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Iron and Metals & Metalloids

Iron and Metals & Metalloids. Chapters 179 & 184 Arthur Amin Olyai. Iron Physiology and Pharmacology. Approx. 30 000 calls to Poison center yearly Usually involves young children < 6 y/o Risk of death without aggressive measures

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Iron and Metals & Metalloids

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  1. Iron and Metals & Metalloids Chapters 179 & 184 Arthur Amin Olyai

  2. Iron Physiology and Pharmacology • Approx. 30 000 calls to Poison center yearly • Usually involves young children < 6 y/o • Risk of death without aggressive measures • Less toxicity form overdose today because of recent changes in iron formulation and dispensing practices

  3. Iron Physiology and pharmacology • Average male 4 g storage • Body stores iron in hemoglobin (2/3), myoglobin, cytochromes, other enzymes/cofactors and ferritin. • Excess Iron is toxic body protects itself by serum protein binding, reg. of GI absorption, and intracellular storage

  4. Iron Physiology and pharmacology • Fe2+ is better absorbed then Fe 3+(most dietary Broken down via ferri-reductacse) • Fe2+ transporter into enterocyte via DMT1 converted to ferritin • If Iron needed moved out of enterocyte as transferrin • Body is also available to slough intestinal cells containing iron if needed

  5. Iron Physiology and Pharmacology • Usu no free iron exists in body • Transferrin regulates how much iron is transported from ferritin , GI tract to liver and spleen for processing • Transferrin can bind up to 4500 iron molecules • TIBC  mostly amount of transferrin

  6. Iron Physiology and Pharmacology • Iron is potent catalyst for oxidants/free radicalsorgan damage membrane lipid peroxidation • Iron is GI irritant diarrhea,vomiting,abd pain, mucosal ulceration, bleeding • Excess free iron enters mitochondriainhib. Oxydative phosphorilation metabolic (lactic ) acidosis • Results: Coagulopathy, hepatotox., myocardial and vascul. dysfunction, encephalopathy • Ferrochel

  7. Iron Toxic Dose • Elemental iron amount ingested is key usu prep. contain 12-33% • FeSo4(20%) vs ped. MVI (10-18%) • Tox effect >10-20 mg/kg • Mod Tox. 20-60 mg/kg • Severe over 60mg/kg

  8. Iron Laboratory Assessment • Be careful about using iron levels to direct management • Deferox on board? • What iron prep was ingested? • 300-500microgr. signif. GI tox. • 500-1000microgr.mod sytemic toxicity • > 1000microgr. signif. morbidity

  9. Iron Laboratory Assessment • Some studies suggest WBC count > 15 000 and glucose level > 150 may indicate iron tox. (controversial) • TIBC little value • Xray may show tablets GI decontamination

  10. Clinical Features • Clinically local toxicity vs systemis tox. • Traditionally five stages seen • Stage 1 <6 hours • Gi symptoms usu within 6 hours • Vomiting a/w acute iron intox. • Stage 2 6-12 hours • Latent stage – symptoms may resolve false reassurance • Volume loss/ worsening met acidosis • Stage 3 first 24 h • Intracell disruption of metabolism shock and lactic acidosis • Iron induced coagulopathy (possibly biphasic)bleeding + hypovolemia • Stage 4 2-5 days • Hepatic stage of iron poisoning • Stage 5 4-6 weeks • Delayed sequelae Gi Obstruction

  11. Iron Treatment • Pt no or minimal symptoms/normal vitals stabilize ABC observe 6h • GI decontamination/Chelation via Deferoxamine • Dialysis not effective • Antiemetics may be used • If hypotensivesymptomatically support • If coagul.Vit K/FFP • Consider CBC CMP LFT Type and cross • ABG not necessary in mild cases

  12. GI Decontamination • Ipecac –not used • Active Charcoal does not absorb iron • Orogastric lavage • if ingestion within 60 min • More useful smaller pills • Pills on xray may suggest progressive tox. • Whole bowel irrigation-polyethylene glycol solution via NG • 250-500 ml/h in children • 2 liters in adults

  13. Deferoxamine • Chelating agent dicovered in 1960s • Streptomyces pilosus • Removes critical amount of iron-preferantially free iron to restore proper cell. function • Dose: • IM • 90mg/kg max 1 gr in children and 2 gr adults • Repeat 4-6 h • Volume factor • If Dehydrated/hypotensive IV • Second IV line recommended • 5-15mg/kg/h max 6-8gr daily • A/w mucormycosis, RI, pulm.tox.,Yersinia enterocolitica

  14. Determination of Efficacy and Duration of Tx • Controversail- Clinical Dx • Multiple urine samples before and after tx • Vin –rose color change • Deferoxamine challenge test-controversial

  15. Metal & Metalloids • Usu not acute toxicity • A/w signif. Morbidity&mortality • 4 sytems usu affected • Neuro (consider TCA overdose in approp. setting) • GI • Hematologic • Renal • The importance of index case

  16. Lead Epidemiology • M/c chronic metal poisoning • Environmental contaminant • Inc. levels in 1 to 5 y/o a/w • Urban dwelling, built before 1974,poverty, nonhisp. Black race, high pop density • Less lead tox in community 2nd to bans on household/industrial products • Inorganic lead (multisys) vs organic lead (CNS predominate)

  17. Inorganic Lead • Absorption by Resp./Gi tract occasionally if bullet in contact with body fluid (esp.consider release at injury site • Deficiencies of Ca2+,Iron, Cu, Zinc predispose to Inc. Absorption of Lead • 90% stored in bone but also in soft tissue and blood • Can cross placenta/ consider inc. bone turn over in pregnancy • Half life is 30 years

  18. Pathophysiology • CNS (Younger more susceptible) • Progressive astroctye injuryBBB disruption cerebral edema/seizures • Decr. CamP/protein phoph.decr. memory an learning • Altered Ca metabo. altered neurotransmitter release • PNS • Primary segm/ 2ndary axonal degen. • Motor nerves m/c involved • Hematopoietic ( basophilic stippling) • Porphyrin metab./lead induced anemia • Exacerbated by Iron defic. • Inhibition of RBC nucleotidases (degrad. cell. product) • Kidney • Fanconi syndrome partial F. if chronic if longer then 13 years • Aminoaciduria,Glycosuria,Phosphaturia,RTA • Liver • Tox hepatitis, mild inc LFTs, • Depr. reproduc. sys.-low sperm count and func., PMR, clinical hypothyroidism • In Infants colicky abdominal pain

  19. Diagnosis • History of exposure/hobby/environmental most imp. clue.: • Pt may complain of metallic taste • On PE bluish gray gingival lead lines • Arthralgias, Generalized weakness/weightloss/Delayed cognitive development (PbB>10microg/dL) • Mimics many other cond. thalassemia, other toxins, sickle cell etc. • Comb. Abdominal & Neuro dysfunc & Anemia should raise suspicion • CaNa2+-EDTA prov. test not used anymore • Labs: • Xray-lead bandsfailure bone remodeling • Anemia (normo or micro) and basophilic stippling (nonspecific), Inc retic count, Inc serum free hemoglobin • Inc. PbB levels

  20. Tx Inorganic Lead • Standard life support measures • SeizuresBZN, Phenobarb., Gen anaesthesia • Whole Bowel Irrig.(Polyethylene glycol) • if Xray ind. lead flecks etc.tx until clear • 500-2000ml/h po adult vs 100-500ml/h po children • If fishing sinkerssx consult • IV Fluids avoid cerebral edema • Lumbar punccareful, may ppc herniation

  21. Chelation • If encephalopthy or sympt. with PbB level elevated (>100 adult/>70 children) • BAL & CaNa2+-EDTA tx immediately • If mild sympt. or asympt.(PbB 70-100 adults/45-69 children) • DMSA • Asymptomatic (PbB less then 70 adult/45 children) • Tx not indictaed/remove source

  22. Chelation • M/C chelation agents used • BAL • DMSA with or without CaNa2+-EDTA • Po administration-allows GI absorption • High cost • Bind lead via sulfhydryl groups • No signif. Side effects/ minimal essential Vitamin absortion • D-penicillamine- less effective, less expensive • If Encephalopathic 85% suffer some permanent CNS symptoms • If Nephropathy usu partially reversible • GI symptoms usu resolve over 1-16 weeks • Disposition • Remove source otherwise admit • Admit Children over or equal to 70microg/dL • Admit adults with CNS symptoms

  23. Organic Lead • A/w Tetraethyl lead found in leaded gas • Usu CNS effects • Ranges from irritability,insomnia, restlessness,n,v,tremors, chorea, convulsions, mania persistent organic psychosis,dementia • Heptic, Muscle and renal damage can occur • Anemia usu not present • Blood levels may be normal • Tx remove source, symptomatic tx, and chelate if PbB levels elevated only • A/w gasoline sniffing

  24. Arsenic • Tasteless & odorless • M/c acute metal poisoning • 2nd leading cause of chronic metal tox. • Elemental, inorganic and organic salts, and gaseous forms • Found in many compound /industry • Often tools for homo or suicide

  25. Pharmocology • Absortion: • GI, respiratory, skin, or parenteral route • Arsenate (As 5+)easier absorbed GI/mucous membranes • Arsenite (As3+)easier absorbed skin/lipophilic • Binding serum proteins/erythro&leukocytes • 24h redistr. Liver,kidney,spleen, lung,Gi,muscles nervous syshair nails & bones • Excretion • Renal/ rate determines toxicity/arsenate more toxic due to slower excreted • Arsenic crosses placenta Teratogenic

  26. Pathophysiology of Arsenic • Binds reversibly to tissues and enzyme systems via sulfhydryl groups • Small blood vessels dilated and become more permeable • Inflammation & necrosis of GI tract • Cerebral edema and hemorrhage • Myocardial tissue destruction • Fatty degen. Of liver & spleen • Peripheral axonal degener./2ary demylination

  27. Acute toxicity • Symptoms usu occur within 30 min • Hallmark: gastroenteritis with severe nausea, vomiting, & cholera –like diarrhea • Metallic taste in mouth • Hypotension & tachycardia • ECG nonspecific ST-segand T-wave changes, prolonged QT • Vtach with torsades de pointes • Acute encephalopathy, ARF, rhabdomyolysis and death

  28. Chronic Toxicity • Peripheral neuropathy (mostly sensory)stocking-glove distribution • Ascending paralysis • Skin rash (mobilliform) • Nonspecific malaise and weakness • Hyperpigmentation, hyperkeratosis of palms and soles • H/o gastroenteritis 1-6 weeks earlier • Mees lines-nails • Nasal septum perforation • Nonspecific syptoms • Weakness, muscle aches,abd pain,memory loss,personality changes, periorbital&extremity edema, decreased hearing • CNS syptoms-delerium, hallucinations,disorientation/confabulation • Ca- squamous cell & basal skin Ca, resp. tract Ca,hepatic angiosarcoma, and leukemia

  29. Dx • Acute arsenic poisoning suspect if hypotesnion & preceded severe gastroenteritis • Abd xray_radiopaque flecks • Lab: • Normocytic,normochromic, or megaloblastic anemia • Thrombocytopenia • WBC count up in acute and down in chronic tox. • Eosionphilia up to 21% • Basophilic stippling of RBCs • Elevated retic count • ECG prolonged QT • 24h urine arsenic levels-measure after 5 days of seafood free diet (normal is less then 0.05mg/L) • Hair and nail testing

  30. Differential Dx • Septis shock • Encephalopathy • Peripheral neuropathy/Guillain-Barre • Addison dz • Hypo/hyperthyroidism • Korsakoff syndr. • Gastroenteritis/cholera like diarrhea • Porphyria • Other metal tox. thallium & mercury

  31. Treatment • Ensure resp.& Circulatory func • Hemodyn. Monitoring • Usu 2ndary to hypovolemia (usu crystalloids/pressors as needed) • Avoid overhydration • Vtach-tx with lido, amiodarone, & defibrillation • Avoid drugs prolong QT • Replace Mg,K,Ca • Gastrointestinal lavage and activated charcoal • Chelation therapy • BAL –admin immediate/ tx may exceed 19 day tx • DMSA less toxic/ may be substituted or for chronic • D-penicillamine not useful in arsenic tox • 24 urine arsebic level to guide for further tx • Tx seizures with BZN phenobarb. or gen anesthesia • Consider homocide/suicide • Hemodialysis- rarely used only in ARF can remove small amounts

  32. Disposition • Admit if acute or life threatening known or suspected arsenic poisoning • All chronically poisoned pt requiring BAL • Suicidal or homocidal ideation

  33. Arsine • Colorless, nonirritating gas • Found in semiconductor industry, ore smelting, refinery, or arsenic containing insecticides • Attaches to hemoglobin via sulfhydryl groups • Hemolytic anemia, abd pain ARF(hemoglobinuria) • Tx with blood transfusion, exchange transfusions, and hemodialysis for ARF • Chelation tx ie BAL not used

  34. Mercury • Inorganic vs organic forms • Inorganic form subdivided • Elem. Mercury • Mercurous • Mercuric salt • Organic • Short chained alkyls • More toxic to humans • Methyl mercury • Ethyl mercury • Dimethylmercury- lethal in small amounts • Long chained alkyls

  35. Pharmocology • Elem mercury (Inorganic) & Long chained alkyls (organic) • Long chained organic alkyls are biotransformed/resemble inorganic mercury poisoning • Crosses BBBtrapped in CNS • Usu inhaled or absorbed via skin • IM injection • Abscess and granuloma form • Delayed tox • IV injection • PE & DVT • Mercuric salts (inorganic) & short chained alkyls (organic) • Absorbed via GI • Mercuric salts deposit in liver, kidney, & spleen • Organic mercury-short chained type cross membranes accum. additionally in RBCs, CNS and fetus

  36. Pathophysiology • Binds sulfhydryl groups- protein and enzyme sys affected • Methyl mercury inhib choline acetyl transferase interferes with Ach production/deficiency • Mercuric salt Proximal RTA

  37. Clinical Features • Depend on form ingestion • Usu neuro, Gi,& renal effects • CNS effect • M/c 2ndary to short chain alkylsCNS terratogenic effect • Elemental mercury may also cause it (vs mecury salts no effect) • Various sympt. • Erethism,anxiety,depression,irritability,mania, sleep disturbance,shyness,memory loss,tremor • Paresthesia,ataxia, muscle rigidity/spasticity,&hearing and visual impairmentusu short chain alkyls • GI effect • M/c 2ndary to mecury salts a/w errosive gastroenteritis, abdominal pain, cardiovasc.collapse • Elemental and short chain alkyls only mild GI effects- stomatitis, gingivitis, excessive salivation • Renal effects • Elemental and organic- glomerular and tubular damage • Mercury salts ATN within 24 h • Pneumonitis, ARDS, progressive pulmonary fibrosis • Elementalmercury inhalation

  38. Acrodynia • Immune mediated condition develops in children exposed to all form mercury except short chain alkyls • Generalized rash, fever, irritability, splenomegaly, & generalized hypotonia with weakness pelvic and pectoral muscles

  39. Swallowing glass thermometer usu does not produce adverse effect unless GI tract is damaged or contains fistulas

  40. Diagnosis • Exposure History • Constellation S&S tremor, erethism, or acrodynia • Ingestion of mercuric chloride rapid fatal course/erosive gastritis • Often dx is subtle • Labs: • Obtain 24 h urine mercury level (5 day seafood free diet) except for short chain alkyls (biliary excretion) • 10-15 microg/L normal over 20 tox • Levels may be artificially low in chronic • Whole blood levels (merc. Concentr. In RBCs) usu below 1.5micog/dL • MRI: atrophy visual cortex, cerebellar vermis & hemisphere, and postcentral cortex

  41. Differential Diagnosis • Hypothyroidism • Apathetic hyperthyroidism • Metabolic encephalopathy • Senile Dementia • Lithium, theoph., & Phenytoin tox • Parkinsons dz • Carbon monox. Poisoning • Lacunar infarct • Cerebellar dz • Ethanol and sedative-hypnotic drug withdrawal • Iron, arsenic, phosphorus acid or alkali poisoning

  42. Treatment • Removal exposure • Supportive therapy • Gastric lavage & activated charcoal (cathartic not indicated) • Neostigmine may improve motor function in methyl mercury poisoning • BAL contraindicated in methyl mercury poisoning • Exacerbates CNS symptoms • DMSA may be useful in short chain alkyls • Given as second line agent after Gi decontam. • BAL preffered chelator for mercury salts • Adjust dose to clinical response and side effect development • Hemodialysis- can dialyze BAL-mercury complex • Plasma exchange transfusion may be useful

  43. Disposition • All ingestions of mercury salts • All patients known to have or suspected to have inhaled elemental mercury vapor with pulm. injury • All patients receiving BAL therapy

  44. Questions • 1.Which statement concerning iron toxicity is false: • A.Some studies suggest WBC count > 15 000 may indicate toxicity • B. Glucose level > 150 may indicate iron tox. C.TIBC little value • D.Xray may show tablets • E.Nonelemental iron amount ingested is key

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