cadmium iron toxicity

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Cadmium toxicity

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Page 1: Cadmium iron toxicity

Cadmium toxicity

Page 2: Cadmium iron toxicity

•Relatively new metal in terms of humans–Encountered in earth’s crust combined with chlorine (CdCl2), oxygen (CdO),sulphur (CdS) –Exists as small particles in air, result of smelting, soldering or other high temprature industrial processes. •Sources:–natural rock weathering–copper, lead and zinc smelting auto exhaust–cigarette smoke (a cigarette contains 1-2 ug Cd) •Uses:–metal plating –nickel-cadmium batteries–paint pigments (blue)–plastic stabilizers–photographic chemicals–fungicides• readily absorbed and accumulated in plants and Food are most

common routes of exposure for general population

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Pharmacokinetics

• inhalation: – smelters, cigarette smoke–18-50% absorbed

• ingestion:•main source is liver and kidney of meats• 6% absorbed• greater if deficient in calcium, zinc or

iron

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• distribution:– bound to albumin in plasma and red blood cells– transported to liver, pancreas, prostate and

kidney, with eventual transfer to kidney• 50-75% of total body Cd is found in liver and

kidney Metallothionein: protein rich in cysteine

-traps Cd especially in kidney-synthesis induced by Cd

• Elimination:- urine– half-life in humans is 22 - 30 years

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Cadmium toxicity• Caused by excessive exposure to cadmium • No constructive purpose in the human body. • Extremely toxic even in low concentrations,

and will accumulat in organisms and ecosystems

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pathophysiology

–binding to –SH groups – competing with Zn and Se for inclusion into

metalloenzymes– competing with calcium for binding sites

(calmodulin)• Kidney toxicity:– free Cd binds to kidney glomerulus–proximal tubule dysfunction

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• Lung toxicity:– edema and emphysema by killing lung

macrophages• Skeletal effects:– Osteoporosis and osteomalacia (pseudofractures)

• Cancer: – carcinogenic in animal studies– ~8% of lung cancers may be attributable to Cd

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Two mechanisms are involved in cadmium mutagenicity,

Induction of reactive oxygen species and Inhibition of DNA repair Cystein is a precursor to the anti-oxidant protein

glutathione and is also required for metallothionein which is a protein that binds to cadmium specifically

Intracellular, cadmium binds to metallothionein Cadmium is released into the plasma after haemolysis

or when the erythrocytes lifetime has expired Cadmium is transported in blood plasma initially bound

to albumin Cadmium bound to albumin is preferentially taken up

by the liver

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In the liver, cadmium induces the synthesis of metallothionein

After a few days exposure metallothionein-bound cadmium appears in the blood plasma.

Plasma metallothionein play an important role in transport of cadmium

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Mechanism responsible for the selective accumulation of cadmium in proximal tubular cells

Mechanism

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EFFECTS OF POISONING:

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Signs and symptoms of toxicityEating food or drinking water contaminated with high levels of

cadmium can result in: • Vomiting / nausea• Stomach cramps• diarrhea• Kidney damage• Fragile bones• DeathBreathing in cadmium can result in: • Lung damage (chest pain or shortness of breath)• Kidney disease• Fragile bones• Death

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Cadmium detection and treatment• What would cause you to suspect Cd toxicity?- mainly the history• What tests could you do to detect exposure or effects?– detected via increased excretion of proteins, amino acids and

calcium by the kidney (proteinurea)– Urine and blood cadmium levels can be detected– Level of cadmium in liver also may be obtained

• What could you prescribe for treatment?– Acute inhalation: fluid replacement, mechanical ventilation– Acute ingestion: emesis and gastric lavage– Chronic: • chelation therapy is ineffective so only treatment is to remove

source

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Elements like calcium and selenium are shown to have protective effect against cadmium-induced toxicity

Adequate levels of zinc in the body helps to displace cadmium from the tissues

Potent antioxidants like Vitamin C, E, glutathione, methionine, glycine, cysteine has great protective efficiency.

TREATMENT

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Cadmium (Cd)Epidemics/case studiesJapan (1940s)

• effluent (outflow) from a lead-processing plant washed over adjacent rice paddies for many years– rice accumulated high level of Cd– community was poor (and therefore

malnourished with respect to calcium)

– acute toxicity: renal failure, anemia, severe muscle pain• named "Itai-Itai" disease ("ouch,

ouch")

Itai-itai victim

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prevention• Do not smoke. Smoking is the single most important source

of cadmium intake for most persons.• If you maintain a vegetable garden, consider having

fertilizers tested for cadmium. Some fertilizers have been found to be high in cadmium, which may then concentrate in your vegetables. Avoid any use of cadmium containing fungicides near your vegetable gardens.

• Eat a balanced diet that provides enough calcium, iron, protein, and zinc.

• Take inventory of and properly store (out of the reach of children) cadmium-containing products in your home (eg, fungicides, batteries, metals, fabric dyes, ceramic/glass glazes, fertilizer); check the label for cadmium or call the manufacturer to find out if the product contains cadmium.

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Case

• A 2 year old boy presents to the emergency department with a chief complaint of blood-tinged vomiting. His mother was tending to her newborn infant when the patient climbed up and grabbed his mom's bottle of iron pills from the counter. He was able to open the bottle and thinking that the pills looked like candy, he ate them. His mother brought in her bottle of ferrous sulfate 325 mg (65 mg elemental iron) tablets. Counting the iron tablets in the bottle there is a maximum of 15 tablets missing (975 elemental Fe/11kg= 81 mg/kg of elemental iron ingested).

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• Exam: VS T 36.9, P 120, R 30, BP 88/60, weight 12kg (10th percentile). He is alert, and being carried by mom. His skin is pink and warm with good perfusion and capillary refill. HEENT exam is negative. His oral mucosa is moist and there are no lesions. His neck is nontender. Heart regular rhythm and normal rate. Lungs are clear with good aeration. His abdomen is soft and slightly tender in the upper quadrants, with active bowel sound and no guarding. His distal pulses are strong and his distal extremities are warm. He is responding appropriately to mom.

• An abdominal series reveals radiopaque tablets in the stomach and intestine.

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iron toxicity

• Iron overdose has been one of the leading causes of death caused by toxicological agents in children younger than 6 years.

• Iron is used as a pediatric or prenatal vitamin supplement and for treatment of anemia. Iron is particularly tempting to young children because it appears similar to candy.

• Patients with anemia that require frequent blood transfusions also are at risk for developing chronic iron toxicity.

• This condition develops in patients with sickle cell disease, thalassemia, and myelodysplastic syndromes.

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• Iron is a serious and potentially fatal ingestion. It used to be one of the leading causes of fatal poisonings in the pediatric age group.

• Toxicity is based on the amount of elemental iron ingested.

• The most common forms of iron include: ferrous sulfate (20% elemental iron), ferrous fumarate (33% elemental iron), and ferrous gluconate (11%)

• Children's multivitamin with iron preparations contain 8 to 18 mg of elemental iron per chewable tablet. A common iron containing medication is a prenatal vitamin, which has 325 mg ferrous sulfate (65 mg elemental iron) per tablet.

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PATHOPHYSIOLOGY• Iron toxicity can be classified as corrosive or cellular toxicant:• Corrosive toxicity: Iron is an extremely corrosive substance to the GIT.

It acts on the mucosal tissues and manifests as nausea, hematemesis and diarrhea; patients may become hypovolemic because of fluid and blood loss which may aggravate the hypoperfusion, exacerbating lactic acidosis.

• Cellular toxicity: The absorption of excessive quantities of ingested

iron results in systemic iron toxicity. Excessive cellular uptake leads to the generation of free radicals and hydrogen ions through Fenton’s reaction. Excessive free radicals production impairs oxidative phosphorylation causing anaerobic metabolism and lactic acid production. The liver is one of the organs most affected by iron toxicity, but other organs such as the heart, kidneys, lungs, and the hematologic systems also may be impaired.

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• There are other unknown mechanisms for cellular injury.

• Lactic acidosis results from tissue hypoperfusion/cellular hypoxia.

• Free iron may also cause direct damage to the heart leading to decreased myocardial contractility (negative inotropic effect on the myocardium).

• Coagulopathies may occur from effects of iron on clotting factors

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• Fenton’s reaction:• (1) Fe2+ + H2O2 → Fe3+ + OH· (hydroxyl radical) + OH−

• (2) Fe3+ + H2O2 → Fe2+ + OOH· (peroxide radical) + H+

• Iron is absorbed in the intestine. The peak serum level ranges from 2 to 6 hours after ingestion of iron. Iron is absorbed in the ferrous (Fe++) form and is oxidized to the ferric from (Fe+++) within the cells. It is transported in the blood bound to transferrin. The iron binding capacity (transferrin level) is usually 300-500 mcg/dl (TIBC) and normal serum iron levels are 50-150 mcg/dl

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• Both corrosive and cellular toxicities of excessive iron ingestion lead to metabolic acidosis

• • Individuals demonstrate signs of GI toxicity with

ingestions of more than 22 mg/kg, but less than or equal to 40 mg/kg. Moderate-to-severe intoxication occurs when ingestion of elemental iron exceeds 40 mg/kg. Ingestions exceeding 60 mg/kg may be lethal.

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• With a serum iron level of less than 300 mcg/dl, the patient is usually asymptomatic. There is potentially moderate toxicity with an iron level between 300 to 500 mcg/dl. Serum iron levels greater than 500 mcg/dl fall in the severe toxicity range. If the iron tablet is enteric-coated or a sustained-released tablet, the absorption may be delayed and a second level drawn 6-8 hours after ingestion should be considered. The serum iron level may not be reliable if deferoxamine has been given. Other laboratory tests that are recommended are serum electrolytes, BUN, and creatinine. A baseline CBC can be drawn. An abdominal radiograph to look for radiopaque iron pills may be helpful. There are several tests previously used in iron poisoning which are no longer recommended

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SIGNS AND SYMPTOMS• Iron poisoning is often classified into 4 distinct stages.

Understanding the course of poisoning is important, especially the second (recovery) stage, which may lure the physician into a false sense of security and result in premature and inappropriate discharge of a patient.

• Stage 1[the gastrointestinal (GI) phase]: – Nausea and diarrhea, often accompanied by abdominal

pain– When the intoxication is severe, a hemorrhagic component

is observed in conjunction with gastroenteritis. – The combination of fluid and blood loss, with additional

third-spacing, may result in hypovolemia or shock. [fatal in significant% of cases].

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• Stage 2 [recovery phase]:– This stage is characterized by resolution of GI symptoms. – This deceptive phase usually occurs 6-11 hours

postingestion and may last as long as 26 hours. – Metabolic abnormalities during this phase may include

hypotension, metabolic acidosis, and coagulopathy. • • Stage 3: – Stage 3 is characterized by metabolic acidosis. – Elevated liver enzymes and bilirubin are commonly

observed with coagulopathy, indicative of hepatic dysfunction.

– Hypoglycemia may accompany liver dysfunction.

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• Stage 4 [experienced weeks after a severe poisoning]:– This stage is characterized by scarring of the

healing GI tract. The stomach and/or intestines may be affected, resulting in gastric outlet or intestinal obstruction.

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TREATMENTT1. Terminate further exposure.2- Supportive and symptomatic treatment:-For Hypovolemia: Administer vigorous isotonic crystalloid

therapy (e.g., 0.9 isotonic sodium chloride solution, LR solution) to attain and maintain hemodynamic stability.

3- Physical examination and history.4- Prevent further absorption from the gut: Because adsorption to activated charcoal is minimal, whole

bowel irrigation is the GI decontamination method of choice. This is done using Polyethylene glycol bowel preparation administered through NG or OG tube until rectal effluent is clear. [Mode of action: PEG is a Laxative with strong electrolytic and osmotic effects that has cathartic actions in the GI tract.]

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• Enhance elimination (move to the specific antidote)• 6- Specific antidote [Chelating agent]:• Chelation is the mainstay of therapy and is indicated

for:• Serum iron levels >350 μg/dL with evidence of toxicity • Serum iron levels >500 μg/dL regardless of signs or

symptoms.– Deferoxamine: 8 mg of iron is bound by 100 mg of

deferoxamine. It readily chelates iron from ferritin and hemosiderin but not transferrin. The complex is excreted in urine and bile and gives urine a red discoloration (Vin-rosé urine).

– Deferasirox: oral, Binds iron with high affinity in a 2:1 ratio.

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• Deferoxamine chelates the ferric ion (Fe+++). It is given intravenously to patients who are symptomatic with vomiting, diarrhea, increased anion gap metabolic acidosis, gastrointestinal bleeding, lethargy, or hypotension. Deferoxamine therapy is also recommended if the serum iron level is greater than 500 mcg/dl. The iron-deferoxamine complex (ferrioxamine) is water-soluble and is excreted in the urine. It may cause the urine to be pinkish-orange ("vin-rose"). The initial dose of deferoxamine is 15 mg/kg/h. The rate may be increased up to 25 to 40 mg/kg/h. Rapid infusion of deferoxamine may cause hypotension.

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• Mortality is low in iron poisoning patients if they do not have shock or coma. With supportive treatment of patients with shock or coma, the mortality rate is about 50%. If deferoxamine treatment is added, the mortality rate drops to 10%. Patients may be discharged home from the emergency department after 4-6 hours of observation if they are asymptomatic, have serum iron levels less than 300 to 500 mcg/dl, and have a negative abdominal X-ray. A psychiatric evaluation is needed if it was an intentional ingestion.

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