Heavy Metals & Chelators

Heavy Metals & Chelators

• Heavy metals like lead, arsenic, mercury, and iron can be toxic to humans
• Chelators help reduce the toxic effects of heavy metal exposure
• Chelators are organic compounds that form stable bonds with cationic metal atoms, functioning as chemical antagonists and are used as antidotes for heavy metal poisoning

Lead Poisoning

• Lead is a major environmental hazard, found in air and water
• Exposure risk is higher in old homes (pre-1978) with chipped paint and workplaces
• Lead inhibits ferrochelatase and ALA dehydratase, reducing heme synthesis and RBC protoporphyrin
• rRNA degradation is inhibited, causing RBCs to retain rRNA aggregates, known as basophilic stippling

Types of Lead Toxicity

• Acute poisoning can occur from industrial exposure or ingestion of lead-containing paint chips
• Symptoms include acute abdominal colic and CNS changes, with acute encephalopathy in children (high mortality)
• Chronic poisoning (plumbism) presents with peripheral neuropathy, anorexia, anemia, tremor, weight loss, and GI symptoms
• Children may experience growth retardation and neurocognitive deficits
• Succimer is used in cases of chronic lead poisoning.
• Organic poisoning is rare and caused by tetraethyl or tetramethyl lead from old gasoline additives
• Symptoms of organic poisoning include hallucinations, headache, irritability, convulsions, and coma

Clinical findings for lead poisoning

• Elevated free erythrocyte protoporphyrin (FEP) levels due to inhibited Hb synthesis
• Clinical findings also include elevated serum iron and ferritin

Symptoms and Treatment of Lead Poisoning

• Symptoms of LLEEAAD poisoning include:
  • Lead Lines on gingivae (Burton lines) and on metaphyses of long bones on X-ray
  • Encephalopathy and Erythrocyte basophilic stippling
  • Abdominal colic and sideroblastic Anemia
  • Drops (wrist and foot)
• Complications can include developmental delay and encephalopathy in children
• Treatment involves chelation therapy if blood lead levels are ≥ 45 µg/dL
• First-line treatment is succimer (oral agent) and second-line is penicillamine (oral agent)
• Severe cases or encephalopathy are treated with dimercaprol plus EDTA (parenteral), which crosses the blood-brain barrier

Arsenic Poisoning

• Arsenic is present in industrial processes, soils, and released during coal burning
• Disrupts cellular metabolism by binding to sulfhydryl groups on lipoic acid and interferes with ATP production

Acute arsenic poisoning symptoms

• Severe GI discomfort, vomiting, "rice-water" stools, and capillary damage leading to dehydration and shock
• A sweet, garlicky odor may be detected in breath and stool
• Supportive therapy to replace water and electrolytes, along with chelation therapy with dimercaprol, is the prescribed treatment.
• Chronic poisoning causes skin changes, hair loss, bone marrow depression, anemia, nausea, and GI disturbances
• Arsenic is a known carcinogen affecting the liver, lungs, and skin
• Symptoms include vampire-like pigmentary skin changes, skin cancer, vomiting, diarrhea, QT prolongation, with garlic breath

Arsine Gas Toxicity

• Arsine gas exposure is an occupational hazard in metal refinement and the semiconductor industry
• It causes a unique form of toxicity with massive hemolysis
• Pigment overload from the breakdown of erythrocytes can cause renal failure
• Treatment is supportive

Mercury Poisoning

• Inorganic mercury's toxicity comes from mercury-containing materials used in dental labs and manufacturing (batteries, insecticides)
• Organic mercury fungicide is used in agriculture to prevent fungal and bacterial infections of seeds and it's lipid-soluble which allows it to cross cellular membranes
• Mercury causes toxic effects through protein precipitation, enzyme inhibition, and corrosive action
• Mercury binds to sulfhydryl, phosphoryl, carboxyl, amide, and amine groups, inactivating proteins

Symptoms and treatment for mercury poisoning

• Acute poisoning occurs through inhalation of inorganic mercury, with symptoms like chest pain, shortness of breath, nausea, vomiting, kidney damage, gastroenteritis, and CNS damage
• Intensive supportive care with prompt chelation using oral succimer or intramuscular dimercaprol is the prescribed treatment
• Chronic poisoning from mercury vapor inhalation displays a range of symptoms involving the gums, teeth, GI disturbances, neurologic and behavioral changes (erethism)
• Organic poisoning was first recognized in Minamata, Japan (1950s), due to consumption of methylmercury-contaminated fish
• Epidemics have occurred from consuming grain treated with fungicidal organic mercury compounds

Iron Poisoning

• Acute poisoning commonly results from the ingestion of ferrous sulfate tablets by small children
• Symptoms include abdominal pain, vomiting, and GI bleeding
• Toxicity is caused by the formation of free radicals and peroxidation of membrane lipids
• Can progress to anion gap metabolic acidosis and multi organ failure causing GI obstruction
• Deferoxamine and deferasirox are the chelating agents of choice

Chelators for Heavy Metal Toxicity

• Main treatment for toxicity with chelators being able to form complexes with metal ions for easier elimination by the body in urine
• Specific chelating agents must be chosen for the target metal, as non-specific chelation can lead to serious side effects
• EDTA can lower calcium or phosphate levels

Specific Chelators and their Uses

• Dimercaprol is a bidentate chelator forming two bonds with the metal ion, preventing its binding to proteins and enhancing rapid excretion
• Dimercaprol is used in acute arsenic and mercury poisoning and combines with EDTA for lead poisoning, but is highly lipophilic and enters cells easily
• Dimercaprol can cause transient hypertension, tachycardia, headache, nausea, vomiting, paresthesia, and fever (especially in children)
• Long-term use can result in thrombocytopenia and increased prothrombin time
• Succimer is a water-soluble bidentate chelator, which is used orally to treat lead toxicity in children and adults, and is effective in arsenic and mercury poisoning if given within a few hours of exposure
• Succimer causes GI distress, CNS effects, skin rash, or elevated liver enzymes, and less toxic than dimercaprol
• Unithiol is a water-soluble derivative of dimercaprol, given orally or intravenously
• Intravenous unithiol is used for severe acute poisoning by inorganic mercury or arsenic
• Oral unithiol is an alternative to succimer in the treatment of lead intoxication and can cause mild dermatological reactions
• Penicillamine is a penicillin derivative and bidentate chelator, and is used for copper poisoning and Wilson disease
• Penicillamine is water-soluble, well-absorbed, and excreted unchanged, but cause nephrotoxicity, proteinuria, pancytopenia, autoimmune dysfunction, and hemolytic anemia
• Ethylenediaminetetraacetic Acid (EDTA) is a polydentate chelator of divalent and trivalent cations, with primary use in lead poisoning
• EDTA is given as calcium disodium salt (CaNa2EDTA) to prevent hypocalcemia but can cause nephrotoxicity
• Adequate hydration and limiting treatment to less than 5 days reduces toxicity risk when using EDTA
• Deferoxamine, Deferasirox, and Deferiprone are selective for iron and used parenterally for acute iron intoxication and iron overload from blood transfusions in diseases like thalassemia or myelodysplastic syndrome
• Side effect of usage can cause skin reactions
• Long-term use can cause neurotoxicity, hepatic and renal dysfunction