Copper toxicity

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Background

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

Differential Diagnosis

Also seen in Wilson disease

Heavy metal toxicity

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

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