Lead toxicity

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Background

  • Stable metallic element (no. 82)
  • Incredible environmental burden secondary to inclusion in paints, fuels, and industrial uses
  • Average blood levels in US have fallen from 12.8 mcg/dL in the late 1970's to 2mcg/dL mostly due to banning lead in gasoline

MOA

  • Interferes with the action of divalent cations and sulfhydryl groups
    • Particularly toxic to Zinc containing enzymes
    • Binds to calcium activated enzymes with 10,000x great affinity that calcium
  • Directly toxic to renal tubules

Toxicokinetics

Absorption
  • Rapidly and completely absorbed from lungs
  • Minimal absorption through intact skin
  • Variable GI absorption
    • Children absorb more than adults (70% vs. 20%)
    • Affected by nutritional status, calcium stores and iron stores
Distribution
  • Large Vd
  • Distributes to bone, muscles, brain, and blood
  • After weeks mostly in the bones and teeth
    • In adults 94% of total body lead is in the bones and teeth
  • some lead can leave the bones and re-enter blood under certain circumstances
    • pregnancy, periods of breast feeding, fractures, advanced age
Metabolism
  • No metabolism as toxin is elemental
Excretion
  • Excreted in urine and stool
  • Amount excreted varies with age
    • Children retain about 70% while adults only retain about 1%

References

  • Lead paint
  • Occupational
  • Soil contamination
  • Lead dust
  • Water (old pipes, especially when the water is "soft" or acidic)
  • batteries (especially car), weights, ammunition
  • Food (leafy green vegetables grown in lead-containing soil)
  • Moonshine (made in stills that contain lead-soldered parts)
  • Alternative/herbal medications
  • Poorly monitored imported products
    • Eg. Toys imported from China which were coated in lead paints
    • Eg. plates brought by immigrants from Mexico/South America
  • Phased out of gasoline in the 1980s and banned in 1996

Clinical Features

Vastly different presentations between children and adults

Adults

Nervous system
Nephro
  • Highest body levels found in proximal tubules after acute exposure
    • Results in proteinuria, particularly β 2-microglobulin and N-acetylglucosidase.
  • associated with slightly decreased GFRs
Heme
  • Basophilic stippling
    • From precipitation of nuclear contents
  • Inhibitor of heme synthesis
    • Can lead to either a normochromic or hypochromic anemia
Reproductive
  • Can cross placenta
    • Because lead is stored in bones and there is higher bone turnover during pregnancy, women with previous lead toxicity can have lead intoxicated children despite mother being asymptomatic.
  • Higher rate of stillbirths and spontaneous abortion
  • May cause preterm labor and low birth weights
  • May slow mental development and cause lower intelligence later in childhood
  • Decreased sperm counts
Endocrine
  • changes in T4 and TSH (generally with PbB > 40-60ug/dl)
  • altered levels of testosterone, leutonizing hormone, FSH at PbB > 30-40ug/dl
Other
  • May also have GI upset, vomiting, constipation, elevated LFTs
  • Myalgias
  • associated with increased mortality due to cardiovascular disease
  • associated with increased blood pressure
  • May see thin, blue/black line along gingiva, known as Burton's line (more common in chronic poisoning)

Children

Nervous system
  • Encephalopathy appears at lower levels
  • Symptoms: Irritability, apathy, fatigue, obtundation
  • Severe symptoms: Cerebral edema, Seizures
  • Can lead to permanent changes in brain architecture
    • Inhibits enzymes that mediate arborization of synapses and neuronal cellular adhesion molecules
    • Hippcampus thought to be primary sight of action secondary to high zinc levels
  • Disturbs blood brain barrier permeability which can be chronic
  • Long term sequelae
    • Cognitive disturbances (from slight learning disability to profound intellectual disability)
    • Loss of 5 IQ points per 10μg/dL elevation
    • Hyperactivity, aggression and antisocial behaviors
  • Peripheral neuropathy similar in adults and children[1]
Nephro
Heme
  • Similar to adults
Ortho
  • Disturbs bone development
    • Accelerates skeletal maturation which may predispose to osteoporosis later
  • Lead lines on radiographs
    • Generally correlate with levels above 50μg/dL
  • Associated with development of dental caries and periodontal bone loss

Differential Diagnosis

Heavy metal toxicity

Evaluation

Work-Up

  • Lead level
  • UA
  • CBC with smear
  • Chem 7 and divalents
  • LFTs
  • DO NOT LP
    • Cerebral edema may lead to herniation

CDC Recommendations for Lead Testing

  • at age 1 and 2 years
  • at ages 3-6 if never tested for lead
  • if they received services from public assistance programs for the poor such as Medicaid or WIC
  • if they live in a building or frequently visit a house built before 1978 that has recently been remodeled
  • if they have a brother/sister or playmate who has had lead poisoning

Diagnosis

  • Based on lead level

Management

  • Environmental Investigations
    • government programs provide intervention for lead levels > 10ug/dl
  • Chelation:
    • Treat children with acute blood Lead levels >45ug/dL or chronic >70ug/dL[2]
    • Consider treating symptomatic adults with Lead >50ug/dL or asymptomatic >70ug/dL
  • Penicillamine and Succimer
    • Oral medications
    • Only used in children [3]
    • Succimer has not been studied for Lead levels >60ug/dL
    • Succimer 10mg/kg TID x 5d THEN 10mg/kg BID x 14d
    • Penicillamine: second or third-line agent, requires B6 supplementation, contraindicated in patients allergic to penicillin, not approved during pregnancy, more toxic than Succimer
    • Penicillamine dose: 20-40 mg/kg/day PO divided q8hr
    • Penicillamine reported adverse effects include: rash, fever, anorexia, leukopenia, thrombocytopenia, hemolytic anemia, SJS, nephrotoxicity, proteinuria
  • IM BAL (dimercaprol)
    • First line agent if encephalopathy present
      • Consider giving first before EDTA, regardless of encephalopathy
      • As EDTA, if given first, may chelate lead and cross blood brain barrier
    • Onet of action 30 minutes
    • Increases fetal excretion of lead as chelated lead is excreted primarily in bile after 4-6 hours
    • Also increases urinary excretion of chelated lead
    • Agent of choice in renal failure
    • Dosage of 50-75mg/m^2 every 4 hours, full course is 3-5 days
    • Contraindications: liver failure, G6PD (develop hemolysis), peanut oil allergy, pregnancy
  • IV/IM EDTA (edetate calcium disodium)
    • Do not use as sole agent if encephalopathy present (does not cross blood-brain barrier)
    • Must have given BAL for at least 4h if Lead >100ug/dL or encephalopathy present
    • Increases renal excretion of lead 20-50 times
    • Children: 1-1.5gm/m^2/24hrs given in up to 6 divided daily doses
    • Adults: 1.5gm/24hrs in 2 divided doses
    • Full course of treatment is 5 days, may be repeated if patient still symptomatic or PbB > 50ug/dl

See Also

References

  1. ↑ Lead exposure in children: prevention, detection, and management. Pediatrics. Oct 2005;116(4):1036-46.
  2. ↑ Murata K, Iwata T, Dakeishi M, Karita K. Lead toxicity: does the critical level of lead resulting in adverse effects differ between adults and children?. J Occup Health. 2009;51(1):1-12.
  3. ↑ Treatment guidelines for lead exposure in children. American Academy of Pediatrics Committee on Drugs. Pediatrics. Jul 1995;96(1 Patient 1):155-60.


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