Continuing Education Activity

Copper metabolism plays an important role in physiologic homeostasis. Copper toxicity, however, induces several pathologic processes that are detrimental to human health. This discussion highlights the role of the interprofessional team in managing patients with this condition.

Objectives:

• Describe the importance of early recognition of copper toxicity in regards to improving patient outcomes.
• Outline the potential risk factors for copper toxicity.
• Review the first and second-line treatments available to patients with copper toxicity.
• Explain the importance of improving patient education by an interprofessional team to enhance the prevention of copper toxicity.

Introduction

Copper is a trace element (minerals required in amounts 1 to 100 mg/day by adults) found in high concentrations in the brain, liver, and kidney. 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 percent 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 or increased absorption or reduced excretion due to underlying pathologic processes.[5] Copperiedus (copper toxicity) 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 to 20 g). Copper sulfate is an easily accessible chemical in many countries and is even sold over the counter. It is commonly used in farming as a pesticide in the leather industry and making home-made 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 and is caused by a variant in the gene encoding a copper-ATPase enzyme.[7] Copper in the blood exists in two 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 (i.e., 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 remain the mainstay of copper toxicity initial evaluations if 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 will likely be increased). During the hemolytic crisis, methemoglobinemia, other measures of RBC lysis, and decreased blood glutathione are often seen.[12]

Treatment / Management

The therapeutic management of copper toxicity focuses on 4 major principles: Reduction of absorption, close observation, supportive measures with the management of complications, and chelation therapy.[13][10] 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 copper toxicity, although EDTA (Ethylenediaminetetraacetic acid) and DMPS (dimercaptopropanesulfonic acid) may also be used for heavy metal toxicity with copper.[14] However, approximately 30 percent 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 stricture formation 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 (HCC) is not clear, but to date, no study has yet shown an increase in HCC attributable to copper ingestion.

Deterrence and Patient Education

Stopping the over-the-counter sale of copper sulfate and the restriction of purchase, distribution, and sale to authorized agents is important in decreasing the incidence of copper toxicity. Alternatively, over-the-counter availability of copper sulfate can be limited to large crystals as cases of poisoning are usually due to inadvertent/intentional dissolving of the fine powder-like pulverized form of the compound.[6] Copper is an additive to infant formula and can be 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. [Level 5]

Patients at higher risk (i.e., those with Wilson disease) should receive education on modes of excessive copper exposure, avoidance of excessive copper intake, and signs and symptoms that may be concerning for worsening copper overload. Screening of siblings and children of patients with Wilson disease may elucidate those at higher risk.