What is the pathophysiology of lead toxicity?

Updated: Jan 16, 2020
  • Author: Pranay Kathuria, MD, FACP, FASN, FNKF; Chief Editor: Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS  more...
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Answer

The major mechanism of lead toxicity is due to increased generation of reactive oxygen species (ROS) and interference with generation of antioxidants. Lead causes the generation of ROS like hydroperoxide, hydrogen peroxide, and singlet oxygen. ROS are stabilized by glutathione in the body.  Ninety percent of glutathione in the cell exists in reduced form and 10% in oxidative form, and it typically acts as an antioxidant defense mechanism. Glutathione stabilizes ROS, and after being converted (oxidizing) to glutathione disulfide, it is reduced back to GSH by glutathione reductase. Lead inactivates glutathione by binding to GSH’s sulfhydryl group, which causes GSH replenishment to become inefficient, thereby increasing oxidative stress. Lead also interferes with the activity of other antioxidant enzymes including superoxide dismutase and catalase. The increase in oxidative stress leads to cell membrane damage due to lipid peroxidation. Lead blocks the activity of 5-aminolevulinic acid dehydratase and leads to hemoglobin oxidation, which along with the lipid peroxidation can result in red cell hemolysis. [8]

Lead entering the intravascular space binds quickly to red blood cells. Lead has a half-life of approximately 30 days in the blood, from where it diffuses into the soft tissues, including the kidneys, brain, liver, and bone marrow.

Lead then diffuses into bone and is stored there for a period that corresponds to a half-life of several decades. Increased bone turnover with pregnancy, menopause, lactation, or immobilization can increase blood lead levels. Estimations of blood lead levels are more useful for diagnosing acute lead poisoning, whereas the extent of past lead exposure can be estimated by determining the body burden of lead on the basis of results from the edetate (EDTA) calcium disodium (CaNa2 EDTA) lead mobilization test.

Lead is primarily excreted in urine and bile, but the elimination rate varies, depending on the tissue that absorbed the lead. The kidney excretes lead by means of glomerular filtration and tubular secretion. Lead has bidirectional transport across the tubular epithelium. The clearance of lead ranges from 1 to 3 mL/min and is relatively independent of kidney function.

The effects of lead poisoning on the brain are manifold and include delayed or reversed development, permanent learning disabilities, seizures, coma, and even death. The long-term effect of lead exposure is maximal during the first 2 or 3 years of life, when the developing brain is in a critical formative stage.


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