1. Lead poisoning in children
Dr omid yaghini pediatric neurologist

2. EPIDEMIOLOGY
Lead (Pb), a stable metallic element with an atomic number of 82 and atomic weight of 207, was first smelted around 4000 BC as a by-product of silver processing . Despite this knowledge, lead was included as an ingredient of gasoline in the 1920s and continued to be used in paint in some developed countries until the 1970s. In many low-income countries, lead in gasoline and industrialized uses of lead (eg, smelters or refineries) remain major sources of exposure

3. In 2004, 16 percent of all children in the world were estimated to have blood lead levels (BLLs) >10 mcg/dL (0.48 micromol/L) with 90 percent of children with elevated levels living in low-income regions.

4. Risk factors 
Children younger than six years of age (and particularly those younger than 36 months) are more susceptible to the toxic effects of lead than are adults. The prevalence of elevated BLLs is highest among inner-city children who live in deteriorating housing . Lead poisoning is more common among urban than rural children, low-income than middle-income children,

5. TOXICOLOGY
No safe or "nontoxic" BLL exists  reference level corresponding to the 97.5th percentile of BLLs in US children (5 mcg/dL [0.24 micromol/L] as of 2012

7. Inorganic lead is not metabolized but is directly absorbed, distributed, and excreted. Inhaled lead may either be cleared by cilia resulting in ingestion or retained by the lung for rapid and complete absorption. Children absorb a greater proportion of lead from the gastrointestinal tract than do adults (up to 70 percent versus 20 percent). Fasting, iron deficiency, and calcium deficiency also may increase the gastrointestinal absorption of lead 

8. On average, the half-life in each compartment is:
•Blood – 28 to 36 days
•Soft tissue – 40 days
•Mineralizing tissues – Greater than 25 years

9. Molecular toxicology 
Lead is a potent toxic substance with no apparent threshold. Lead interferes with the interactions of divalent cations and sulfhydryl groups. It has widespread physiologic effects because most biochemical reactions are regulated by these agents.

10. Lead can disrupt signal transduction cascades by activating protein kinase C, competing with magnesium and inhibiting cyclic nucleotide hydrolysis by phosphodiesterases, or inhibiting function at the N-methyl-D-aspartate-type glutamate receptor . Lead also can uncouple mitochondrial oxidative phosphorylation in the central nervous system.

11. •ALA dehydratase is inhibited at levels of 10 and 15 mcg/dL (0
•ALA dehydratase is inhibited at levels of 10 and 15 mcg/dL (0.48 and 0.72 micromol/L) in children and adults, respectively.
•Elevation of erythrocyte protoporphyrin occurs at levels of 30 mcg/dL (1.48 micromol/L).
•Reduced hemoglobin synthesis is found in children at levels of 40 (1.93 micromol/L) and in adults at levels of 50 mcg/dL (2.41 micromol/L), respectively.

12. Acute encephalopathy 
Acute encephalopathy occurs at BLLs greater than 100 to 150 mcg/dL (4.8 to 7.2 micromol/L) and is indicated by persistent vomiting, altered or fluctuating state of consciousness, ataxia, seizures, or coma. Cerebral edema is a variable finding, more often present in younger than older children. Children with lead encephalopathy may develop inappropriate antidiuretic hormone secretion, partial heart block, and marked decrease in renal function

13. Hearing loss
The hearing loss occurs primarily in the higher frequencies and may contribute to learning and behavior problems

14. Peripheral neuropathy
Peripheral neuropathy, rare in children with isolated lead poisoning, is more common in children with concomitant sickle cell anemia. Decreased nerve conduction velocity occurs at BLLs as low as 20 mcg/dL 

15. Neurobehavioral deficits
Detectable blood lead levels (BLLs) are associated with irreversible neurocognitive deficits and a lower limit for this toxicity has not been established. there is no safe lead level and none should be considered "normal. Furthermore, studies suggest that a permanent pattern of cognitive dysfunction may result from lead poisoning in the first several years of life , and in-utero lead exposure may adversely affect infant neurodevelopment (measured at 24 months) independent of post-natal BLL.

16. Hematologic 
 Lead poisoning in children rarely results in anemia . The two major mechanisms are decreased hemoglobin synthesis and hemolysis. Decreased hemoglobin synthesis has been well documented at BLLs of 40 mcg/dL. Acute, high-level lead poisoning (BLL >70 mcg/dL [3.4 micromol/L]) has been associated with hemolytic anemia.

17. Renal 
 In the child, lead appears to have an effect on renal function even at levels below 10 mcg/dL(0.48 micromol/L. Subtle abnormalities in renal tubular function, associated with aminoaciduria, glycosuria, and increased excretion of low-molecular weight proteins can occur. Lead nephropathy, which is characterized histologically by chronic interstitial nephritis

19. DIAGNOSIS
Lead poisoning is diagnosed by an elevated venous blood lead level (BLL). Specific interventions for lead poisoning start at BLLs ≥5 mcg/dL  

20. Asymptomatic patients
 The diagnosis of lead toxicity usually is made through a lead screening program because most children with lead toxicity do not have overt clinical symptoms although neurobehavioral abnormalities are frequently present

21. Symptomatic patients 
They include cognitive impairment, language delay, and behavior problems at low concentrations and progress to vomiting, colicky abdominal pain, fatigue, renal insufficiency, and encephalopathy at higher concentrations. Lead poisoning should be included in the differential diagnosis for children with any of these complaints or conditions

22. EVALUATION
 A careful history should be obtained from the families of all children suspected of toxic lead exposure. The history should include:
●Onset and severity of symptoms of toxicity ●Nutritional history with particular attention to intake of iron and calcium
●History of pica
●Family history of lead poisoning
●Foreign birthplace and recent foreign residence
●Assessment of potential sources of lead exposure: work history of the parents and other significant caregivers, hobbies, age of the home and history of home renovations, source of water supply, location and condition of play areas,

23. Physical examination 
There are few specific findings on physical examination that can help identify the presence of lead poisoning.
Delayed language development and neurobehavioral dysfunction are important features and should raise concern for lead poisoning when present.
Lethargy is particularly concerning because it indicates encephalopathy.
Lead lines, at the junction of the teeth and gums, are rarely seen. If present, they usually indicate severe and prolonged lead exposure .

24. Laboratory evaluation
 The laboratory evaluation of the child with lead poisoning should include a repeat venous blood lead level (BLL) to confirm the diagnosis. BLLs should also be obtained in the patient's siblings, housemates, and/or playmates. Parents may also require testing

25. Additional tests 
 In patients with elevated BLLs, screening for iron deficiency anemia should also occur (eg, complete blood count, ferritin, and C-reactive protein) ●Serum electrolytes
●Blood urea nitrogen and creatinine
●Serum calcium and magnesium
●Alanine and aspartate aminotransferases
●Urinalysis

26. Diagnostic imaging
Radio-opaque lead flecks in the intestinal tract suggesting recent ingestion are found inconsistently. However, their presence may have implications for treatment at the time of diagnosis
Lead lines at the end of growing long bones are found only in children with moderate lead toxicity , long-bone radiographs are notuseful as part of the diagnostic evaluation of children with lead levels less than 45 mcg/dL  .

27. GENERAL MANAGEMENT
The only effective long-term treatment is ending further lead exposure by eradication of environmental lead contamination.Chelation therapy may be necessary depending upon the degree of blood lead elevation. However, it has limited efficacy.

29. Nutritional interventions
Adequate nutritional intake of calcium, vitamin C, and iron and regular meals should be routinely recommended to minimize lead absorption and prevent pica . Fasting should be avoided because it increases intestinal lead absorption .