What are the clinical manifestations and treatment approach for acute and chronic metal toxicity?

Metal Toxicity: Clinical Manifestations and Treatment

Acute Metal Toxicity Syndromes

Aluminum Toxicity

Acute aluminum neurotoxicity presents with agitation, confusion, myoclonic jerks, major motor seizures, and can progress to coma and death, with plasma aluminum levels of 400-1,000 µg/L. 1

• Acute syndrome develops from dialysate contamination (150-1,000 µg/L aluminum) or from combined ingestion of aluminum gels plus citrate salts (Bicitra, Shohl's solution) in patients with GFR <30 mL/min/1.73 m². 1
• Citrate salts (citric acid, sodium citrate, calcium citrate) markedly enhance intestinal aluminum absorption and should never be given simultaneously with aluminum-containing medications. 1
• Most symptomatic patients with acute aluminum neurotoxicity from dialysate contamination or aluminum-citrate combinations have died. 1

Iron Toxicity

Acute iron intoxication requires standard measures including gastric lavage, airway management, shock control with IV fluids and vasopressors, and correction of acidosis, with deferoxamine as an adjunct therapy. 2

• Deferoxamine mesylate is indicated for acute iron intoxication but is an adjunct to, not a substitute for, standard supportive measures. 2
• Induction of emesis with syrup of ipecac and gastric lavage are part of the standard treatment protocol. 2

Arsenic and Chromium

Acute poisoning with arsenic and chromium can be fatal. 3

• These metals represent the most severe acute toxicity risk among heavy metals. 3
• Exposure commonly occurs via ingestion, inhalation, or skin absorption. 3

Chronic Metal Toxicity Syndromes

Aluminum: Dialysis Encephalopathy

Dialysis encephalopathy develops insidiously after 12-24 months of dialysis, presenting with personality changes, progressive speech disorder (stuttering, stammering, hesitant speech), motor disturbances (twitching, myoclonic jerks, motor apraxia), hallucinations, spatial disorientation, and paranoid behavior. 1

• Plasma aluminum levels are typically 150-350 µg/L. 1
• Symptoms characteristically worsen shortly after dialysis and fluctuate initially, but become persistent over time. 1
• Most untreated patients die within 6-12 months after symptom onset. 1
• EEG findings differ from generalized slowing seen in other metabolic encephalopathies. 1

Aluminum: Bone Disease

Aluminum-related bone disease presents with bone pain, characteristic "waddling" gait, proximal muscle weakness, and fractures, associated with dialysate aluminum levels above 100 µg/L. 1

• This disorder was historically called "fracturing dialysis osteomalacia." 1
• Bone biopsy showing increased aluminum staining of bone surface (>15-25%) with adynamic bone or osteomalacia is the gold standard for diagnosis. 1

Manganese Toxicity (Manganism)

Manganese overload initially causes non-specific symptoms (headache, asthenia, irritability, fatigue, muscular pains) but progresses to a neurodegenerative syndrome with psychiatric symptoms, cognitive defects, motor dysfunction, and emotional disturbances resembling Parkinson's disease. 1, 4

• Manganism causes neuronal cell death in basal ganglia structures, making functional recovery limited and treatment options inadequate for reversing chronic neurotoxicity. 1, 4
• Brain MRI shows high-intensity signals in globus pallidus correlating with elevated manganese levels. 1, 4
• Toxicity occurs with IV doses >500 mg/d in adults or >40 mg/kg/d in pediatric patients, but even 110 mg/d causes elevated blood concentrations. 1
• Long-term parenteral nutrition (>30 days with manganese intake >55 mg/day) with liver dysfunction or iron deficiency are high-risk scenarios. 1, 4

Copper Toxicity

Copper toxicity symptoms include hematemesis, hypotension, melena, coma, headaches, behavioral changes, fever, diarrhea, abdominal cramps, Kayser-Fleischer rings (brown ring-shaped markings in eyes), and jaundice, with long-term toxicity causing kidney, liver, heart, and brain failure. 1

• Cholestasis impairs the liver's ability to excrete copper, resulting in chronic copper toxicity. 1
• Genetic disorders (Wilson's disease, Menke's syndrome) cause pathological copper accumulation. 1, 5

Lead, Cadmium, Mercury

These metals cause chronic syndromes through oxidative stress, free radical formation, protein and DNA conformational changes, and inhibition of biological functions. 6, 7

• Lead exposure disproportionately affects lower-income, inner-city communities due to older housing stock and historical industrial contamination. 3
• Heavy metals induce oxidative stress by generating free radicals and reducing antioxidant levels. 8
• They alter protein and DNA conformation and inhibit their function. 8

Diagnostic Approach

Aluminum

Measure serum aluminum yearly and every 3 months in patients receiving aluminum-containing medications; baseline levels should be <20 µg/L. 1

• Perform deferoxamine (DFO) test if serum aluminum is 60-200 µg/L, if clinical signs/symptoms of toxicity exist, or prior to parathyroid surgery with aluminum exposure history. 1
• DFO test protocol: infuse 5 mg/kg DFO during the last hour of dialysis, measure serum aluminum before infusion and 2 days later before next dialysis. 1
• Test is positive if increment of serum aluminum is >50 µg/L. 1
• Do not perform DFO test if serum aluminum >200 µg/L to avoid DFO-induced neurotoxicity. 1
• Aluminum bone disease is predicted by rise in serum aluminum >50 µg/L following DFO challenge combined with intact PTH <150 pg/mL (16.5 pmol/L). 1

Manganese

Measure whole blood or RBC manganese concentrations (not serum alone) when manganese excess or toxicity is suspected, especially in long-term parenteral nutrition (>30 days, manganese intake >55 mg/day) with liver impairment or iron deficiency. 1, 4

• Brain MRI showing high-intensity signals in globus pallidus confirms diagnosis and correlates with elevated manganese levels. 1, 4
• Check for concurrent iron deficiency, as low iron causes competitive transport protein dysfunction leading to manganese accumulation. 1, 4
• Monitor at 40-day intervals minimum based on biological half-life. 1, 4

Copper

Measure plasma copper concentrations; with levels <12 µmol/L and CRP >20 mg/L, deficiency is likely; with values <8 µmol/L with or without elevated CRP, repletion is indicated. 1

• Elevated free copper levels occur in Alzheimer's disease, infections, hemopathies, hemochromatosis, hyperthyroidism, liver cirrhosis, hepatitis, and pregnancy. 1

General Approach

Evaluate suspected heavy metal exposure with thorough occupational and social histories, physical examination, and laboratory tests/imaging as needed. 3

• Pregnant and breastfeeding patients and young children are particularly vulnerable due to effects on fetal and child development. 3

Treatment Algorithms

Aluminum Toxicity Treatment

The first step is removing any aluminum-containing additives from dialysate and medications; maintain dialysate aluminum <10 µg/L. 1

• Never give citrate salts simultaneously with aluminum-containing medications. 1
• For confirmed toxicity, use deferoxamine chelation therapy. 1
• If neurological symptoms worsen during first month of treatment, do not withdraw penicillamine; consider short courses of 2,3-dimercaprol (BAL) while continuing treatment. 5

Manganese Toxicity Treatment

Immediately discontinue all manganese-containing additives including parenteral nutrition formulations, supplements, and environmental exposures. 1, 4

• Treat when whole blood or serum manganese values exceed twice the upper limit of normal laboratory reference ranges. 1, 4
• Provide iron supplementation if iron deficiency is present to correct competitive transport protein binding. 1, 4
• Chelation therapy options include EDTA (ethylenediaminetetraacetic acid) and para-aminosalicylic acid (PAS). 1, 4
• Set realistic expectations: functional recovery from established manganism is limited due to irreversible basal ganglia neuronal death. 1, 4

Copper Toxicity Treatment

For acute copper toxicity, administer oral D-penicillamine starting at 250-500 mg/day, then increase by 250 mg increments every 4-7 days to maximum of 1000-1500 mg daily in 2-4 divided doses. 1

• Oral zinc is validated for Wilson's disease where blood copper is low but sequestered in liver. 1
• In veterinary medicine, molybdenum is a recognized treatment option. 1

Iron Toxicity Treatment

Deferoxamine mesylate is indicated as adjunct therapy for acute iron intoxication and for chronic iron overload from transfusion-dependent anemias. 2

• Long-term deferoxamine therapy slows hepatic iron accumulation and retards or eliminates progression of hepatic fibrosis. 2
• Deferoxamine is not indicated for primary hemochromatosis; phlebotomy is the method of choice. 2
• Iron mobilization is relatively poor in patients under age 3 with little iron overload; do not give unless significant iron mobilization (≥1 mg/day) can be demonstrated. 2

Wilson's Disease (Copper Overload) Treatment

Penicillamine capsules are indicated for Wilson's disease treatment with two objectives: minimize dietary copper intake to 1-2 mg/day and promote excretion/detoxification of excess tissue copper. 5

• Exclude chocolate, nuts, shellfish, mushrooms, liver, molasses, broccoli, and copper-enriched cereals from diet. 5
• Use distilled or demineralized water if drinking water contains >0.1 mg/L copper. 5
• Treatment produces marked neurologic improvement, fading of Kayser-Fleischer rings, and gradual amelioration of hepatic dysfunction and psychic disturbances. 5
• Noticeable improvement may not occur for 1-3 months. 5
• If neurological symptoms worsen during first month of penicillamine therapy, do not withdraw the drug; temporary interruption increases risk of sensitivity reaction upon resumption. 5
• If symptoms continue worsening for one month, consider short courses of 2,3-dimercaprol (BAL) while continuing penicillamine. 5

General Chelation Therapy Principles

Chelation therapy is commonly used to treat metal toxicity, where chelating agents bind metal ions to form complex ring-like structures ("chelates") to enhance elimination. 8, 9

• Each metal requires a specific chelation agent based on different reactivity with ligands. 8
• Combination therapy with chelating agent plus antioxidant leads to improved outcomes. 8
• Metal chelators have drawbacks including redistribution of some metals to the brain (increasing neurotoxicity), loss of essential metals (copper, zinc), and serious adverse effects like hepatotoxicity. 9

Hyperkalemia/Hypermagnesemia-Induced Cardiac Arrest

For cardiac arrest with suspected hyperkalemia or hypermagnesemia, administer calcium chloride (10%) 5-10 mL OR calcium gluconate (10%) 15-30 mL IV over 2-5 minutes. 1

• For magnesium cardiotoxicity and cardiac arrest, give IV magnesium 1-2 g MgSO4 bolus IV push. 1

Critical Pitfalls to Avoid

Aluminum

• Do not perform DFO challenge test if serum aluminum >200 µg/L due to risk of DFO-induced neurotoxicity. 1
• Do not give citrate salts with aluminum-containing medications as citrate markedly enhances aluminum absorption. 1
• Do not withdraw treatment if neurological symptoms worsen initially; temporary interruption increases sensitivity reaction risk. 5

Manganese

• Do not assume dietary manganese causes toxicity; dietary intake does not lead to toxicity because gut absorption is tightly regulated (upper limit 11 mg/day from diet). 1, 4
• Do not delay evaluation in patients with liver disease; they are at highest risk due to impaired biliary excretion. 1, 4
• Do not overlook iron deficiency as independent contributor to manganese accumulation. 1, 4
• Do not use serum manganese alone; whole blood manganese is more accurate. 4
• Do not expect full neurological recovery; manganese causes irreversible basal ganglia neuronal death. 1, 4

Copper

• Do not attribute hallucinations to iron deficiency; investigate other causes as hallucinations are not a recognized manifestation of iron deficiency. 10
• Monitor liver and renal function during copper supplementation to prevent multi-organ copper toxicity. 11

General

• Do not use charcoal for ingestions of caustic substances, metals, or hydrocarbons. 1
• Do not ignore occupational and environmental exposure history; patients may not be aware of all exposures. 1
• Do not overlook pregnant/breastfeeding patients and young children who are particularly vulnerable to developmental effects. 3