Copper Quiz

Correct: Copper sulfate ointments and solutions were used to assist with wound debridement up until the 1960’s. Treatments with copper sulfate for burns were well documented to cause hemolysis. Their use eventually fell out of common practice.

Wrong answers: The first answer is incorrect because copper sulfide is an ore precursor used in the smelting and purification process of Copper ores. It has no known medical role. However, historically smelter-workers are exposed to arsenic fumes that were contaminants to the copper sulfide ore slurry. The second answer is incorrect because copper sulfate induced emesis was rapidly identified to be dangerous and therefore quickly removed from quackery medical practice. Although, the third answer seems plausible, it is neither true or is a significant cause of iatrogenic copper toxicity.

Of the following chemical compositions, only copper sulfate has a remarkable blue appearance that is typical of this substance. Copper sulfate is currently mostly used for maintenance of septic tank systems, specifically to remove invading roots. The other copper containing compounds range from black to deep red, but certainly are not this remarkable color.

Correct: Hot water and an acidic environment lead to leaching of copper from copper pipes. This is especially true in instances where carbonated fluid back-flows into a copper pipe near a heat source. Case reports have demonstrated significantly elevated copper levels.

Incorrect answers: High temperature cooking with copper alloys actually forms a copper carbonate barrier that is insoluble. Himalayan sea salt likely does not have enough copper to cause significant toxicity. A hardened stainless steal spoon could gouge elemental copper, but when used for cooking copper forms a copper carbonate impermeable layer that would make significant mechanical shaving of copper into food highly unlikely. Owing to the low temperature of “Moscow Mules”, it is unlikely the alcohol content or citric acid contained within the lime juice would lead to significant leaching of copper.

Correct: The cupric form of copper (Cu++) readily dissolves in water.

Incorrect: Elemental copper has no charge does not easily dissolve. One must consider that in copper alloy piping and cook wear, there is an equilibrium between soluble and insoluble copper compounds and the surface of the metal. But, this equilibrium highly disfavors solubility. Although cuprous copper (Cu+) is water soluble, it is unstable and is rapidly oxidized to cupric copper. Cu+++ is a theoretical valence state not isolated in nature.

Correct: The most common of copper deficiency is zinc excess, which impairs intestinal absorption of copper.

Incorrect: Dietary copper deficiency is exceedingly rare. The majority of people obtain the 1 mg daily required copper from their drinking water. Zinc excess, not deficiency is the most frequent cause of copper deficiency. Menke’s disease is an X-linked congenital condition due to a deficiency of the CuATPase in the gut lumen. Therefore, male children with Menke’s disease are unable to absorb sufficient amounts of copper. They develop characteristic “kink, brittle hair”, severe developmental delay, and succumb to their illness by the ages of 3-10.

Correct: During the initial phase of a copper overdose because copper is being reduced by vitamin C during transport in hepatocytes. Furthermore, ceruloplasmin binding sites have a low Kd for copper become saturated quickly, which means there is a higher fraction bound to albumin and in the serum, compared with post oxidation and distribution.

Incorrect: Cu++ is much more widely distributed, protein bound, and much more difficult to chelate, at least when compared to Cu+. Copper, as with most metals, are more difficult to chelate once they are distributed to the tissues. The final answer is incorrect because it may take many days for the level to result. Especially if chelation should be initiated in the acute phase, the medical toxicologist should not wait to chelate if the ingestion is reasonably verifiable and dangerous.

Correct: Matrixmetalloproteinases require zinc for their active sites.

Incorrect: All of the other enzymes have been shown to require copper as a cofactor. Interestingly, deficiency in these enzymes is likely responsible for Menke’s disease.

Correct: The vast majority of copper is excreted into the feces through the biliary tree after it has complexed with ceruloplasmin.

Incorrect: Copper is excreted, unlikely mercury or lead, so the body is able to effectively eliminate excess copper through endogenous chelation with ceruloplasmin. Copper is not secreted directly into the gut lumen. Perspiration occurs with eccrine glands and not apocrine glands; furthermore, neither are a route for copper elimination. Copper does not have a significant renal clearance.

Correct: Sulfhydryl containing compounds such as glutathione and the chelator, DMSP, have been shown to increase the rate of Cu++ reduction to Cu+. This is important because it allows for the production of reaction oxygen species via the Haber-Weiss and Fenton reactions.

Incorrection. Cytochrom C oxidase is incorrect because it does not reduce Cu++. Although methylene blue could theoretically reduce Cu++, data surrounding its inadvertent application to worsen copper toxicity are limited. Although NADPH and NADH are electron donors, they do not directly reduce Cu++.

Correct: During massive absorptions, copper induces creation of free radical species, depletion of glutathione, and augmentation of lipid peridoxidation leads to the formation of compromised lipid membrane bilayers, thereby contributing to intravascular hemolysis and all of the consequences associated with it.

Incorrect: Methemoglobinemia is incorrect because copper sulfate does not induce methemoglobinemia. Furthermore, although O2-Sat is on low side , there are other explanations for a low O2-sat, such as hemolytic anemia. Tube dislodgment is not the most likely explanation because the patient still has a reasonable, albeit slightly compromised respiratory status. Were the tube truly dislodge, one would expect a more rapid clinical decline. Finally, even though the patient is in the Amazon jungle, an acute decompensation even from the most lethal of the Plasmodium spp. is unlikely to cause such an acute decline.

Correct: Chelation with D-Penicillamine and supportive care is the only correct answer.

Incorrect: Hyperbaric oxygen therapy will likely worsen the production of ROS and may worsen hemolysis. Methylene blue has no clear role in the treatment of copper toxicity, even with elevated methemoglobinemia levels. This is most likely because most of the elevated methemoglobin levels are due to free methemoglobin within the serum and not within intact RBC’s. Cannulation with V-V ECMO is not indicated because the patient does not have respiratory failure due to intrinsic pulmonary pathology.

Correct: Out of the answer choices above, the only correct answer is that the histopathologic pattern of copper toxicity is characterized by centrilobular necrosis. As necrosis occurs, sequester copper-ceruloplasmin complexes are released into the blood stream, which then drastically raises the whole blood copper concentration.

Incorrect: all of the other answer choices are incorrect

Correct: The most likely answer is metal fume fever caused by copper ion fumes. This could easily causes respiratory symptoms, low grade fever, and generalized malaise. Further clues suggesting to this diagnosis are the fact that he works in a pipe factory and a vent was inadvertently closed.

Incorrect: Although the patient’s temperature is only an oral temperature, the fact he has a normal mental status and is neuro intact suggest against heat stroke. The patient was unlikely to be exposed to carbon monoxide because he is a smoker and his level is 6. Although definitive testing with blood cooximetry should be conducted, an initial normal value is strongly suggestive of an alternative cause. The patient does have a history of welding into refrigeration systems or exposure to chemical weapons, which makes phosgene an exceedingly unlikely answer.

Correct: Wilson’s disease is caused be a deficiency in the ATP7B gene which is involved in the maturation of ceruloplasmin. Therefore, decreased activity of this enzyme leads to defreased ceruloplasmin levels, decreased biliary excretion of copper, a higher tissue level of copper, and a paradoxically decreased serum copper level. Acute copper toxicity will cause an increased level of ceruloplasmin and serum copper concentration.

Incorrect: all of the other answers are incorrect. In Wilson’s disease, active ceruloplasmin is deficient which leads to a decrease in both serum copper and ceruloplasmin concentrations. Acute overdose, leads to overload of the flux through the pathway, increasing serum copper and ceruloplasmin.

Correct: BAL can bind copper cations, but it is reliably excreted through the biliary tree. So for patients with confirmed acute copper toxicity AND acute renal failure,  chelation therapy with BAL is indicated. Please note that BAL may be slightly less efficacious as D-Penicillamine or Trientine.

Incorrect: D-Pencillamine and Trientine can be utilized for chelation therapy in patients with acute copper toxicity in the setting of normal renal function. However, this patient does not have normal renal function. Both of these compounds chelate copper and need to be excreted through the kidney, so neither of these pharmacologic interventions are likely appropriate. EDTA is not indicated for acute copper toxicity.

Correct: of the answers above, only single pass albumin dialysis has been shown to be effective for copper overload in patients with Wilson’s Disease. The mechanism of action is that albumin is included into the diasylate, which then binds free copper cations from the dialysis fluid. A case report showed normalization of copper levels. A caveat here is that this is a case report on a patient with a metabolic copper dysfunction, not an acute overdose. Nonetheless, in dire cases when chelation therapy may not be enough, perhaps this approach can be considered, especially as the technology matures.

Incorrect: It is important to note that no form of conventional dialysis effectively eliminates copper cations from the patient’s body.

Correct: This is a difficult question, but clearly there is only one correct answer. IM BAL should be adminisered to symptomatic patients. This is a cheap and effective disaster medicine intervention.

Incorrect: The first answer is unreasonable for a resource poor area. It is true all patients should be evacuated if possible, but this may not be possible. Furthermore, in a disaster, it is unethical to leave behind asymptomatic patients as an experiment as a test to see if ongoing exposure is occurring. Water decontamination at the environmental level is unlikely feasible for a resource poor area. Although oral succimer is likely a fantastic intervention it should reserved for symptomatic AND exposed persons who can tolerate PO. If it is possible to set up a regional tertiary care center for exposed patients who are symptomatic and refractory, that should be done. D-Penicillamine has not been tested for IM dosing. Furthermore, in this resource poor area, only the symptomatic should be chelated.