Copper toxicity

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
• Uses
  • Pipes
  • Cookware
  • Electrical wire
  • Medical devices (copper IUD)
  • Dietary supplements
  • Bordeaux solution (used as a pesticide)
• Seen in Wilson disease

Toxicokinetics

• Absorbed in the GI tract
  • Bound by ceruoplasmin
• Elimination via biliary system
  • Minimal renal elimination
• V_D : 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 CV collapse
    • Likely multifactorial
• Chronic
  • Wilson disease
  • CNS
    • Ataxia
    • Tremor
    • Parkinsonism
    • Dysphagia
    • Dystonia
  • Behavioral
    • Mood changes
  • Occular
    • Kayser-Fleischer rings

Differential Diagnosis

Heavy metal toxicity

• Aluminum toxicity
• 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

• Clinical diagnosis, as copper levels will likely take days to result
• BMP
• Hepatic function tests
• CBC
• PT/PTT/INR
• Copper level
  • No set number that establishes a prognosis
• Ceruloplasmin level
• Abdominal films to assess for foreign bodies
• Levels
  • 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

• Consult Toxicology or Poison Control Center

References

Nelson, L. Gold. In: Goldfrank's Toxicologic Emergencies. 9th Ed. New York: McGraw-Hill; 2011: 1256-1265