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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

Iron and Metals & Metalloids

Chapters 179 & 184

Arthur Amin Olyai

iron physiology and pharmacology
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
iron physiology and pharmacology3
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
iron physiology and pharmacology4
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
iron physiology and pharmacology5
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
iron physiology and pharmacology6
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
iron toxic dose
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
iron laboratory assessment
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
iron laboratory assessment9
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
clinical features
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
iron treatment
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
gi decontamination
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
deferoxamine
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
determination of efficacy and duration of tx
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
metal metalloids
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
lead epidemiology
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)
inorganic lead
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
pathophysiology
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
diagnosis
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
tx inorganic lead
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
chelation
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
chelation22
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
organic lead
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
arsenic
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
pharmocology
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
pathophysiology of arsenic
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
acute toxicity
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
chronic toxicity
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
slide31
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
differential dx
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
treatment
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
disposition
Disposition
  • Admit if acute or life threatening known or suspected arsenic poisoning
  • All chronically poisoned pt requiring BAL
  • Suicidal or homocidal ideation
arsine
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
mercury
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
pharmocology38
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
pathophysiology39
Pathophysiology
  • Binds sulfhydryl groups- protein and enzyme sys affected
  • Methyl mercury inhib choline acetyl transferase interferes with Ach production/deficiency
  • Mercuric salt Proximal RTA
clinical features40
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
acrodynia
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
slide42
Swallowing glass thermometer usu does not produce adverse effect unless GI tract is damaged or contains fistulas
diagnosis43
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
differential diagnosis
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
treatment45
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
disposition46
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
questions
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
questions51
Questions
  • 2.Which of the following is incorrect about treatment in iron toxicity
  • A. GI decontamination/Chelation via Deferoxamine is commonly done
  • B.Dialysis is very effective
  • C.Antiemetics may be used
  • D.If hypotensive support symptomatically
  • E.If coagulopthic give Vit K/FFP
questions52
Questions
  • 3. Which of the following is incorrect in Chelation therapy in arsenic poisoning

A. BAL is administer immediate

B. Treatment may exceed 19 days

B. DMSA is less toxic

C. D-penicillamine is not useful in treatment of arsenic poisoning

D. 24 urine arsenic level are not useful

questions53
Questions
  • 4. Which of the following is not present in the condition known as acrodynia
  • A.It is a immune mediated condition develops in children exposed to all form mercury except short chain alkyls
  • B.Generalized rash
  • C.Fever and Irritability
  • D.Splenomegaly, & generalized hypotonia
  • E. Weakness of abdominal and deltoid muscles
questions54
Questions
  • 5. The following are treatment options in mercury poisoning except
  • A. All are correct
  • B. Gastric lavage & activated charcoal and cathartic are usually not indicated
  • C. Neostigmine may improve motor function in methyl mercury poisoning
  • D.BAL contraindicated in methyl mercury poisoning
  • E.Hemodialysis- can dialyze BAL-mercury complex
answers
Answers
  • 1.E
  • 2.B
  • 3.D
  • 4.E
  • 5.A