Similarly, stagnant water or hot water,¹⁰⁰ even if not highly acidic,¹⁰⁴ can accumulate copper ions from pipes and cause poisoning.^7,36

Although most natural water contains a small quantity of copper (4–10 μg/L), it is tightly bound to organic matter and therefore not orally bioavailable. Copper pipes typically add about 1 mg of copper to the daily intake of an adult. The Environmental Protection Agency guidelines permit up to 1.3 mg/L of copper in drinking water,²⁹ although in some areas intermittent concentrations may rise as high as 60 mg/L.

Metallic copper is ideal for electrical wiring because it is highly malleable and can be drawn into fine wire. Its electrical conductivity is only exceeded by silver. Similarly, its excellent heat conductivity accounts for its widespread use in cookware. Although the metal is reactive with air, it forms a resistant layer of insoluble copper carbonate on its surface. It is this water- and air-resistant compound that accounts for the green coloration of ornamental roofing and statues. Because copper is a soft metal, it must be strengthened prior to use in structural applications or as a coinage metal. This is most commonly done by the creation of copper alloys. Brass is an alloy of copper compounded with as much as 35% zinc. Similarly, bronze contains copper combined with up to 14% tin. Gun metal is an alloy that contains 88% copper, 10% tin, and 2% zinc. Sterling silver and white gold also contain copper.

Metallic copper (Cu⁰), although not in itself poisonous, may react in acidic environments to release copper ions. The metallic copper contraceptive intrauterine device derives its efficacy from the local release of copper ions.¹⁴ Metallic copper bracelets, worn by patients with rheumatoid arthritis and other ailments, purportedly derive their far-reaching antiinflammatory effect through dermal copper ion absorption and distribution to affected tissues.¹¹⁹ Local copper ion release is responsible for the occasional case of dermatitis that occurs following skin exposure to copper metal.⁵² Ingestion of large amounts of metallic copper (eg, as coins) may rarely produce acute copper poisoning.^95,125 Poisoning under these circumstances is a result of the release of large amounts of copper ion from copper alloy by the acidic gastric contents. Also, inhalation of finely divided metallic copper dust or bronze powder, used in industry and for gilding, may produce life-threatening bronchopulmonary irritation, presumably as a consequence of the local release of ions.^34,45

The majority of patients suffering from acute copper poisoning are exposed to ionic copper. In copper sulfate, also known as cupric sulfate, the copper atom is in the +2 oxidation state. Copper sulfate is used as a fungicide and algicide, and to eradicate tree roots that invade septic, sewage, and drinking water systems.⁹³ Copper sulfate is the most readily available form and is the form involved in the majority of nonindustrial copper salt exposures. Copper sulfate was a favorite ingredient in many home chemistry sets because of its brilliant blue color when dissolved in water. Although serious poisoning, particularly in children, led regulatory agencies in the United States to restrict its use, it accounts for the most consequential chemistry set–related toxic exposures reported in other countries.⁷⁹ Similarly, homegrown copper sulfate crystals from kits are occasionally responsible for fatal poisonings.⁴³

Cuprous salts, containing copper in the +1 oxidation state, are unstable in water and readily oxidize to the cupric form. There are numerous copper salts with varying oxidation states used in industry and agriculture (Table 95–1), many of which are not poisonous. Because those salts that are water soluble are more likely to be toxic, it is important to determine the nature of the copper product implicated in an exposure. Analogously, when examining the medical literature, it is critical to discern which form of copper is involved in the scientific experiment or case report before applying the results to clinical practice.

Copper is an essential metal that our body stores in milligram amounts (100–150 mg). Daily requirements of copper are approximately 50 μg/kg in infants and 30 μg/kg in adults. The average daily intake of copper in the United States noted in NHANES III is about 1.2 mg.³⁷

The daily requirement is satisfied by nuts, fish, and green vegetables such as legumes, although our largest source is generally from drinking water. Copper deficiency is exceedingly rare even in the poorest communities and is most frequently acquired through the excessive zinc intake.⁸³ There are genetic aberrations, such as Menkes “kinky-hair” syndrome, in which intestinal copper uptake is impaired. Menkes syndrome is characterized by mental retardation, thermoregulatory dysfunction, hypopigmentation, connective tissue abnormalities, and pili torti (kinky hair). Interestingly, with the increased focus on the role of copper in neurodegenerative disorders and cancer, some authors suggest intentionally depleting patients of their copper stores with tetrathiomolybdate, an experimental copper chelator.⁴⁰

Copper is absorbed by an active process involving a copper adenosine triphosphatase (CuATPase, also known as the Menkes ATPase) in the small intestinal mucosal cell membrane (see below). The gastrointestinal absorption varies with the copper intake and the food source,⁴⁸ and is as low as 12% in patients with high copper intake. In the presence of damaged mucosa, such as following acute overdose, the fractional absorption is likely to be significantly higher.⁶⁹ Once absorbed, copper is rapidly bound to high-affinity carriers, such as ceruloplasmin, and low-affinity carriers, such as albumin, for transport to the liver and other tissues.¹²⁰ Under normal circumstances the amount of unbound copper in the blood is well below 1%. After being released locally in the reduced form from its carrier, copper uptake by the hepatic cells occurs via a specific uptake pump.⁹⁷ This process, which is facilitated by the reducing agent ascorbic acid, provides a potential window, however brief, for detoxification of the ion by chelating agents. In acute overdose, a high fraction of the plasma copper remains bound to low-affinity proteins, such as albumin, and thus is biologically active.

In the hepatocyte, complex trafficking systems exist (involving ceruloplasmin, metallothionein, and other metallochaperones within the cytoplasm) to prevent copper toxicity and to aid delivery to the appropriate enzymes.⁹⁴ A distinct Cu-ATPase, located on certain subcellular organelles such as the trans-Golgi network or pericanalicular lysosomes, assists in the appropriate localization and elimination, respectively, of the metal.¹²¹ By this mechanism, copper is either incorporated into enzymes or released, as a metallothionein–copper complex, directly into the biliary system for fecal elimination.

Some copper released from the liver is bound primarily to ceruloplasmin, an α₂-sialoglycoprotein with a molecular weight of 132,000 Da. ­Ceruloplasmin-bound copper accounts for approximately 90% to 95% of serum copper. Ceruloplasmin is a multifunctional protein that binds 6 atoms of copper per molecule. Copper bound to this carrier has a plasma half-life of approximately 24 hours. Ceruloplasmin is also involved in the mobilization of iron from its storage sites, and it serves an analogous role as a ferroxidase during the ferrous–ferric conversion. Cu⁺ is oxidized directly by ceruloplasmin, thereby avoiding the generation of reactive oxygen species.

There are several important copper-containing enzymes in humans (Table 95–2). The common link among these enzymes is their participation in reduction-oxidation (redox) reactions in which a molecule, typically oxygen, donates or shares its electrons with another compound. In this respect, the physiology, chemistry, and toxicology of copper are most similar to that of iron. In fact, “blue-blooded” animals, such as octopi and spiders, use copper in hemocyanin, a blue pigment, in an analogous manner that “red-blooded” animals use iron in hemoglobin.

The volume of distribution of copper is 2 L/kg and the t_1/2 of erythrocyte copper is 26 days. The elimination of copper occurs predominantly through biliary excretion following complexation with ceruloplasmin. Biliary excretion approximates gastrointestinal absorption and averages 2000 μg/24 h.⁹⁴ Renal elimination under normal conditions is trivial, accounting for approximately 5 to 25 μg/24 h.

Copper in water may be tasted at concentrations of 1 to 5 mg/L, and a blue-green discoloration is imparted when the concentrations are greater than 5 mg/L.³³ Acute gastrointestinal effects occurs when drinking water contains more than 25 mg/L,⁵³ although concentrations as low as 3 mg/L are associated with abdominal pain and vomiting in many, without a rise in the serum copper concentrations.⁹² In one blinded, randomized study comparing copper-adulterated water to pure water, women appeared more sensitive than men to copper, but both groups were symptomatic when the copper concentration in the water was 6 mg/L.⁶

Redox Chemistry

Because copper is a transition metal, it is capable of assuming one of several different oxidation (or valence) states, and it is an active participant in redox reactions. In particular, participation in the Fenton reaction and Haber-Weiss cycle explains the toxicologic effects of copper as a generator of oxidative stress and inhibitor of several key metabolic enzymes (Fig. 12–2).⁵⁷ In the presence of sulfhydryl-rich cell membranes, such as those on erythrocytes, cupric ions are reduced to cuprous ions, which are capable of ­generating superoxide radicals in the presence of oxygen.⁶⁴ This one-electron ­reduction of oxygen regenerates the cupric ion, allowing redox cycling and continuous generation of reactive oxygen species (Fig. 95–1). In particular, the mitochondrial electron transport chain and lipid membranes serve as ready sources of electrons for copper reduction, establishing a chain of events that ultimately leads to mitochondrial or membrane dysfunction, respectively.⁸²

Erythrocytes

Cupric ion inhibits sulfhydryl groups on enzymes in important antioxidant systems, including glucose-6-phosphate dehydrogenase and glutathione reductase.¹⁰¹ However, while support for these effects is only indirect, intraerythrocyte concentrations of reduced glutathione fall demonstrably following copper exposure. This effect is presumably part of the protective role that glutathione, a nucleophile or reducing agent, normally has on oxidants, such as either cupric ions or the reactive oxygen species they generate.^76,77 Thus, in the setting of copper poisoning, in which excessive quantities of oxidants are produced, the depletion of glutathione presumably augments peroxidative membrane damage.

The importance of hemoglobin-derived reactive oxygen ­species is demonstrated by the lack of hemolysis in the presence of copper under anaerobic conditions or in an environment saturated with carbon ­monoxide.¹¹ The in vitro hemolytic activity of copper sulfate is reduced by albumin and several sulfhydryl containing compounds, including d-penicillamine and succimer.¹ Interestingly, dimercaptopropane sulfonate (DMPS), another sulfhydryl containing compound often used as a chelator, exacerbates copper-induced hemolysis. This paradoxical effect is variably attributed to concomitant inhibition of superoxide dismutase, an important antioxidant enzyme, or to the ability of DMPS to efficiently reduce either membrane dithiols or cupric ions, in either case increasing the generation of superoxide.²

Hemolysis frequently occurs within the first 24 hours following with acute copper poisoning.^26,110,124 This rapidity of hemolysis differs markedly from most other oxidant stressors, which may take several days, and is likely a result of the differing nature of the erythrocyte insult. That is, the hemolysis following most oxidant exposures is caused by precipitation of hemoglobin as Heinz bodies and subsequent erythrocyte destruction by the reticuloendothelial system. Hemoglobin precipitation may also occur in the setting of acute copper poisoning, particularly following less substantial exposure. Additionally, and accounting for the early hemolysis, copper also directly oxidizes the erythrocyte membrane, thereby initiating red cell lysis independently of the reticuloendothelial system.⁹⁹ Oxidant-induced disulfide cross-links in the erythrocyte membrane reduce its stability and flexibility, thereby predisposing to early cell rupture.³

Copper-induced oxidation of the heme iron within the erythrocyte produces methemoglobinemia.⁸⁰ Given the high incidence of hemolysis, the methemoglobin is commonly released within the plasma. In this situation, methylene blue may not reliably reduce the ferric iron.

Liver

Although most of the accumulated copper in hepatocytes is rapidly complexed with metallothionein or otherwise used, unsequestered copper ions participation in redox reactions. Hepatic cells are protected from copper toxicity in vitro by induction of metallothionein with zinc or cadmium salts or by the infusion of metallothionein prior to exposure. These interventions demonstrate the toxicologic significance of free intracellular copper. These findings also explain the therapeutic use of zinc acetate in patients suffering from Wilson disease, because copper itself is not a good inducer of metallothionein in humans.

Copper ions also generate hydroxyl radicals, which are potent inducers of both lipid peroxidation, and other reactive oxygen species. The peroxidative effect on biologic membranes is more significant in animals deficient in vitamin E and is prevented by vitamin E replacement, presumably because of the role of vitamin E as a free radical scavenger.¹⁰⁸ These effects are most pronounced in mitochondria, perhaps as a consequence of the reduction of cupric to cuprous ion in these organelles.^42,109 Copper also accumulates in the cellular nuclei, where localized production of hydroxyl radicals may form DNA adducts and cause apoptosis.⁹⁸ Histologically, liver damage follows a centrilobular pattern of necrosis (Chap. 23).

The sequelae of the potent hepatotoxic effects of copper are not isolated to the liver. Once liver necrosis occurs, typically at liver copper concentrations greater than 50 mg/g dry weight, massive release of copper into the blood occurs, which may be of sufficient magnitude to cause hemolysis. This sequence of events is common during the crises of Wilson disease and may allow for an understanding of the delayed secondary episode of hemolysis that occurs in some copper-poisoned patients.

Kidney

The kidneys bioaccumulate copper, where it is bound primarily to metallothionein. Reactive oxygen species are probably also responsible for the nephrotoxic effects of unbound copper. Pathologic analyses of the kidneys of oliguric or anuric patients typically reveal acute tubular necrosis that may demonstrate hemoglobin casts. These findings suggest that kidney failure may result indirectly from the hemoglobinuria induced by the massive release of free extracellular hemoglobin. The urinary hemoglobin, like myoglobin, may undergo conversion to ferriheme or release its iron, either of which results in oxidative stress on the renal tubular epithelial cell. Additionally, free extracellular hemoglobin may cause renal vasoconstriction through the local scavenging of nitric oxide within the renal arterioles.

Central Nervous System

Although charged entities such as copper ions do not readily cross the blood–brain barrier, elevated cerebrospinal fluid copper concentrations are characteristic of chronic copper overload conditions such as Wilson disease.¹¹² This accumulation is accomplished through carrier-mediated transport of albumin-bound, not ceruloplasmin-bound, copper into the central nervous system.

Acute Copper Salt Poisoning

The acutely lethal dose of ingested copper sulfate is suggested to be 0.15 to 0.3 g/kg, but this is unverified. Gastrointestinal irritation is the most common initial manifestation of copper salt poisoning. This syndrome includes the rapid onset of emesis, abdominal pain, and less frequently gastroduodenal hemorrhage, ulceration, or perforation.^6,28 Blue coloration of the vomitus may occur following the ingestion of certain copper salts, particularly copper sulfate.⁸¹ Blue vomitus is not, however, pathognomonic for copper poisoning and also occurs in patients who ingest boric acid, methylene blue, or food dyes. Other common symptoms include retrosternal chest pain and a metallic taste.

Given its location within the gastrointestinal tract, the liver receives the initial and most substantial exposure to any ingested copper. In the patients with more severe acute copper sulfate poisoning, hepatotoxicity is a frequent, although rarely an isolated,⁵⁵ manifestation. Jaundice, while among the most common clinical and biochemical findings following overdose, can be due to hepatocellular injury or hemolysis.⁸

Hemolysis is more common than hepatotoxicity, and occurs invariably in those patients with liver damage.¹⁰⁶ As noted, copper-induced hemolysis often occurs rapidly following exposure and may be severe (see Toxicology and Pathophysiology above and Chap. 22). In most reported cases, the discovery of significant methemoglobinemia occurs early in the clinical course and is rapidly followed by hemolysis. Because free methemoglobin is filterable, methemoglobinuria may occur, although it cannot be differentiated from other heme forms in the urine without specialized testing.

Kidney and lung toxicities occur occasionally and represent extraery­throcytic manifestations of the oxidative effects of the copper ions. In spite of massive intravascular hemolysis, hemoglobinuric kidney failure is uncommon in patients who receive adequate volume-replacement therapy.²⁶

Hypotension and cardiovascular collapse occur in patients with the most severe poisoning and is likely multifactorial in origin.¹⁰⁵ Undoubtedly, intravascular volume depletion from vomiting and diarrhea is involved. However, the severity and poor patient outcome despite appropriate volume repletion suggests that the direct effects of copper on vascular and cardiac cells are also involved. Sepsis, as a result of transmucosal bacterial invasion from the gastrointestinal tract, may also be partially responsible.⁶⁹

Depressed mental status, which ranges from lethargy to coma, or seizures following acute poisoning is likely an epiphenomenon related to damage to other organ systems. An altered level of consciousness is particularly common in patients with hepatic failure, and the presentation is comparable to that of hepatic encephalopathy from other causes. In patients with chronic copper poisoning, such as Wilson disease, neurologic manifestations are prominent and typically involve movement disorders (see Chronic Copper Poisoning below).

Intravenous injection of copper sulfate reportedly produces a clinical syndrome identical to that which occurs following ingestion, although the gastrointestinal findings may be less pronounced.^13,16,86 Subcutaneous administration of a veterinary copper glycinate solution produced skin necrosis in the area of the injection.^9,87

Although not strictly a form of copper poisoning, inhalation of copper oxide fumes generated during welding or other industrial processes may produce metal fume fever, a syndrome historically called “brass chills” or “foundry workers’ ague.” Patients with this syndrome present with cough, chills, chest pain, or fever that is most likely immunologic, and not toxicologic, in origin (Chap. 124). However, copper oxide formation, unlike zinc oxide, only occurs at extremely high temperatures, accounting for the relative infrequency of the copper-induced metal fume fever.

Chronic Copper Poisoning

Although hepatolenticular degeneration, known as Wilson disease, is a condition of chronic copper overload, there are qualitative similarities to acute copper poisoning. Wilson disease is an inherited, autosomal ­recessive disorder of copper metabolism affecting approximately 1 in 40,000 persons. The gene implicated in this disease (ATP7B) codes for a hepatocyte membrane-bound, copper-binding protein that is required for the maturation of ceruloplasmin and the biliary excretion of copper. Transgenic replacement models, in which human ATP7B is expressed in deficient animals, demonstrate normalization of copper excretion.⁷⁵ The absence of this gene, and the resultant increase in hepatic copper concentrations, produces ­continuing oxidative stress on the hepatocyte and cellular necrosis with the inevitable development of cirrhosis. Patients undergo periodic fluctuations in the extent of their copper-induced hepatotoxicity, and episodes of severe hepatotoxicity are frequently associated with hemolysis as stored copper is released from dying hepatocytes.

The adverse effects of copper on the lenticular nucleus in the basal ganglia cause movement disorders such as ataxia, tremor, parkinsonism, dysphagia, and dystonia.^70,85 No other forms of copper poisoning are associated with substantial or direct neurotoxicity. Psychiatric manifestations, such as behavioral changes or mood disorders, may also occur. Accumulation of copper within the cornea accounts for the characteristic green-brown Kayser-Fleischer rings. Although the affected patient’s serum copper concentrations are decreased, the individuals typically have a reduced ceruloplasmin concentration and an elevated urinary copper concentration. Treatment involves lifelong therapy with d-penicillamine, trientine (triethylenetetramine), or molybdenum salts if the patient is d-penicillamine sensitive. Zinc acetate, approved by the US Food and Drug Administration (FDA) as a maintenance therapy, induces the formation of intestinal metallothionein and thereby blocks copper absorption by enhancing intestinal mucosal cell sequestration. Orthotopic liver transplantation results in improvement in nearly all aspects of the disease, including the central nervous system and ophthalmic manifestations.⁹⁶

Chronic exogenous copper poisoning is uncommon in adults but is reported following the use of copper-containing dietary supplements.⁸⁴ However, subacute or chronic exposure is common in children in some parts of the world. This condition, commonly called childhood cirrhosis in India or idiopathic copper toxicosis elsewhere, generally occurs following excessive dietary intake of copper due to copper contamination of milk from brass storage vessels. The affected children may have a genetic predisposition to copper accumulation, as signs of chronic liver disease develop by several months of age and progress rapidly thereafter.^56,103 Both serum copper and ceruloplasmin concentrations are markedly elevated, which differentiates this disease from Wilson disease. The incidence of the disease has fallen dramatically, probably as a result of improved nutrition and replacement of utensils and storage containers containing copper with those made of steel. A family of four developed abdominal pain, malaise, tachycardia, and anemia after approximately one month of eating homegrown vegetables treated with copper oxychloride pesticide.⁴⁴ Each patient had anemia and a high normal or slightly elevated serum copper concentration.

“Vineyard sprayer’s lung,” first described in 1969, refers to the occupational pulmonary disease that occurred among Portuguese vineyard workers applying Bordeaux solution, a 1% to 2% copper sulfate solution neutralized with hydrated lime (Ca(OH)₂).⁸⁹ The patients developed interstitial pulmonary fibrosis and histiocytic granulomas containing copper. Many of these workers also developed pulmonary adenocarcinoma, hepatic angiosarcoma, and micronodular cirrhosis, raising the possibility of a carcinogenic effect of chronic copper exposure.⁹⁰ There is also a suggestion of an increased incidence of pulmonary adenocarcinoma among smelters, who are, however, exposed to many other xenobiotics, including arsenic, a known carcinogen.⁷¹ Copper is not on the list of suspected carcinogens compiled by the International Agency of Research on Cancer.

Ophthalmic effects of copper salts, primarily following occupational exposure, include irritation of the corneal, conjunctival, or adnexal structures. Chronic ophthalmic exposure to particulate elemental copper or one of its alloys may result in chalcosis lentis, from the Greek word chalkos, or copper. This chronic exposure manifests as a green-brown discoloration of the lens or cornea, similar to Kayser-Fleischer rings.

Real-time testing for copper is impractical, and almost all management decisions must be based on clinical criteria. Copper concentrations are often obtained for confirmatory or investigative purposes. Although never adequately studied, whole-blood copper concentrations may correlate better with clinical findings than serum copper concentrations.²⁸ The rapid movement of copper from the serum into the erythrocyte presumably explains this finding. However, although there is a statistical relationship between the whole-blood copper concentrations and the severity of poisoning,^28,118 there is little correlation between clinical findings at any given copper concentration, regardless of which biologic tissue is measured. Similarly, other than at extremely high or low concentrations, there is no defined concentration at which the prognosis may be established with certainty. Reported serum copper concentrations in patients with hemolysis range from 96 to 747 μg/dL, and reported concentrations in patients with severe poisoning are 6600 μg/dL⁴³ and 8267 μg/dL.²⁷ Serum copper concentrations in 11 patients with copper-induced acute kidney failure ranged from 115 to 390 μg/dL.²⁵ The urinary copper excretion per 24 hours is up to approximately 25 μg under normal circumstances and is reportedly as high as 628 μg/24 h in patients with copper poisoning.

Occasionally, there is a secondary rise in serum copper concentrations, which likely results from release during hepatocellular necrosis. This secondary rise typically occurs in patients with life-threatening poisoning, and clinical evaluation is far more important and relevant than serial copper concentrations.¹⁰⁶

Elevated copper concentrations are also noted in patients with inflammatory conditions, biliary cirrhosis, pregnancy, and estrogenic oral contraceptive use.²¹ These conditions are associated with an elevated ceruloplasmin, and while the serum copper concentrations rise, the fraction of bound copper in the serum remains normal. Copper concentrations in the erythrocyte remain normal. Patients with Wilson disease have elevated hepatocyte copper content, but their serum copper concentrations are generally below normal unless hepatic necrosis is occurring.⁷²

Although serum ceruloplasmin concentrations rise in patients with acute copper poisoning,¹¹⁸ presumably reflecting increased hepatic synthesis, the ceruloplasmin concentration cannot be used to define prognosis. Tissue metallothionein concentrations may also rise following copper poisoning, but the implications of this finding, which is limited by the inability to rapidly obtain tissue samples, are unknown.⁶⁶ Ceruloplasmin concentrations are low in patients with Wilson disease, reflecting aberrant enzymatic activity.

Routine laboratory testing following acute copper salt poisoning should include an assessment for both intravascular hemolysis and hepatotoxicity. Differentiation of these etiologies as a cause for jaundice is made using standard methodologies, such as comparison of the bilirubin fractions and an assessment of the hepatic enzymes and hemoglobin; that is, indirect bilirubin is proportionally elevated in patients with hemolysis, whereas the direct fraction rises in patients with hepatocellular necrosis. The determination of intravascular hemolysis can be aided with the identification of a low serum haptoglobin or an elevated lactate dehydrogenase. An assessment of the patient’s electrolyte and hydration status is warranted. The prothrombin time may be prolonged in the absence of liver injury or disseminated intravascular coagulopathy as a direct effect of free copper ions on the coagulation cascade.⁸⁰ In addition, many reports document an abnormal glucose 6-phosphate dehydrogenase (G6PD) activity, suggesting causation for hemolysis. However, interpretation of G6PD activity is difficult, because copper poisoning interferes with the measurement of G6PD.

Although copper metal embedded in the skin is clearly visible on radiography, topically applied copper salts are not visualized.¹⁵ The clinical ­usefulness of radiographs to identify ingested copper solutions has not been studied. Obtaining an abdominal radiograph, while probably of limited benefit, may be justified, because it occasionally demonstrates the presence of radiopaque material in the gastrointestinal tract. Early efforts to use magnetic resonance imaging to identify Wilson disease are underway.^23,107

Supportive care is the cornerstone to the effective management of patients with acute copper poisoning, emphasizing antiemetic therapy, fluid and electrolyte correction, and normalization of vital signs prior to the consideration of chelation therapy. Gastrointestinal decontamination is of limited concern because the onset of emesis generally occurs within minutes of ingestion and is often protracted. In patients who present shortly after the ingestion of a liquid copper solution and who have not yet vomited, aspiration with a nasogastric tube may remove copper ions in solution or suspended in gastric materials. In one case, even after extensive vomiting, nasogastric aspiration still removed a blue solution, but removing this remaining volume is unlikely to provide significant clinical benefit.¹⁷ Although oral activated charcoal is unlikely to be harmful, it is of unproved benefit, and it may hinder the ability to perform gastrointestinal endoscopy to evaluate the corrosive effects of a copper salt on the mucosal surface.¹⁷ For this reason, even though activated charcoal may adsorb the remaining copper in the proximal gastrointestinal tract, it is relatively contraindicated in most situations. Advanced therapy for patients with kidney failure may include hemodialysis, and for patients with life-threatening hepatic failure, liver transplantation may be needed.

Chelation Therapy

Chelation therapy should be initiated when hepatic, hematologic complications, or other concerning or severe manifestations of poisoning are present. Studies on the efficacy of chelation therapy following acute copper salt poisoning are limited. Even when administered early and appropriately, organ damage and death still occur. Application of the data from the existing literature is complex because of the lack of controlled studies of human copper poisoning. Although animal models and uncontrolled human data exist, the results are frequently contradictory. Three chelators are clinically available, and most data regarding dosing and efficacy data are derived either from chelator use in the treatment of patients with Wilson disease or from their effects on copper elimination during chelation of patients manifesting toxicity from other metals.

Most patients with copper poisoning are initially treated with intramuscular British anti-Lewisite (BAL).¹¹³ Although BAL may be less effective, its use is appropriate in patients in whom vomiting or gastrointestinal injury prevents oral d-penicillamine administration. Furthermore, because the BAL–copper complex primarily undergoes biliary elimination, whereas d-penicillamine undergoes renal elimination, BAL proves useful in patients with kidney failure. When tolerated, d-penicillamine therapy should be started simultaneously or shortly after the initiation of therapy with BAL (Antidotes in Depth: A25).

Calcium disodium ethylenediaminetetraacetate (CaNa₂EDTA) reduces the oxidative damage induced by copper ions in experimental models.¹²³ However, it does not greatly enhance the elimination of copper when used for the chelation of other metals.¹¹⁴ In addition, short-term use of CaNa₂EDTA inactivates dopamine β-hydroxylase in humans, presumably by chelating the copper moiety from its active site.³² However, because the in vivo activity of this enzyme is restored following the addition of exogenous copper, the potential for inhibition of the formation of neuronal norepinephrine during the treatment of acute poisoning is unknown. Successful clinical use of CaNa₂EDTA is reported.^38,86,113 Interestingly, CuCaEDTA is used as a copper supplement in animals, and overdose of this formulation results in copper poisoning suggesting that its chelating ability is limited.³⁹ (See Antidotes in Depth: A27).

d-Penicillamine (Cuprimine), a structurally distinct metabolite of penicillin, is an orally bioavailable monothiol chelator. It is used in the treatment of lead, mercury, and copper toxicity, as well as in the management of rheumatoid arthritis and scleroderma. It has also more recently been investigated for its antiangiogenesis effects in cancer therapy, which occur by chelation of copper that serves as a cofactor for growth factors, such as fibroblast growth factor.¹¹⁵ d-Penicillamine is effective in preventing copper-induced hemolysis in patients with Wilson disease. Its protective mechanism is primarily mediated through chelation of unbound copper ions, rendering them unable to participate in redox reactions.⁶² The d-penicillamine–copper complex undergoes rapid renal clearance in patients with competent kidneys. The use of d-penicillamine is not formally studied in patients with acute copper salt poisoning, but case studies and animal models suggest that copper elimination is enhanced.^18,41,51 In patients with Wilson disease, it dramatically increases the urinary elimination.¹¹⁷ The recommended adult dose is 1 to 1.5 g/d given orally in four divided doses, and although formal pediatric dosing recommendations are not available, some recommend the adult dose and others suggest 20 mg/kg/d orally every 12 hours.⁴⁹ d-Penicillamine is also indicated for the treatment of chronic exogenous copper poisoning, such as Indian childhood cirrhosis. Initiation early in the course of disease and discontinuation of the exposure to copper are associated with hepatic recovery and dramatically improved survival rates.¹²

Although d-penicillamine appears to be effective, it is associated with several significant complications. In nearly 50% of patients treated with d-penicillamine for Wilson disease, there is worsening of the neurologic findings.²⁰ Subacute toxicities of d-penicillamine include aplastic anemia, agranulocytosis, kidney and lung toxicity, and loss of trace metals.⁵⁴ Long-term use of d-penicillamine is also associated with the development of cutaneous lesions and immunologic dysfunction. However, in the brief treatment necessary for acutely poisoned patients, the major risk is the potential for hypersensitivity reactions that occur in 25% of patients who are allergic to penicillin. This hypersensitivity reaction is likely related to contamination of the pharmaceutical preparation with penicillin, rather than immunologic cross-reactivity.^50,59 The use of d-penicillamine during pregnancy is associated with congenital abnormalities, although all of the data are derived from women with Wilson disease who were receiving long-term therapy.⁹¹

Succimer is sometimes described as an ineffective copper chelator, although it is able to triple the baseline copper elimination in a murine model. Given its ease of use, relative safety, and benefit in experimental models,¹ succimer may be used in lieu of d-penicillamine in patients with mild or moderate poisoning. Under these circumstances, the use of standard lead poisoning dosing regimens is warranted (Chap. 96 and Antidotes in Depth: A26).

DMPS, an experimental chelator that is gaining popularity for the treatment of arsenic poisoning, prevents acute tubular necrosis in copper-poisoned mice.⁷⁸ DMPS also proved to be the most effective of a panel of chelators in a murine model of copper sulfate poisoning,⁵⁸ and it substantially increased urinary copper elimination in nonpoisoned, healthy individuals.¹¹⁶ However, DMPS, unlike d-penicillamine, forms intramolecular disulfide bridges, which liberates an electron. Although this accounts for its potency as a reducing agent, it also probably explains its propensity to worsen copper-induced hemolysis in vitro.² Because an adequate analysis of risk versus benefit is unavailable, DMPS should not be used to chelate copper-poisoned patients at this time.

Trientine (triethylenetetramine), an orally bioavailable chelator, is the second-line therapy for patients with Wilson disease, but its use in patients with acute copper poisoning is unreported. It has recently been studied for its role as a copper chelator in patients with Alzheimer disease.³¹ Zinc therapy to induce metallothionine synthesis, which is also of proven efficacy in Wilson disease, has an unknown role in the treatment of acute copper poisoning. The need for several weeks of zinc therapy prior to realizing full efficacy makes its therapeutic use in acutely poisoned patients questionable. Although large oral doses of zinc salts may limit the absorption of copper ion, the concomitant gastrointestinal irritant effects of zinc ion make this therapy impractical.

Tetrathiomolybdate, an FDA-recognized chelator with orphan drug status although not marketed, may be available through compounding pharmacies, typically as ammonium tetrathiomolybdate. In uncontrolled studies, tetrathiomolybdate is suggested to benefit copper-poisoned animals,⁸⁸ but its use in acute copper poisoning in humans is unstudied. Tetrathiomolybdate depleted the copper stores in a patient with cancer who purchased the compound over the Internet as an “alternative” antiangiogenesis therapy.⁶⁷

Clioquinol, a xenobiotic used 50 years ago as an antiparasitic, was discontinued due to epidemic optic neuropathy that may have been associated with its ability to chelate copper ions.¹⁰² Clioquinol is currently under investigation as a therapy for Alzheimer disease,¹⁰ but it has not been studied for patients with acute or chronic copper poisoning.

Extracorporeal Elimination

Limited data exist regarding the elimination of copper ions by various extracorporeal means. Hemodialysis membranes undoubtedly allow copper ions to cross, based on the epidemics in which hemodialysis using copper-rich water inadvertently resulted in copper poisoning.³⁵ Although 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 hemodialysis would have little clinical usefulness. This fact is supported by case reports in which serum, tissue, or dialysate concentrations of copper are assessed.^4,86 Furthermore, given the propensity of hemodialysis to lyse erythrocytes, which may release stored copper and worsen toxicity, hemodialysis is not recommended except as indicated for kidney failure.

Molecular adsorbents recirculating system (MARS) and single-pass albumin dialysis (SPAD), modified forms of hemodialysis in which albumin is included in the dialysate, are reported to rapidly and substantially lower the serum copper concentrations in patients with fulminant Wilson disease, allowing a bridge to hepatic transplantation.^24,30 A single patient with Wilson disease was treated with albumin dialysis using a 44 g/L albumin-containing dialysate and a slow dialysate flow rate (1–2 L/h) in a manner similar to routine continuous venovenous hemodiafiltration; this reportedly removed 105 mg of copper and normalized the serum copper concentration.⁶³ The risk associated with hemolysis likely remains, and caution should be used when extrapolating therapy from Wilson disease to exogenous copper poisoning.

Exchange transfusion is of undefined, but probably limited, benefit in acute copper sulfate poisoning.^73,124 Plasma exchange enhanced the elimination of copper in patients with fulminant Wilson disease.^61,63 Copper removal ranged from 3 to 12 mg per treatment, but it is unclear if either of these removal techniques would be beneficial following an ingestion of gram quantities of copper sulfate. The same warning as above about inadvertent red cell lysis applies.

Peritoneal dialysis is not useful in patients with fulminant Wilson disease.⁶⁵ Peritoneal dialysis removed less than 700 μg in a copper sulfate–poisoned child whose copper concentration was 207 μg/dL.⁴⁶ However, in the same patient, the addition of albumin to the dialysate removed 9 mg of copper at a time when the child’s serum copper concentration had already fallen substantially.

Management of the hepatic toxicity requires little more than standard supportive care. The potential benefit of N-acetylcysteine has not been studied, although it is useful in many forms of fulminant hepatic failure and is warranted in most hepatotoxic patients. Liver transplantation should be considered, but specific criteria for transfer to a specialized liver unit or for transplant, other than those that are applicable for Wilson disease or other more common etiologies of fulminant hepatic failure, are undefined.

There are no controlled data on the treatment of acute copper poisoning in pregnancy. The available data on pregnant women with Wilson disease document that d-penicillamine is teratogenic and that zinc may be the preferred therapy.

• The toxic effects of copper are primarily mediated by oxidative stress on the erythrocyte and hepatocyte, and this similarity to iron salt poisoning adds a framework for the conceptual understanding of the disease.

• Chelation is most commonly performed with BAL and d-penicillamine.

• Succimer is more familiar to most clinicians and has fewer associated adverse effects; therefore, it is an acceptable alternative.

• Extracorporeal elimination is unlikely to be of benefit. Fortunately, exhaustive research into diseases of copper metabolism, particularly Wilson disease, which has periodic exacerbations similar to acute copper poisoning, has provided insight into managing patients with acute copper salt poisoning.

References