Heavy metal Poisoning

Lead exposure in adults usually occurs via the respiratory route through many occupations: battery plant worker, metal welder, painter, construction worker, lead miner, firing range worker, glass blower, and ship builder. Another source of lead poisoning in adults is ingestion of “moonshine” alcohols that have been distilled in lead-containing pipes [135, 136]. Exposure to leaded gasoline can increase organic lead exposure. After absorption, lead can have detrimental effects to many organ systems including the nervous, hematological, renal, cardiovascular, GI, and endocrine systems. Lead can cause a decrease in the integrity of the blood-brain barrier by disrupting the intracellular junction of capillary endothelium. This results in increased capillary leak into the CNS and a resultant increase in intracranial fluid. Lead can also disrupt several neurotransmitter systems in the CNS by increasing spontaneous release of dopamine, acetylcholine, and γ-aminobutyric acid (GABA), by blocking N-methyl D-aspartate (NMDA) glutamate receptors and increasing levels of protein kinase C. A process termed “pruning” in which necessary neural pathways are protected and unnecessary neural pathways are destroyed, peaks when children are around 2 years of age. By interfering with the neurotransmitters of the CNS, lead causes ineffective “pruning” in which necessary neural pathways are destroyed and unnecessary neural pathways are enhanced.

Microcytic anemia is a classic finding in lead toxicity. Lead inhibits several heme synthesis enzymes: aminolevulinic acid (ALA) synthetase, δ-ALA dehydratase, coproporphyrinogen decarboxylase, and ferrochelatase, leading to elevated erythrocyte protoporphyrin levels. In addition to decrease heme synthesis, lead weakens erythrocyte membranes shortening the erythrocyte life span. A clinical finding in, but not unique to, plumbism is basophilic stippling. Basophilic stippling is a result of the inhibition of pyrimidine-5-nucleotidase. In children, the anemia caused by lead is often complicated by iron deficiency and other nutritional deficiencies that decrease effective hemoglobin synthesis. Lead-protein complexes deposit in the proximal tubular cells of the kidney and are accompanied by mitochondrial swelling in this same region. Lead interferes with mitochondrial respiration and phosphorylation in the kidney, leading to glycosuria, aminoaciduria, and phosphaturia. Chronic high-dose lead exposure has been shown in animal models to cause renal failure through tubular atrophy, interstitial fibrosis, and glomerular sclerosis. These findings can also be seen in other forms of kidney failure. The skeletal system serves as the main reservoir for lead. With chronic lead exposure lead stores in bone can have a half-life of 5–19 years. Soft tissues may be subjected to increased lead exposure during times of accelerated bone turnover, such as during childhood growth, after a long bone fracture, or during pregnancy. In children lead causes increased calcification of cartilage in the bone metaphysis resulting in increased metaphysis density. Hypertension has been associated with chronic lead exposure. Lead likely affects vascular smooth muscle cells by causing a decrease in Na+/K+-ATPase activity with a subsequent increase in Na+/Ca2+ pump activity, and increased calcium-mediated contractility. Lead may also alter vascular smooth muscle activity by increasing protein kinase C.

The clinical aspects of lead toxicity are widely described; however, there is no clear “toxidrome” and it is difficult to define expected symptoms at certain BLLs. The reason for this difficulty likely involves the many variables affecting the clinical effects of lead exposure:age at time of exposure,length of exposure time, genetic predisposition to effects, environmental factors, nutritional status, and underlying medical problems of the patient. Lead toxicity can present with symptoms in a variety of different organs. There are both similarities and differences in the way that children and adults are affected by lead toxicity. In children, the neurological consequences of plumbism are the greatest concern. Serious neurological problems from lead toxicity are most commonly described in children between the ages of 18–36 months. Symptoms at BLLs of 50–100 µg/dL may be obvious or subtle and can include intermittent irritability, hyperactivity, and developmental delay in one particular skill. Higher levels or more chronic exposure can result in ataxia, lethargy, seizures, and coma. There is controversy over the cognitive effects of lower BLLs (BLLs less than 10 µg/dL). Some epidemiological studies have reported an inverse correlation between elevated BLLs in children and IQ,but not all published data are in agreement with this association. Epidemiological studies that examine this topic have the difficult task of trying to control for all possible confounding variables. Adults can also experience neurological symptoms with plumbism. Signs of encephalopathy including seizure, coma, and papilledema usually occur at BLLs over 150 µg/dL. At BLLs above 80 µg/dL memory problems, insomnia, and personality changes have been reported. More subtle signs are seen in adults with BLLs of 40–70 µg/dL and can be similar to those symptoms seen with depression. Other clinical manifestations of lead poisoning in children and adults include a normocytic or microcytic anemia, abdominal pain, constipation, hepatotoxicity, and pancreatitis. Peripheral neuropathy, with resultant foot and wrist drop, is well described in adults and is occasionally seen in children – particularlythose with underlying sickle cell disease. Nephrotoxicity has been reported in all age groups with lead toxicity; a Fanconi’s syndrome with aminoaciduria, glycosuria, and phosphaturia has been more commonly described in the adult population. Saturnine gout is a phenomenon seen in adult patients and is due to impaired uric acid clearance by the kidneys. There is concern that chronic lead exposure can raise blood pressure; however, two recent meta-analyses found a less than robust association. Sperm abnormalities have also been associated with BLL of ≥40 µg/dL in workexposed men. Lead can cross the placenta and has been associated with spontaneous abortion, prematurity, and developmental delay. Lead is also excreted in breast milk. Lead exposure does not have any clear association with carcinogenicity in humans. Inorganic lead is classified as a probable carcinogen (group 2A) and organic lead is not classifiable in regards to carcinogenicity (group 3) by the IARC. These data coupled with clinical studies suggest that lead is, at worst, a weak carcinogen. Organic lead, such as tetraethyl lead, at high doses can cause predominately neurological symptoms similar to a generalized encephalopathy including delirium, ataxia, and seizures. Neurological symptoms from organic lead are reported at lower levels than what would be typically expected with inorganic lead.

Diagnosis

The best initial test for evaluating a patient with suspected lead poisoning is a whole BLL obtained by venipuncture. A BLL should be sent in a lead-free tube and is usually measured by atomic absorption spectrophotometry. It is important to recognize that whole BLLs can be used to guide management but may not reflect lead in other organ systems, such as the CNS or bone. Capillary lead levels can be used for screening purposes, but may be falsely elevated if there is lead on the skin where the sample is drawn from. A disadvantage of BLLs is that most laboratories are not equipped to report same-day results. BLLs that are done during chelation therapy can be elevated from lead that is pulled out of soft tissues and into the bloodstream. Zinc or erythrocyte protoporphyrin may also be elevated with lead toxicity but are not asensitive test and can be elevated in other conditions that interfere with heme synthesis such as iron deficiency, sickle cell anemia, and vanadium toxicity. The protoporphyrin tests are more likely to be elevated with chronic lead toxicity than with acute lead toxicity. Additional laboratory tests that may be useful in the evaluation of a patient with suspected plumbism should be guided by the history and physical exam, and may include a complete blood count, a comprehensive metabolic panel, and a urinalysis. These tests can also provide a baseline for management of possible side effects if chelation therapy is initiated. Radiographic imaging may help to support the diagnosis of lead poisoning and can also help to illicit the etiology of exposure in some cases. In a patient with the possible ingestion of a lead-containing object, an abdominal x-ray should be obtained.Any patient with suspected plumbism and a history of bullet wound, should have an x-ray of the area of bullet impact to visualize any retained bullet fragments. Radiographs of long bones of children with BLLs of 70 µg/dL or greater may show increased densities at the metaphyses, also referred to as “lead lines”. Findings indistinguishable from “lead lines” are also seen with bismuth, phosphate, and fluoride toxicity. Chronic lead exposure may be quantified using bone x-ray fluorescence technology. This is a test that has been used in research studies and is not typically utilized in the clinical setting. A head computed tomography scan should be obtained on any patient with suspected plumbism and acute CNS symptoms to evaluate for evidence of cerebral edema.

Treatment

The management of children with elevated BLLs should follow the guidelines set forth by the Centers of Disease Control and Prevention. Some state health departments have slight variations in these guidelines. It is important to recognize that the first step in management of a patient with elevated lead levels is prompt removal from the source. The local health department should be contacted and should assist with identification of the source and containment of the lead source in a pediatric patient with a BLL greater than 20 µg/dL or with two separate BLLs within the 15–19 µg/dL range. A recent Cochrane review of 12 studies concluded that there was no clear benefit of educational initiatives and/or dust control measures, and there was insufficient evidence to comment on soil abatement in regards to lowering pediatric BLLs in a population. Chelation therapy in asymptomatic children is usually not initiated unless a patient has a BLL of 45 µg/dL or greater; chelating patients with levels less than this does not show any benefit on cognitive outcomes. Oral chelation is recommended for those patients who are asymptomatic and have BLLs of 45–69 µg/dL. Patients who have BLLs greater than 69 µg/dL or who are symptomatic should have parenteral chelation. Screening of adults that have workplace lead exposure should be guided by Occupational Safety and Health Administration’s recommendations: Asymptomatic adults with BLLs less than 70 µg/dL do not require chelation, oral chelation is recommended for mild symptoms or BLLs of 70–100 µg/dL, and parenteral chelation therapy is advised for symptoms of lead-induced encephalopathy and/or BLLs greater than 100 µg/dL. The oral chelator that is approved by the FDA for lead poisoning in children over 1year of age is DMSA. The pediatric dose of DMSA is 10mg/kg per dose every 8 hours for 5 days followed by 10 mg/kg per dose every 12 hours for 14days. Although DMSA is not officiallyrecommended in adults,the dose that has been most widely used is 10–30 mg/kg per day for 5 days. Adverse reactions are not limited to, but include, neutropenia, hemolytic anemia, and elevation of aspartate and alanine aminotransferase. Edetate calcium disodium (Calcium EDTA) is a parenteral chelator approved by the FDA for adult and pediatric plumbism. Edetate calcium disodium can be administered intravenously or intramuscularly. The recommended intravenous dose in adults for severe lead poisoning is 1–1.5 g/m2 per dayinfused over 8–12hours for a total of 5 days; after 2 days a repeat 5-day course can be administered if indicated. The recommended pediatric intravenous dose for severe lead poisoning is 1–1.5 g/m2 per day divided into equal doses infused every 8 or 12 hours, an additional 5-day course can be given after 2 days if indicated. The following serious side effects have been reported with edetate calcium disodium: fever, hypersensitivity immune reaction, hypotension, nephrotoxicity, and thrombophlebitis. Care should be taken when using edetate calcium disodium in a patient with renal insufficiency, and the dose may need to be modified or an alternative chelator may need to be used. Edetate calcium disodium may increase intracranial pressure and, in patients with cerebral edema, the manufacturer recommends using the intramuscular route or alternatively using the intravenous route with a slow infusion rate. It has been reported that edetate calcium disodium may exacerbate symptoms when given as the sole chelator to a patient with a high BLL, and that dimercaprol should be given in conjunction with edetate calcium disodium in the patient who has symptomatic lead poisoning or a BLL over 70µg/dL. If the patient can take oral medications,DMSA can be used instead of dimercaprol [168]. Edetate disodium without calcium should not be used because of the risk of hypocalcemia. Another FDA approved chelator for lead toxicity is dimercaprol. It is administered by deep intramuscular (i.m.) injection. In severe plumbism dimercaprol is administered at a dose of 4 mg/kg i.m. every 4 hours for 2–7 days in both pediatric and adult patients. In mild lead poisoning the recommended dose is 4 mg/kg i.m. for the first dose followed by 3 mg/kg i.m. every 4 hours for 2–7 days. Adverse reactions with dimercaprol include fever, hypertension, tachycardia, and injection site abscesses. Dimercaprol is administered in peanut oil and should usually be avoided in patients with peanut allergies. Secondary to the number of side effects associated with dimercaprol, its use should be limited to symptomatic patients who cannot take oral DMSA. D-Penicillamine is not approved by the FDA for lead poisoning and should only be used in cases of serious lead poisoning in which other chelators have had unacceptable side effects. D-Penicillamine can cause the life-threatening side effect of agranulocytosis and can also cause severe dermatological and renal conditions. Bowel irrigation with a polyethylene glycol-electrolyte solution should be considered if a patient has lead-containing objects in the GI tract that could easilytransit through the GI tract. Agastroenterologist or surgeon may need to be contacted for removal of a larger lead-containing object out of the GI tract if it is likely that the object will not move adequately with GI peristalsis. Likewise patients with evidence of lead poisoning may require surgical removal of lead containing bullet fragments lodged in soft tissues and/or joint spaces