Lead poisoning pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aksiniya Stevasarova, M.D. Leena Josephin Jetty, M.B.B.S[2]
Overview
Lead poisoning is a medical condition, also known as saturnism, plumbism, or painter's colic caused by increased blood lead levels. Lead may cause irreversible neurological damage as well as renal disease, cardiovascular effects, and reproductive toxicity. Humans have been mining and using this heavy metal for thousands of years, poisoning themselves in the process due to accumulation and exposure. These dangers have long been known, though the modern understanding of their full extent and the small amount of lead necessary to produce them is relatively recent; blood lead levels once considered safe are now considered hazardous, with no known threshold. Reducing these hazards requires both individual actions and public policy regulations. [1]
Pathophysiology
Pathogenesis
- Lead has no known physiologically relevant role in the body.
- Lead a divalent metal similar to calcium, iron and zinc uses channels like calcium channel or Divalent Metal Transporter(DMT) and enters the cells and acts as a cofactor to enzymes.[2]
- Once Lead is absorbed it gets deposited in the bones(70% in adults and 95% in children).
- Roughly 1% circulates in the blood,99% of which is in the RBC’s.[3]
- The toxicity of lead comes from its ability to mimic other biologically important metals, most notably calcium, iron and zinc which act as cofactors in many enzymatic reactions.
- Following ingestion, lead is able to bind to and interact with many of the same enzymes as these are metals, but due to its differing chemistry, does not properly function as a co-factor, thus interfering with the enzyme's ability to catalyze its normal reaction(s).
- Lead toxicity symptoms arise are thought to occur by interfering with an essential enzyme delta-AminoLevulinic Acid Dehydratase, or ALAD. ALAD is a zinc-binding protein which is important in the biosynthesis of heme, the co-factor found in hemoglobin. Lead poisoning also inhibits the enzyme ferrochelatase which catalyzes the joining of protoporphyrin IX and Fe2+ to form Heme. [4] [5]
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Brain
- Lead exposure in childhood is associated with decreased brain volume; this might be due to reduced neuronal size/dendritic arborisation and this reduced volume of brain persists into adulthood.[6]
Kidney
- Lead exposure is a known risk factor for Chronic Kidney Disease(CKD)[7]
- Nephrotoxic effects include
- Intra nuclear inclusion bodies in Proximal Tubule cells
- Tubulo interstitial fibrosis
- It can cause decrease in Glomerular Filtration Rate(GFR).
CVS
- Lead causes cellular changes that are characteristic for hypertension and atherosclerosis.
- Laboratory studies revealed that chronic ,Low level lead exposure increases oxidative stress, decreases nitric oxide levels and induces vast spasm by activating protein kinase C there by causing hypertension.
- By inactivation of nitric oxide, increased hydrogen peroxide levels, inhibition of endothelial repair, impairing angiogenesis, promoting thrombus formation causes atherosclerosis.[8]
Genetics
- So far three polymorphic genes have been identified to be able to potentially influence the bioaccumulation and toxicokinetics of lead in humans. These genes are delta-aminolevulinic acid dehydratase (ALAD) gene, the hemochromatosis gene and the vitamin D receptor (VDR). Their relation to susceptibility especially to lead nephrotoxicity in high lead-exposed workers has been established. [9] [10]
- Delta -aminolevulinic acid dehydratase (ALAD) plays an important role in lead poisoning, and polymorphisms in the ALAD gene might affect the symptoms the individual patients experience. [11]
References
- ↑ [www.atsdr.cdc.com]
- ↑ Kayaaltı Z, Akyüzlü DK, Söylemezoğlu T (February 2015). "Evaluation of the effect of divalent metal transporter 1 gene polymorphism on blood iron, lead and cadmium levels". Environ Res. 137: 8–13. doi:10.1016/j.envres.2014.11.008. PMID 25483413.
- ↑ Barry PS (May 1975). "A comparison of concentrations of lead in human tissues". Br J Ind Med. 32 (2): 119–39. doi:10.1136/oem.32.2.119. PMID 1131339.
- ↑ Jaffe EK, Martins J, Li J, Kervinen J, Dunbrack RL (2001). "The molecular mechanism of lead inhibition of human porphobilinogen synthase". J Biol Chem. 276 (2): 1531–7. doi:10.1074/jbc.M007663200. PMID 11032836.
- ↑ Scinicariello F, Murray HE, Moffett DB, Abadin HG, Sexton MJ, Fowler BA (2007). "Lead and delta-aminolevulinic acid dehydratase polymorphism: where does it lead? A meta-analysis". Environ Health Perspect. 115 (1): 35–41. PMC 1797830. PMID 17366816. Check
|pmid=value (help). - ↑ Cecil KM, Brubaker CJ, Adler CM, Dietrich KN, Altaye M, Egelhoff JC, Wessel S, Elangovan I, Hornung R, Jarvis K, Lanphear BP (May 2008). "Decreased brain volume in adults with childhood lead exposure". PLoS Med. 5 (5): e112. doi:10.1371/journal.pmed.0050112. PMC 2689675. PMID 18507499.
- ↑ Batuman V, Landy E, Maesaka JK, Wedeen RP (July 1983). "Contribution of lead to hypertension with renal impairment". N Engl J Med. 309 (1): 17–21. doi:10.1056/NEJM198307073090104. PMID 6406892.
- ↑ Vaziri ND (August 2008). "Mechanisms of lead-induced hypertension and cardiovascular disease". Am J Physiol Heart Circ Physiol. 295 (2): H454–65. doi:10.1152/ajpheart.00158.2008. PMC 2519216. PMID 18567711.
- ↑ Wang A, Wang Q, Song Q, Xu J (2009). "[Study of ALAD and VDR gene polymorphisms associated with lead nephrotoxicity susceptibility]". Wei Sheng Yan Jiu. 38 (3): 326–9. PMID 19548578.
- ↑ Wu S, Yan C, Shen X (2004). "[Molecular genetic susceptibility to lead poisoning]". Wei Sheng Yan Jiu. 33 (2): 226–8, 232. PMID 15209014.
- ↑ Shaik AP, Jamil K (2008). "A study on the ALAD gene polymorphisms associated with lead exposure". Toxicol Ind Health. 24 (7): 501–6. doi:10.1177/0748233708095770. PMID 19028776.