Cobalt Quiz

The correct answer is “beer drinker’s cardiomyopathy.” Numerous reports have suggested there is an association of higher incidence of cardiomyopathy with cobalt sulfate (CoSO₄), which is used as a foam stabilizer. Autopsy findings demonstrated cardiac tissue concentrations of cobalt that were 10 times higher than average. However, it is unclear how much chronic alcoholism contributed to these patients condition. Encephalopathy is associated with metals such as lead and aluminum. SLE is typically more associated with drugs such as hydralazine, procainamide, isoniazid, quinidine, and phenytoin. Acquired brittle bone disease and renal failure describes the disease “Itai-Itai”, which is caused by exposure to cadmium.

The urinary cobalt concentration will be highest on Monday afternoon. This occurs because during the acute phase of exposure, there is an increased urinary cobalt excretion. This subside over several days and urinary cobalt excretion decreases, and more cobalt is eliminated in the bile. The lowest urinary concentration would on Monday morning before work. None of the other answers are correct.

The only mechanism on the list that doesn’t contribute to cobalt’s pathophysiology is “displacement of iron from the heme moiety.”

Much of the toxicity of cobalt comes from the fact the most common cobalt salts are in the form Co₂₊, so it competes with divalent cations that are cofactors for enzymatic processes. Co₂₊ also inhibits alpha-ketoglutarate dehdrogenase, which slows down the metabolism of the citric acid cycle. Co₂₊ binds to the sulfhydryl groups of lipoic and dihydrolipoic acids, inactivating them as cofactors for conversion of pyruvate to acetyl-CoA and alpha-ketoglutarate to succinyl-CoA. Of note, NAD+ is a cofactor for these reactions and NADH is created, which could explain why Cobalt toxicity may be worsened in alcoholics. In lungs and nervous tissue, CoCl₂ can react O₂ to form superoxide free radicals. CoCl2 inhibits tyrosine iodinase, which leads to hypothyroidism. Because cobalt binds transferrin, it can stimulate erythropoesis and cause a reticulocytosis.

Cobalt is added to tungsten to make a metal that is several time harder than steel. The exposure is usually pulmonary due to concentrations of metal fumes that are 10x higher than the ambient environment. The pulmonary syndrome is called “hard metal disease”. Although drill bit manufactures do use cobalt, production of tungsten carbide containing products currently is the most common source.

Metal-on-metal hip implants have been associated with elevated chromium levels in the serum, blood, urine, and hair. The theory for the observed association is that over time friction at the articular interface between the two metal surfaces eventually leads to scraping of trace alloy from the surface which then dissolved and distributes through the tissues. Metal-on-metal hips are less commonly used now.

Although occupational cobalt exposure is associated with all of the answer stems, occupational is the most common. Up to 3-5% of workers who have exposure to cobalt develop occupational asthma, which is thought to be immune mediated.

Multinucleated giant cells on H&E stain of BAL aspirates are characteristic of “hard-metal disease”. There can also be interstitial pneumonitis. Cobalt may elicit an immune reaction in lung tissue similar to beryllium. Bright red macrophages on oil-red-O are characteristic of vaping associated lung injury. Type 2 (glandular), not type 1 (squamous) are seen in the BAL of “hard-metal disease”. Abundant neutrophils on H&E may be more characteristic of an invasive bacterial infection.

Cardiac MRI may show diffuse edema on T2-weighted images. Furthermore, delayed-phase contrast may show diffuse hyperenhancement. This narrows the differential of the etiology to toxin induced or amyloidosis. Radiology should be closely consulted as subtle findings regarding pattern of edema and contrast uptake are required to differentiate the two. This test should only be applied to a patient with an higher pretest probability of cobalt cardiomyopathy, eg. with a documented elevated serum cobalt. Echocardiogram does not differentiate the etiology of cardiomyopathy, unless it is focal ischemia. High sensitivity troponin is only a marker for myocardial damage. An elevated serum cobalt level does not rule-in or rule-out cobalt cardiomyopathy.

Mosier BA, Maynard L, Sotereanos NG, Sewecke JJ. Progressive Cardiomyopathy in a Patient With Elevated Cobalt Ion Levels and Bilateral Metal-on-Metal Hip Arthroplasties. Am J Orthop. 2016;45(3):E132-5.

The correct answer is B12. B12, or cobalamin, is a cobalt containing vitamin which is a cofactor for enzymes involved in transfer of methyl groups. The cofactor contains cobalt, and supplementation with B12 could lead to elevated urinary cobalt levels. Therefore, if the cobalt level is elevated, the next step is to speciate the urinary cobalt ratio of inorganic:organic can be determined. A high ratio of inorganic:organic cobalt suggests possible toxicity. Although Folate is involved in overlapping metabolic pathways, it does not contain cobalt. Riboflavin (B2) does not contain cobalt and toxicity from excess dietary consumption is rare. Niacin (B3) does not contain cobalt; toxicity from excess niacin involves flushing of the skin and may cause hepatotoxicity; deficiency results in pellagra, which can be memorized by “B3 3 D’s”. The 3 D’s are dermatitis (patches of hyperpigmentation, diarrhea, dementia. Wormwood oil extract contains alpha-thujone, which can cause seizures and hallucinations; however, no cobalt is present.

In the case of a patient with an elevated urinary cobalt level and vague chronic complaints, a whole blood level would be most appropriate. Serum cobalt may assist in diagnosis; but in general, metals should be assayed using whole blood because this test captures metal cations that are within the RBC. Urine cobalt speciation would likely confirm elevated inorganic urinary cobalt, but would not be the best next test. MRI soft tissue hip may be indicated to assess for local tissue reaction, but this is not the best next test.

Aggressive and targeted therapy is preferred for a critically ill patients with cardiogenic shock and acidemia. Ca₂NA-EDTA has been shown to be the most effective chelator, although strong evidence is lacking. IV thiamine may help with concommitant metabolic deficiencies that are contributory to cardiogenic shock. NAC has also been shown to effectively chelate cobalt, so it may be used as an adjunct; furthermore, it may play a role in reduction of reactive oxygen species formed by reactions of O2 with cobalt. BAL has not been shown to be an effective chelator of cobalt.