Clinical Diagnosis of Poisoning of Heavy Metals Flashcards
LO
- Clinical and forensic toxicology of important metals including As, Pb, Tl and Hg
- Pharm kinetics and metabolism of important heavy metals and relationship to acute and chronic toxicity
- Laboratory techniques for detection and measurement of heavy metals in biological fluids and tissues
Define a metal
Define a Metalloid
Define a heavy metal
Trace amounts of some heavy metals are essential for human health, what are some of these heavy metals?
Fe, Cu, Co, Z, Se and Cr
Are heavy metals used in our everyday lives?
Heavy metals are rare in the earth’s crust by extensively used in our everyday lives
What are some examples of heavy metals thats are likely to cuase toxicity if extensively used?
Cr, As, Cd, Hg and Pb
What types of heavy metals can be detected in whole blood and urine?
What is lead, Pb been used in?
- Pb has been used in domestic and industrial applications for hundreds of years
- Toxicity has been recognised for almost as long
- It is the most heavily regulated and researched of the heavy metals
- Some degree of exposure is almost universal
What action has helped to remove the environmental exposure of the population to lead?
- Removal of lead-solder from tin cans and regulated on use of lead in petrol over previous 15-20 years has reduced the population environmental exposure
- Use of ‘unleaded petrol’ has further reduced environmental exposure
- ‘Control of lead at work (CLAW) 2002 regulation approved code of practice’ results in improved industrial hygiene and surveillance reducing industrial exposure
What are some examples of lead poisoning sources?
- Lead in pipes plus acidic treatments- contaminated water
- Industrial
- Hobbies (stained glass windows)
- Renovating homes (old lead paints)
- Auyverdic medicines/imported medicines
- Paints from imported toys
- Kohl make up
- Soil and dust
Why are children more susceptible to lead poisoning?
- Adults and children can be involved in cases of lead toxicity
- Children and more susceptible as they have a faster rate of growth and development hence absorption
- More likely putting things in their mouth i.e., toys or crawling on floors with dust exposure
- Conditions including PICA put children at increased ris
- Foetus can be exposed as lead crosses the placenta
What are the routes of exposure for lead?
GI
Lungs
Retained Pb based foreign bodies route of ongoing exposure
Skin
Tell me about the GI route of exposure to lead
o First major route of absorption
o Children absorbing up to 50-80% of ingested lead
o Where adults 3-10%
o Increased absorption if Ca or Fe deficiency present
Tell me about the lungs exposure to lead
o Second major route of exposure
o Amount absorbed depends on number of factors
o Including size of particle
o Almost all inhaled lead absorbed
Tell me about the skins route of exposure to lead
o Inorganic lead is not absorbed
o Organic lead is well absorbed
Is most exposure to organic or inorganic lead?
Inorganic
What is organic lead used in?
Organic lead used (tetraethyl and tetramethyl) in petroleum industry but cases of exposure are rare
Tell me about the pharmacokinetics of lead
- In the body 5% of lead forms an interchangeable pool between soft tissue and blood
- Remaining 95% sequestered in bone
- About 93% of inorganic lead entering the body is bound rapidly to erythrocyte membranes and haemoglobin with a half-life of around 35 days
- With chronic exposure less lead enters the bone but is bound to proteins (possibly metallothionine) increasing the half-life in blood
- Half-life of Pb in bone is 20-30 years
Tell me about the mechanism of haematological toxicity for lead
- ‘Critical organ’ for organic lead is the bone marrow
- Inhibition of key enzymes in haem biosynthetic pathway
- This would only be of clinical significance with chronic exposure
- Acute lead exposure can get haemolytic anaemia
- Increases urine porphyrins
- Formation of zinc protophyrin in the blood
- Microcytic hypochromic anaemia
- Reticulocytes on blood film
- Pb also inhibits pyrimidine 5 nucleotidase
- Leaves clumps of RNA in erythrocytes
- Visible on blood film as basophilic stippling
Tell me the mechanism of CNS toxicity for lead
- Other main ‘critical organ’ for Pb is CNS
- Associated with various types of brain damage including:
o Problems with thinking (cognition)
o Difficulties with organising actions, decision, and behaviours (executive functions)
o Abnormal social behaviours (aggression)
o Difficulties in organising fine movements (motor control) - Lead causes activation of protein kinase C (PKC) and a preferentially binds to PKC than its activator calcium
- Results in problems with neurotransmitter release
- Clinical effects difference from chronic to acute toxicity and dependent on blood concentrations
Will children suffer neurological effects at higher or lower concentrations than adults?
Lower
Neurological adverse effects in children have been associated with blood lead levels previously thought to cause no harm
o <10 µg/dl (<0.5µmol/L): reduction in IQ performance and other neuropsychological effects including hearing
o <5 µg/dl(<0.24 µmol/L): decrease IQ, lower academic achievement, and reductions in specific cognitive measures
Less severe neurological and behavioural effects have been document in lead-exposed workers with BLLs ranging from 40-120 µg/dL (1.93 to 5.80 µmol/L). What are someof these effects?
o Decreased libido
o Depression/mood changes
o Diminished cognitive performance
o Diminished hand dexterity
o Dizziness
o Fatigue
o Headache
o Forgetfulness
o Impaired concentration
o Paresthesia
o Reduced IQ scores
Late signs of lead intoxication in persons exposed to chronically high lead levels are…?
slowed nerve conduction and forearm extensor weakness (wrist drop)
What does autonomic neuropathy result in?
results in abdominal colic and pain, sometimes with diarrhoea and vomiting, sometimes constipation
What are the most common presenting features of lead poisoning?
Abdominal symptoms together with marked general weakness, fatigue and malaise are the most common presenting features
What does upper abdominal pain and lower abdominal pain indicate?
Upper= More acute exposure to lead
Lower= more chronic exposure to lead
In children acute exposure to very high blood lead levels may produce what?
encephalopathy plus ataxia, coma, convulsions, death, hyperirritability, and stupor
In adults, lead encephalopathy occurs at extremely high what?
BLLs
Organic lead highly lipophilic therefore CNS effects predominate. What are some of these effects?
o Encephalopathy
o Delirium
o Confusion
o Anorexia
o Vomiting
o Weakness
o Fatigue predominate
What is the mechanism of renal toxicity with lead?
- As organic lead exposure continues, next organ to be affected is the kidney
- The lowest BLL which lead has an adverse effect on the kidney is unknown
- Lead nephrotoxicity is characterised by
o Proximal tubular nephropathy
o Glomerular sclerosis
o Interstitial fibrosis - Biochemically can see increased serum creatinine (reduced glomerular filtration)
- Fanconi type syndrome mostly found in children (defects in proximal tubular reabsorption causing glycosuria, phosphaturia, generalised aminoaciduria and bicarb wasting)
Refer to lecture for cases surrounding lead poisoning
What is the treatment for lead?
*** Toxbase states **
o Reasonable to offer treatment to symptomatic children or with BLL >2.4µmol/L (>50 µg/dl)
o Note that there is reliable evidence that chelation therapy does not improve cognitive function in children <3 years with BLL <2.2µmol/L(<45µg/dl)
*** In children BLL 0.5 to 2.4 µmol/L **
o Remove from source
o FBC, Ferritin, Renal, Liver, Bone profile
o Correct Ca and Fe deficiency
o Repeat BLL in 1 month
o No role for Na Ca EDTA test
What is the treatment of heavy metal poisoning?
- Dialysis, hemofiltration, and plasma exchange previously used
- Once metal become distributed in extravascular compartment, so much in tissues that these techniques have negligible effects
- May be necessary to manage renal failure
- There are certain antidotes i.e., Prussian blue for thallium
- Treatment generally with chelating agents
What is the criteria for chelating agents?
o Available in a suitable form for administration, preferably oral
o Neither the agent nor the chelate with the element must be toxic
o Any side effects such be minimal i.e., EDTA given as calcium salt to minimalize endogenous Ca chelation
o Agent or chelate must not be metabolised to re-release the element i.e., citrate a good chelating agent but is readily metabolised
o The thermodynamic association constant for the agent with the element must be favourable compared to that of the element with the body constituents
o The chelate must be readily excreted in urine or bile
Do the blood concentrations of the metal generally rise or fall further during chelation? Why?
Rise further
Probably secondary to removal to element from tissue
Lead- CaNa EDTA
- Children with blood lead 2.4-3.3 µmol/L (50-70 µg/dl) in addition to above- chelate with sodium calcium edetate 40mg/kg twice daily (or 75mg/kg/daily) by IV infusion for 5 days
- Monitor BLL for Zn during chelation
- Repeat BLL after 1 week
- May need further course if >2.2 µmol/L
Arsenic is present in different oxidation states, have different toxicities
What are some symptoms of acute arsenic exposure?
o Vomiting and diarrhoea
o Haematuria and acute renal failure
o Abdominal pain, facial oedema, upper respiratory tract difficulty and obstructive jaundice if over long period
o After 3 weeks- anorexic and features of neuritis (weakness, salivation, trembling, loss of tendon reflexes, impaired cutaneous sensation)
o Mees Lines
Arsenic- symptoms Palmer Keratosis
What is the treatment for arsenic?
* Toxbase states:
o Consider need in patients who are symptomatic and/or have elevated blood/ urine As
- Options DMPS (dimercaptopropane-1-sulfonate) or DMSA (dimercaptosuccinic acid)
- Insufficient data to suggest which is preferred but evidence favours DMPS
- DMPS oral (unless acute GI features i.e., vomiting and diarrhoea) then given IV, DMSA oral
- Continue chelation with 5 days courses until relief of systemic clinical features
- Monitor urine and blood As to aid deciding whether further chelation is needed
What is the toxicity of mercury dependent on?
o Organic vs inorganic
o Oxidation state
How is organic mercury produced?
Organic mercury
Elemental mercury
Mercurous mercury salt
Mercuric Mercury salts
Thallium, mechanism of toxicity?
- Thought to enter cells by its similar size and ionic charge to potassium
- Can exchange and compete with K to cause disruption to fundamental cellular metabolism
- Toxicity depends on ability to bind with sulphydryl groups in mitochondrial membrane and neuronal axons
- TI interferes with mitochondrial energy production
- TI reported to form insoluble complexes with riboflavin possible explaining why gives similar symptoms to this vitamin deficiency i.e., alopecia, dermatitis and neuropathy
What are the symptoms of acute thallium poisoning and the time frame in which they occur?
- Acute poisonings
o Symptoms may be delayed 12-24 hours
o May not see maximum for 2-3 weeks
o Recovery slow
How do you measure the levels of thallium and what is the treatment?
*** Measure blood and urine Tl **
o If blood >50nmmol/L or urine >100nmol/L significant exposure
o Then chelate
* Treatment
o Agent Prussian blue
o Tl containing complex excreted in faeces
o Continue chelating until Tl can no longer be detected in urine
o If Prussian blue not available, then use repeat activated charcoal
Tell me about Atomic absorption
What does ICPMS stand for and tell me what each compoenent does?
**Inductively coupled plasma mass spectrometry **
* ICP
o Inductively coupled plasma
o High temperature source of positive ions
o Plasma is a highly energised ionised gas
o Gas used in plasma is argon
o Gas lit using initial spark
o Spark amplified and maintained by RF coil i.e., inductive coupling
*** MS **
o Single quadrupole mass filter most commonly used
o Triple quadruple
o High resolution
o Time of flight
*** Optical emission **
ICPMS
