Continuing Education Activity

Copper toxicity arises when copper accumulates beyond physiologic needs, disrupting cellular and organ function. While copper plays a critical role in enzymatic reactions, connective tissue formation, and neurologic processes, excess levels can trigger oxidative stress, mitochondrial injury, and multi-organ damage. Clinical manifestations may range from gastrointestinal distress to hepatic failure and neuropsychiatric symptoms, depending on the severity and duration of exposure. Causes include genetic disorders such as Wilson’s disease, excessive supplementation, and environmental or occupational exposure. Timely diagnosis, guided by clinical suspicion and laboratory testing, is crucial for mitigating complications and reducing long-term morbidity.

Through this course, participants gain a comprehensive understanding of copper metabolism, clinical presentation, diagnostic strategies, and therapeutic approaches to copper toxicity. The content underscores the importance of interprofessional collaboration among internists, hepatologists, neurologists, pharmacists, dietitians, and laboratory specialists. By coordinating patient education, monitoring, chelation therapy, and dietary adjustments, the healthcare team provides integrated, evidence-based care. This collaborative model improves early detection, tailors interventions to individual risk, and ultimately enhances patient safety and treatment outcomes.

Objectives:

• Evaluate the importance of early recognition of copper toxicity in improving patient outcomes.
• Identify the potential risk factors for copper toxicity.
• Compare the first and second-line treatments available to patients with copper toxicity.
• Describe how comprehensive, high-quality patient education delivered by an interprofessional team plays a critical role in preventing copper toxicity and reducing related complications.

Introduction

Copper is a trace element (minerals required in amounts of 1 to 100 mg/day by adults) found in high concentrations in the brain, liver, and kidneys. However, because of their size, bone and muscle contain more than half of the copper in the body.[1] Copper is bound to ceruloplasmin in the liver, which transports the copper from the liver to the peripheral tissues. Approximately 50% of copper is excreted in the bile, while the remaining half is excreted through other gastrointestinal secretions.[2] As such, the gastrointestinal tract is the major regulator of copper homeostasis.

While copper is required as an important catalytic cofactor in redox chemistry for many proteins, when present in excess, free copper ions can cause damage to cellular components. A delicate balance between the uptake and efflux of copper ions determines the amount of cellular copper.[3] Excess copper induces not only oxidative stress but also DNA damage and reduced cell proliferation.[4] Ingestion of more than 1 g of copper sulfate results in symptoms of toxicity. Copper toxicosis can be classified as primary when it results from an inherited metabolic defect and secondary when it results from high intake, increased absorption, or reduced excretion due to underlying pathologic processes.[5] Copper toxicity (copperidus) can be caused by consuming acidic foods cooked in uncoated copper cookware or exposure to excess copper in drinking water or other environmental sources.

Etiology

Many instances of copper toxicity are often the result of accidental consumption or installation of contaminated water sources, copper salt-containing topical creams for burn treatments, acidic foods cooked in uncoated copper cookware, or in suicide attempts; the lethal dose of ingested copper is 10-20 g. Copper sulfate is a readily available chemical in many countries and is often sold over-the-counter. It is commonly used in farming as a pesticide in the leather industry and for making homemade glue. The burning of copper sulfate in houses and shops (as a good luck charm and for some religious activities) is a common practice among Buddhists and Hindus. The bright blue color of the hydrated form of copper sulfate crystals is alluring to children and is a frequent reason for inadvertent poisoning.[6] Wilson disease is an autosomal recessive disorder characterized by excessive copper accumulation, resulting from a mutation in the gene encoding a copper-ATPase enzyme.[7] Copper in the blood exists in 2 forms: bound to ceruloplasmin (85% to 95%), and the rest "free," loosely bound to albumin and other small molecules.

Epidemiology

The incidence of copper poisoning varies largely by region, but it is uncommon in Western countries; it is more common in South Asian countries, where it is more prevalent in rural populations. Copper toxicity risks are higher for neonates and infants as they have an immature biliary excretion system and enhanced intestinal absorption.[1] Copper overload is also a feature of Indian childhood cirrhosis, endemic Tyrolean infantile cirrhosis, and idiopathic copper toxicosis.[8]

History and Physical

Signs of overt acute copper toxicity depend somewhat on the mode of copper overload, with ingestions presenting most commonly with gastrointestinal side effects such as abdominal pain, hematemesis, melena, jaundice, anorexia, severe thirst, diarrhea, and vomiting associated with erosive gastropathy.[6] Evidence of characteristic blue-green material in emesis/stool is highly suggestive. Altered mentation, headache, coma, and tachycardia may also accompany GI side effects.[9] Patients with an intravascular mode of copper toxicity (ie, contaminated hemodialysis fluid infusion) can present with signs/symptoms of intravascular hemolysis, and individuals with glucose-6-phosphate deficiency are at higher risk for the hematologic adverse effects of copper. Neurological symptoms such as depression, fatigue, irritability, excitation, and difficulty focusing are reported too. In most severe forms, copper toxicity leads to rhabdomyolysis, cardiac and renal failure, methemoglobinemia, intravascular hemolysis, hepatic necrosis, encephalopathy, and ultimately death.[10]

Evaluation

Measurement of urine and blood copper levels, in addition to serum ceruloplasmin levels, remains the mainstay of initial evaluations for copper toxicity if a history and physical exam raise clinical suspicion.[11] Fecal evaluation of copper levels may also be obtained in the evaluation of acute copper poisoning. Other laboratory evaluative tests include measures of kidney function, hemolysis, and liver damage (namely liver function tests, including ASL/ALT, which are likely to be increased). During a hemolytic crisis, methemoglobinemia, other measures of RBC lysis, and decreased blood glutathione levels are often observed.[12]

Treatment / Management

The therapeutic management of copper toxicity focuses on 4 major principles: reduction of absorption, close observation, supportive measures to manage complications, and chelation therapy.[10][13] In the early stages, pharmacologic doses of zinc may be effective in delaying the onset of symptomatic disease because zinc competes with copper for absorption in the gastrointestinal tract. Zinc also induces metallothionein (an endogenous chelator of metals) in enterocytes, which has a greater affinity for copper than for zinc, causing it to bind luminal copper and thereby preventing its entry into the circulation.[3] 

D-penicillamine is the primary chelator used in the treatment of copper toxicity, although ethylenediaminetetraacetic acid (EDTA) and dimercaptopropanesulfonic acid (DMPS) may also be used for the treatment of heavy metal toxicity, including copper.[14] However, approximately 30% of patients do not tolerate long-term therapy because of side effects, and it may not be the treatment of choice in patients with neurologic symptoms. Trientine has traditionally been used as a second-line agent for those intolerant of D-penicillamine to enhance cupriuresis. A liver transplant may be necessary in severe cases, although liver transplantation is not recommended for patients with neurological and psychiatric symptoms.[13] Ammonium tetrathiomolybdate is another potential therapy but has not yet been approved in the US. In severe cases, plasmapheresis, exchange transfusion, molecular adsorbent recirculating system (MARS), or dialysis may be required as bridges to transplant if a transplant is deemed necessary.

Differential Diagnosis

Other heavy metal toxicities may present similarly and also must be ruled out. In children, chronic copper toxicity may be phenotypically very similar to Pink disease (infantile acrodynia).[15]

Prognosis

Prognosis is poor if not treated promptly with chelation and supportive measures, as 14% to 36% of the patients pass away within a few hours of a toxic ingestion.[10] However, with prompt and effective management, the neurologic, psychiatric, and hepatic abnormalities gradually improve with treatment, and liver biochemical test results usually return to normal.

Complications

Ingestion may lead to the formation of strictures throughout the gastrointestinal tract. Acute liver failure can occur due to direct copper toxicity-induced tissue necrosis.[6] Whether patients are at increased risk of hepatocellular carcinoma is not clear, but to date, no study has yet shown an increase in hepatocellular carcinoma attributable to copper ingestion.

Deterrence and Patient Education

Stopping the over-the-counter sale of copper sulfate and restricting its purchase, distribution, and sale to authorized agents is crucial in reducing the incidence of copper toxicity. Alternatively, the over-the-counter availability of copper sulfate may be limited to large crystals, as cases of poisoning are usually due to the inadvertent/intentional dissolution of the fine, powder-like form of the compound.[6] Copper is an essential nutrient added to infant formula and is also found in breast milk. An increase in copper breast milk concentrations has not been observed following the insertion of the copper intrauterine device. As such, the use of a copper IUD is not expected to impact lactation and is considered compatible with breastfeeding.[16]

Enhancing Healthcare Team Outcomes

Treatment is most effective when it is applied early in the course of the encounter. This necessitates that all interprofessional healthcare team members, including clinicians, mid-level practitioners, nurses, and pharmacists, be familiar with identifying the signs and symptoms of copper toxicity and take action to initiate prompt treatment and management of the patient's condition, resulting in better outcomes. Patients at higher risk (ie, those with Wilson disease) should receive education on modes of excessive copper exposure, strategies for avoiding excessive copper intake, and signs and symptoms that may be concerning for worsening copper overload. Screening siblings and children of patients with Wilson disease may help identify those at higher risk.

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References

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Hordyjewska A, Popiołek Ł, Kocot J. The many "faces" of copper in medicine and treatment. Biometals. 2014 Aug;27(4):611-21. [PMC free article: PMC4113679] [PubMed: 24748564]

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Malkarnekar SB, Anjanappa R, Naveen L, Kiran BG. Acute methemoglobinemia with hemolytic anemia following bio-organic plant nutrient compound exposure: Two case reports. Indian J Crit Care Med. 2014 Feb;18(2):115-7. [PMC free article: PMC3943120] [PubMed: 24678158]

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Murray KF, Carithers RL., AASLD. AASLD practice guidelines: Evaluation of the patient for liver transplantation. Hepatology. 2005 Jun;41(6):1407-32. [PubMed: 15880505]

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Sinkovic A, Strdin A, Svensek F. Severe acute copper sulphate poisoning: a case report. Arh Hig Rada Toksikol. 2008 Mar;59(1):31-5. [PubMed: 18407869]

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Salmon MA, Wright T. Chronic copper poisoning presenting as pink disease. Arch Dis Child. 1971 Feb;46(245):108-10. [PMC free article: PMC1647565] [PubMed: 5555482]

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Berens P, Labbok M., Academy of Breastfeeding Medicine. ABM Clinical Protocol #13: Contraception During Breastfeeding, Revised 2015. Breastfeed Med. 2015 Jan-Feb;10(1):3-12. [PubMed: 25551519]

Disclosure: Amor Royer declares no relevant financial relationships with ineligible companies.

Disclosure: Tariq Sharman declares no relevant financial relationships with ineligible companies.