Page 13 of 31

PH9.3 | PH9.3 | Heavy Metal Poisoning and Chelation — SDL Guide — SDL Guide (Part 2)

Per-Metal Toxicology: Lead, Mercury, Arsenic, Iron, Copper

Each heavy metal has a characteristic clinical profile that enables recognition even before confirmatory testing, based on the exposure history, the affected organ system, and specific findings.

Lead poisoning (plumbism):
Sources: old lead paint (pica in children), leaded petrol exhaust (historical), battery manufacturing, smelting, lead-containing Ayurvedic preparations. Lead accumulates primarily in bone (accounts for 95% of the body lead burden in adults). Blood lead reflects recent and active mobilisation.

Clinical features: (1) Haematological — microcytic anaemia with basophilic stippling of red cells (pathognomonic); lead lines (Burton's lines) — blue-black deposits of lead sulfide on the gingival margin near the teeth. (2) Neurological — in children: lead encephalopathy (irritability, learning disability, hyperactivity, seizures, coma); in adults: predominantly peripheral motor neuropathy ('wrist drop', 'foot drop' — due to demyelination of motor nerves). (3) Renal — tubular dysfunction; chronic nephropathy. (4) GI — colicky abdominal pain (lead colic), constipation.

Diagnosis: blood lead level (BLL); free erythrocyte protoporphyrin (FEP) or zinc protoporphyrin (ZPP) — elevated; X-ray: 'lead lines' at metaphyses of long bones (dense opaque bands at the growth plate) in children; may see lead objects in the GI tract on abdominal X-ray.

Chelation: BLL >45 mcg/dL → DMSA (succimer) oral preferred in children; BLL >70 mcg/dL OR encephalopathy → BAL + EDTA combination (synergistic; begin BAL 4 hours before EDTA to prevent redistribution of lead to the brain during EDTA mobilisation).

Mercury poisoning:
Sources: thermometer breakage (elemental mercury vapour), industrial catalysts, chloralkali plants, artisanal gold mining (amalgam burning), contaminated fish (methylmercury). Occupational exposure via respiratory route; dietary via fish consumption.

Clinical features: (1) Elemental Hg vapour inhalation: acute bronchitis and pneumonitis; subacute CNS effects (tremor, erethism — described classically as 'mad as a hatter' referring to hatters who used mercury nitrate in felt curing). (2) Inorganic mercury: proximal renal tubular damage — aminoaciduria, glucosuria (Fanconi syndrome), proteinuria. (3) Methylmercury: Minamata disease — progressive cerebellar ataxia, sensory neuropathy, constricted visual fields, deafness; in congenitally exposed infants: severe cerebral palsy-like picture.

Chelation: DMSA or DMPS preferred; BAL used historically but causes redistribution of mercury to the brain (BAL-Hg complex is lipid soluble and CNS-penetrant) — DMSA/DMPS are preferred for CNS mercury because their complexes are more water-soluble.

Arsenic poisoning:
Sources: groundwater contamination (West Bengal, Bihar, Bangladesh), pesticides (organoarsenicals), wood preservatives, traditional medicines. Acute ingestion (large dose) — 'rice water' diarrhoea, cardiovascular collapse, QTc prolongation. Chronic exposure — 'raindrops on dusty road' hyperpigmentation, Mees' lines (white transverse bands on nails), arsenical keratosis, blackfoot disease (peripheral vascular disease from chronic arsenicosis), and carcinogenesis (Bowen's disease, skin SCC, lung, bladder cancer).

Chelation: DMSA, DMPS, or BAL (for acute arsenic poisoning). Chronic arsenicosis management is primarily removal from source + nutritional support; chelation has limited benefit once structural damage is established.

Iron poisoning:
Sources: iron supplement tablets (particularly ferrous sulfate — the most common cause of paediatric poisoning deaths in many countries). The five stages are described in the pathophysiology section above. Diagnosis: serum iron at 4–6 hours (>300 mcg/dL concerning; >500 mcg/dL definitely toxic); TIBC (iron >TIBC indicates free iron circulating). Deferoxamine is indicated for serum iron >500 mcg/dL or significant clinical toxicity at lower levels; the 'vin rosé' urine confirms chelation is working.

Wilson's disease (copper):
Presentation: Liver (hepatitis, cirrhosis, acute liver failure in young adults), Neuropsychiatric (dysarthria, wing-beating tremor, dystonia, behavioural changes), Ocular (Kayser-Fleischer rings — golden-brown rings at the corneal periphery visible on slit lamp, pathognomonic when present). Psychiatric presentation may precede neurological diagnosis by years. Chelation: D-penicillamine (first-line); trientine (second-line if D-penicillamine not tolerated); zinc acetate (prevents copper absorption — used for maintenance and in presymptomatic patients); liver transplantation in acute liver failure (corrects the metabolic defect).

Chelating Agents: PK, PD, Indications and ADRs

Understanding the pharmacological properties of each chelating agent is essential for both correct selection and anticipation of adverse effects during therapy.

Dimercaprol (BAL):
Oily liquid with a strong garlic odour; administered by deep IM injection only — painful. Rapidly absorbed and distributed; metabolised and excreted within hours. The metal-BAL complex is hepatically cleared and excreted in bile. ADRs: injection site pain, hypertension (particularly systolic, lasting ~30 min after injection), tachycardia, headache, vomiting, fever. Nephrotoxicity (BAL is itself nephrotoxic — avoid or use cautiously in renal impairment). The gold standard contraindication: DO NOT USE IN IRON OR CADMIUM POISONING — forms highly toxic, CNS-redistributing complexes. Also avoided in hepatic failure.

Calcium disodium EDTA (CaNa₂EDTA):
Given IV or IM; IV preferred for severe poisoning. Forms very stable chelates with lead (and other multivalent metals). Does not cross the blood-brain barrier well — therefore does not chelate lead from the CNS; must be combined with BAL (which is more lipid-soluble and CNS-penetrant) in patients with lead encephalopathy. ADRs: nephrotoxicity (proximal tubular damage — monitor urine output and creatinine); hypercalcaemia (less common with the calcium form). Must NOT use sodium EDTA (Na₂EDTA alone) — would chelate endogenous calcium causing severe hypocalcaemia and cardiac arrest.

DMSA (succimer):
Oral capsules; available for outpatient use. Well tolerated. ADRs: GI upset, transient LFT elevation, rash, neutropenia (rare). Blood lead can rebound after stopping — may require repeated courses. Advantage: can be used in children living at home without hospitalisation (BLL 45–70 mcg/dL). Does not cross the blood-brain barrier effectively in humans.

Deferoxamine:
Given IM or as slow IV infusion (maximum 15 mg/kg/hour; rapid IV infusion causes hypotension — rate-limiting step). Extremely selective for iron and aluminium. The ferrioxamine complex turns urine orange-pink ('vin rosé'). Contraindications: severe renal failure (ferrioxamine cannot be excreted). ADRs: hypotension (especially with rapid infusion), visual disturbances with prolonged therapy (retinal toxicity), ARDS with high-dose prolonged infusion. NEVER used for lead, mercury, arsenic — no efficacy.

D-penicillamine:
Oral; metabolised in the liver; primarily used in Wilson's disease. Forms a stable, urinary-excreted copper-penicillamine complex. ADRs: hypersensitivity (early — rash, fever, lupus-like reaction), immune complex glomerulonephropathy (proteinuria), aplastic anaemia, myasthenia gravis-like syndrome (dose-dependent), loss of taste (ageusia — transient). Requires monthly FBC and urinalysis monitoring. Contraindicated in penicillin allergy (cross-reactivity possible but not absolute — proceed with caution).

Clinical Decision-Making in Heavy Metal Poisoning

Clinical decision-making in heavy metal poisoning requires matching the correct chelator to the metal, considering the severity of poisoning, and monitoring for both efficacy and chelator-related toxicity.

The most important metal-chelator pair rules:
1. Lead encephalopathy (BLL >70 mcg/dL, symptomatic): BAL + EDTA combination. Critical sequence: start BAL 4 hours BEFORE EDTA. Rationale: EDTA mobilises lead from bone into the bloodstream; without BAL coverage, the sudden rise in blood lead crosses the blood-brain barrier and worsens encephalopathy. BAL given first provides CNS-penetrant chelation before EDTA's mobilisation effect.
2. Paediatric lead poisoning without encephalopathy (BLL 45–70 mcg/dL): DMSA oral — preferred because it is oral, less toxic, and permits outpatient management.
3. Iron poisoning with systemic toxicity: Deferoxamine IV — do NOT use BAL (toxic) or EDTA (ineffective).
4. Wilson's disease (copper): D-penicillamine first-line; trientine if not tolerated.
5. Arsenic/mercury acute poisoning: DMSA or DMPS preferred; BAL acceptable but note the CNS redistribution risk for mercury.

Monitoring chelation therapy:
- Blood lead levels: repeat at end of each DMSA course to guide further treatment. Lead rebounds from bone after chelation — further courses may be needed.
- Renal function: all chelators that enhance urinary metal excretion risk tubular toxicity. EDTA and BAL are the most nephrotoxic.
- D-penicillamine: monthly FBC (for aplastic anaemia), urinalysis (for proteinuria).
- Deferoxamine: urine colour (vin rosé confirms activity); visual fields and retinal examination with prolonged courses.

When to stop chelation:
Chelation is continued until blood/urine metal levels fall below symptomatic thresholds and symptoms are controlled. For Wilson's disease, D-penicillamine (or trientine) is typically lifelong — stopping therapy causes rapid copper reaccumulation and acute liver failure (a well-documented, potentially fatal complication if the patient discontinues treatment on their own).