Copper toxicity: Difference between revisions

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==Background==
==Background==
*Transition metal
[[File:Kupferfittings 4062.jpg|thumb|Copper piping.]]
*Essential nutrient
[[File:Copper wire comparison.jpg|thumb|Unoxidized copper wire (left) and oxidized copper wire (right)]]
*Exposure from diet, medicinal uses, nutritional supplements, and occupational exposures
*Widely available metal
**Multiple case reports of zinc toxicity related to ingestion of United States pennies which contain 97.5% zinc
*Obtained from various foods including nuts, fish, and green vegetables
==Toxicokinetics==
*Numerous poisonings from copper pipes
*Absorbed primarily in the jejunum
**Occurs from storage of acidic substances (lemon/orange juice), pipes exposed to carbon dioxide from carbonation process, stagnant, and hot water which leach out copper from pipes
*Excreted via the GI tract with minimal amounts excreted in the urine
 
*Accumulates in erythrocytes
===Copper Uses===
**Whole blood concentrations are 6-7x higher than in the serum
*Pipes
*Inverse relationship with copper
*Cookware
**Excess zinc absorption will cause a counterregulatory response resulting in copper elimination
*Electrical wire
*Medical devices (copper IUD)
*Dietary supplements
*Bordeaux solution (used as a pesticide)
 
===Toxicokinetics===
*Absorbed in the GI tract
**Bound by ceruoplasmin
*Elimination via biliary system
**Minimal renal elimination
*V<sub>D</sub> : 2L/kg
*Copper sulfate
**Most common acute poisoning
**Lethal dose is 0.15-0.3g/kg
*Toxicity is caused through redox reactions
**Fenton reaction
**Haber-Weiss cycle
**Generates oxidative stress, inhibiting key metabolic enzymes, particularly in cell membranes and mitochondria
*Organ specific damage
**Erythrocytes
***Membran dysfunction resulting in hemolysis
***Occurs within the first 24 hours
**Hepatic
***Excess copper not bound by metallothionein participates in redox reactions and cause lipid peroxidation
***Centrilobular necrosis
***After necrosis there is a release of massive amounts of copper into the blood causing a secondary hemolysis
**Renal
***ATN with hemoglobin casts, likely from hemolysis
 
==Clinical Features==
==Clinical Features==
*'''Acute'''
===Acute===
**GI distress
*GI irritation
***Nausea
**Emesis (may be blue based on copper compound, but is not pathognomonic)
***Vomiting
**Abdominal pain
***Abdominal pain
**Gastroduodenal hemorrhage, ulceration, and perforation
***GI bleeding
**Metallic taste
***Partial and full thickness burns causing strictures with zinc chloride solutions with >20% zinc
*Hepatic
**Inhalation
**Jaundice
***Lacrimation
*Hematologic
***Rhinitis
**Hemolysis
***Dyspnea
**May see methemoglobinemia
***[[Acute Lung Injury]]
*Renal
***[[Acute Respiratory Distress Syndrome]]
**Renal failure uncommon
***[[Metal fume fever]]
*Hypotension and cardiovascular collapse
*'''Chronic'''
**Likely multifactorial
**Zinc induced copper deficiency
 
***Reversible [[sideroblastic anemia]]
===Chronic===
***Reversible [[myelodysplastic syndrome]]
*[[Wilson's disease]]
**Progressive myeloneuropathy
*CNS
***Spastic gait
**Ataxia
***Sensory ataxia
**Tremor
**Parkinsonism
**Dysphagia
**Dystonia
*Behavioral
**Mood changes
*Occular
**Kayser-Fleischer rings
 
==Differential Diagnosis==
==Differential Diagnosis==
===[[Heavy metal]] toxicity===
''Also seen in [[Wilson's disease]]''
*[[Aluminum toxicity]]
{{Heavy metals list}}
*[[Antimony toxicity]]
 
*[[Arsenic toxicity]]
*[[Barium toxicity]]
*[[Bismuth toxicity]]
*[[Cadmium toxicity]]
*[[Chromium toxicity]]
*[[Cobalt toxicity]]
*[[Copper toxicity]]
*[[Gold toxicity]]
*[[Iron toxicity]]
*[[Lead toxicity]]
*[[Lithium toxicity]]
*[[Manganese toxicity]]
*[[Mercury toxicity]]
*[[Nickel toxicity]]
*[[Phosphorous toxicity]]
*[[Platinum toxicity]]
*[[Selenium toxicity]]
*[[Silver toxicity]]
*[[Thallium toxicity]]
*[[Tin toxicity]]
*[[Zinc toxicity]]
==Evaluation==
==Evaluation==
''Clinical diagnosis, as copper levels will likely take days to result''
*BMP
*BMP
*Hepatic function tests
*CBC
*CBC
*Copper level
*PT/PTT/INR
*Ceruloplasmin level
*Copper and ceruloplasmin level
*Abdominal films to assess for foreign bodies
*Abdominal films to assess for foreign bodies
*MRI
 
**Will show increase T<sub>2</sub> signal in the dorsal columns of the cervical cord
===Copper level===
''No set number that establishes a prognosis <ref> Gulliver JM. A fatal copper sulfate poisoning. J Anal Toxicol. 1991;15: 341-342. </ref>''
*Whole blood = 70–140 μg/dL (11–22 μmol/L)
*Total serum = 120–145 μg/dL (18.8–22.8 μmol/L)
*Free serum  = 4–7 μg/dL (0.63–1.1 μmol/L)
*Ceruloplasmin = 25–50 μg/dL (3.9–7.8 μmol/L)
*Urine = 5–25 μg/24 h (.078–3.9 nmol/L)
 
==Management==
==Management==
*Oral toxicity
===Supportive care===
**Supportive Care
*Antiemetics
***Hydration
*Fluid and electrolyte repletion
***H<sub>2</sub> receptor antagonists or PPI
*GI decontamination unlikely to benefit
***Antiemetics
*Activated charcoal contraindicated
**Consider whole bowel irrigation
 
*Inhalation
===Chelation===
**Supportive care
''Recommended in cases with hematologic or hepatic complications''
***Oxygen therapy
*Most commonly used are BAL and D-penicillamine
***Bronchodilators
*[[British anti-Lewisite]] (BAL)
**Metal fume fever
**Beneficial in patients with vomiting who are unable to take D-penicillamine
***Usually self limiting
**Useful in those with renal failure
***CXR usually normal
*D-penicillamine
*Chelation
**Should be started as soon as able to tolerate PO
**Limited data on use, and data present is based off of case reports and treatment for lead toxicity <ref>Majlesi, N. Zinc. In: Goldfrank's Toxicologic Emergencies. 9th Ed. New York: McGraw-Hill; 2011: 1342</ref>
**Begin simultaneously with BAL or soon after
**Consider in patients with hemodynamic compromise
**Prevents copper induced hemolysis in patients with wilson disease
**CaNa<sub>2</sub>EDTA, British anti-Lewisite, DTPA were all successfully used in case reports
**Undergoes renal clearance
**1000mg/m<sup>2</sup>/d IV CaNa<sub>2</sub>EDTA every 6 hours
**'''1.0-1.5 g/d given PO in 4 divided doses'''
***Based on a successful case report, but should be given in conjunction with toxicology or poison control center
**Can be used for acute and chronic copper poisoning
*Dermal Exposures
**Complications
**Do not use water in metallic zinc exposures
***Worsening of neurologic findings
***Concern metal will ignite
***Aplastic anemia
**Remove zinc with forceps and apply mineral oil to affected skin
***Agranulocytosis
*Copper replacement
***Renal and pulmonary disease
**Oral copper alone shown to improve hematopoietic effects and prevent further neurological deterioration <ref> Rowin J, Lewis SL. Copper deficiency myeloneuropathy and pancytopenia secondary to overuse of zinc supplementation. J Neurol Neurosurg Psychiatry. 2005;76:750-751. </ref>
***Hypersensitivity reactions in 25% of patients with pencillin allergies
***Congenital abnormaliies in pregnenancy
*CaNa<sub>2</sub>EDTA
**Will reduce oxidative damage
**Does not enhance elimination
*[[Succimer]]
**Ineffective copper chelator 
**Does increase copper elimination in murine models
**Dose is the same as lead dosing
*DMPS
**Not recommended for treatment of copper poisoning
**Can worsen copper induced hemolysis
*[[Trientine]]
**Second line chelator for wilson disease
**No reports in acute copper poisoning
*Tetrathiomolybdate
**FDA chelating agent with orphan drug status
**No human studies but showed benefits in animal models
 
===Extracorporeal Elimination===
''Unlikely to benefit''
*Exchange transfustion
**Limited benefit
*Hemodialysis
**Not recommended
**Membranes allow copper ions to cross
**Unlikely to be clinnicall useful
**May also lyse erythrocytes release stored copper causing worsening toxicity
*Molecular adsorbents recirculating system (MARS) and Single Pass Albumin Dialysis (SPAD)
**Rapidly and substantially lower serum copper concentraions
**Risk of hemolysis
*Plasma Exchange
**Enhanced elimination of copper by 3-12 mg
**Unclear if benficial after large ingestions
**Risk of hemolysis
*Peritoneal Dialysis
**Not useful
 
==Disposition==
==Disposition==
*Consult Toxicology or Poison Control Center
*Consult Toxicology or [[poison control]]
 
==Medication Dosing==
{{MedicationDose
| drug = Penicillamine
| dose = 1-1.5g/day PO in 4 divided doses
| route = PO
| context = Oral chelation
| indication = Copper toxicity
| population = Adult
}}
 
==See Also==
*[[Toxicology (main)]]
*[[Heavy Metals]]
 
==References==
==References==
<references/>
<references/>
Majlesi, N. Zinc. In: Goldfrank's Toxicologic Emergencies. 9th Ed. New York: McGraw-Hill; 2011: 1339-1344
*Nelson, L. Copper. In: Goldfrank's Toxicologic Emergencies. 9th Ed. New York: McGraw-Hill; 2011: 1256-1265
 
[[Category:Toxicology]]

Latest revision as of 21:22, 20 March 2026

Background

Copper piping.
Unoxidized copper wire (left) and oxidized copper wire (right)
  • Widely available metal
  • Obtained from various foods including nuts, fish, and green vegetables
  • Numerous poisonings from copper pipes
    • Occurs from storage of acidic substances (lemon/orange juice), pipes exposed to carbon dioxide from carbonation process, stagnant, and hot water which leach out copper from pipes

Copper Uses

  • Pipes
  • Cookware
  • Electrical wire
  • Medical devices (copper IUD)
  • Dietary supplements
  • Bordeaux solution (used as a pesticide)

Toxicokinetics

  • Absorbed in the GI tract
    • Bound by ceruoplasmin
  • Elimination via biliary system
    • Minimal renal elimination
  • VD : 2L/kg
  • Copper sulfate
    • Most common acute poisoning
    • Lethal dose is 0.15-0.3g/kg
  • Toxicity is caused through redox reactions
    • Fenton reaction
    • Haber-Weiss cycle
    • Generates oxidative stress, inhibiting key metabolic enzymes, particularly in cell membranes and mitochondria
  • Organ specific damage
    • Erythrocytes
      • Membran dysfunction resulting in hemolysis
      • Occurs within the first 24 hours
    • Hepatic
      • Excess copper not bound by metallothionein participates in redox reactions and cause lipid peroxidation
      • Centrilobular necrosis
      • After necrosis there is a release of massive amounts of copper into the blood causing a secondary hemolysis
    • Renal
      • ATN with hemoglobin casts, likely from hemolysis

Clinical Features

Acute

  • GI irritation
    • Emesis (may be blue based on copper compound, but is not pathognomonic)
    • Abdominal pain
    • Gastroduodenal hemorrhage, ulceration, and perforation
    • Metallic taste
  • Hepatic
    • Jaundice
  • Hematologic
    • Hemolysis
    • May see methemoglobinemia
  • Renal
    • Renal failure uncommon
  • Hypotension and cardiovascular collapse
    • Likely multifactorial

Chronic

  • Wilson's disease
  • CNS
    • Ataxia
    • Tremor
    • Parkinsonism
    • Dysphagia
    • Dystonia
  • Behavioral
    • Mood changes
  • Occular
    • Kayser-Fleischer rings

Differential Diagnosis

Also seen in Wilson's disease

Evaluation

Clinical diagnosis, as copper levels will likely take days to result

  • BMP
  • Hepatic function tests
  • CBC
  • PT/PTT/INR
  • Copper and ceruloplasmin level
  • Abdominal films to assess for foreign bodies

Copper level

No set number that establishes a prognosis [1]

  • Whole blood = 70–140 μg/dL (11–22 μmol/L)
  • Total serum = 120–145 μg/dL (18.8–22.8 μmol/L)
  • Free serum = 4–7 μg/dL (0.63–1.1 μmol/L)
  • Ceruloplasmin = 25–50 μg/dL (3.9–7.8 μmol/L)
  • Urine = 5–25 μg/24 h (.078–3.9 nmol/L)

Management

Supportive care

  • Antiemetics
  • Fluid and electrolyte repletion
  • GI decontamination unlikely to benefit
  • Activated charcoal contraindicated

Chelation

Recommended in cases with hematologic or hepatic complications

  • Most commonly used are BAL and D-penicillamine
  • British anti-Lewisite (BAL)
    • Beneficial in patients with vomiting who are unable to take D-penicillamine
    • Useful in those with renal failure
  • D-penicillamine
    • Should be started as soon as able to tolerate PO
    • Begin simultaneously with BAL or soon after
    • Prevents copper induced hemolysis in patients with wilson disease
    • Undergoes renal clearance
    • 1.0-1.5 g/d given PO in 4 divided doses
    • Can be used for acute and chronic copper poisoning
    • Complications
      • Worsening of neurologic findings
      • Aplastic anemia
      • Agranulocytosis
      • Renal and pulmonary disease
      • Hypersensitivity reactions in 25% of patients with pencillin allergies
      • Congenital abnormaliies in pregnenancy
  • CaNa2EDTA
    • Will reduce oxidative damage
    • Does not enhance elimination
  • Succimer
    • Ineffective copper chelator
    • Does increase copper elimination in murine models
    • Dose is the same as lead dosing
  • DMPS
    • Not recommended for treatment of copper poisoning
    • Can worsen copper induced hemolysis
  • Trientine
    • Second line chelator for wilson disease
    • No reports in acute copper poisoning
  • Tetrathiomolybdate
    • FDA chelating agent with orphan drug status
    • No human studies but showed benefits in animal models

Extracorporeal Elimination

Unlikely to benefit

  • Exchange transfustion
    • Limited benefit
  • Hemodialysis
    • Not recommended
    • Membranes allow copper ions to cross
    • Unlikely to be clinnicall useful
    • May also lyse erythrocytes release stored copper causing worsening toxicity
  • Molecular adsorbents recirculating system (MARS) and Single Pass Albumin Dialysis (SPAD)
    • Rapidly and substantially lower serum copper concentraions
    • Risk of hemolysis
  • Plasma Exchange
    • Enhanced elimination of copper by 3-12 mg
    • Unclear if benficial after large ingestions
    • Risk of hemolysis
  • Peritoneal Dialysis
    • Not useful

Disposition

Medication Dosing

Penicillamine 1-1.5g/day PO in 4 divided doses PO

See Also

References

  1. ↑ Gulliver JM. A fatal copper sulfate poisoning. J Anal Toxicol. 1991;15: 341-342.
  • Nelson, L. Copper. In: Goldfrank's Toxicologic Emergencies. 9th Ed. New York: McGraw-Hill; 2011: 1256-1265
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