Clinical Diagnosis of Poisoning of Heavy Metals Flashcards
1
Q
LO
A
- 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
2
Q
Define a metal
A
3
Q
Define a Metalloid
A
4
Q
Define a heavy metal
A
5
Q
Trace amounts of some heavy metals are essential for human health, what are some of these heavy metals?
A
Fe, Cu, Co, Z, Se and Cr
6
Q
Are heavy metals used in our everyday lives?
A
Heavy metals are rare in the earth’s crust by extensively used in our everyday lives
7
Q
What are some examples of heavy metals thats are likely to cuase toxicity if extensively used?
A
Cr, As, Cd, Hg and Pb
8
Q
What types of heavy metals can be detected in whole blood and urine?
A
9
Q
What is lead, Pb been used in?
A
- 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
10
Q
What action has helped to remove the environmental exposure of the population to lead?
A
- 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
11
Q
What are some examples of lead poisoning sources?
A
- 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
12
Q
Why are children more susceptible to lead poisoning?
A
- 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
13
Q
What are the routes of exposure for lead?
A
GI
Lungs
Retained Pb based foreign bodies route of ongoing exposure
Skin
14
Q
Tell me about the GI route of exposure to lead
A
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
15
Q
Tell me about the lungs exposure to lead
A
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
16
Q
Tell me about the skins route of exposure to lead
A
o Inorganic lead is not absorbed
o Organic lead is well absorbed
17
Q
Is most exposure to organic or inorganic lead?
A
Inorganic
18
Q
What is organic lead used in?
A
Organic lead used (tetraethyl and tetramethyl) in petroleum industry but cases of exposure are rare
19
Q
Tell me about the pharmacokinetics of lead
A
- 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
20
Q
Tell me about the mechanism of haematological toxicity for lead
A
- ‘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
21
Q
Tell me the mechanism of CNS toxicity for lead
A
- 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
22
Q
Will children suffer neurological effects at higher or lower concentrations than adults?
A
Lower
23
Q
Neurological adverse effects in children have been associated with blood lead levels previously thought to cause no harm
A
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
24
Q
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?
A
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
25
Late signs of lead intoxication in persons exposed to chronically high lead levels are...?
slowed nerve conduction and forearm extensor weakness (wrist drop)
26
What does autonomic neuropathy result in?
results in abdominal colic and pain, sometimes with diarrhoea and vomiting, sometimes constipation
27
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
28
What does upper abdominal pain and lower abdominal pain indicate?
Upper= More acute exposure to lead
Lower= more chronic exposure to lead
29
In children acute exposure to very high blood lead levels may produce what?
encephalopathy plus ataxia, coma, convulsions, death, hyperirritability, and stupor
30
In adults, lead encephalopathy occurs at extremely high what?
BLLs
31
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
32
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)
33
Refer to lecture for cases surrounding lead poisoning
34
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
35
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
36
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
37
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
38
Techniques for metal measurement measure what?
* Techniques for metal measurement measure total metal therefore chelate and free
* Need to monitor rebound after cessation of chelation
* Treatment as vascular space is replenished from other body compartments
39
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
40
Lead- treatment
* In adults’ guidance slightly different. If BLL <2.4µmol/L (< 50 µg/dL) and patient asymptomatic and not pregnant, reasonable to monitor impact of cessation. Repeat BLL in 2 weeks
* If BLL >2.4 µmol/L (>50µg/dL) should be considered for chelation
* Note for children and adults, chelation can be NaCa edetate or DMSA
* DMSA not license in UK but can be given orally and less zinc deficiency
* Laboratory deals with cases of mildly raised BLL above reference range in Wales (adults and Children)
* Contact clinician/patient/ family
* Case record including identification of likely source
* If source unknown investigation of water, soil, site visit
* Cascade testing for other family members or neighbours
* Patient information leaflets
41
Lead- reference ranges
* Controversy over blood lead reference ranges
* Adults and children previously <0.48µmul/L (<10µg/dL
* Evidence that adverse cognitive effects at blood lead <0.48 µmol/L particularly between 0.24 and 0.5 µmol/L (5-10µg/dL)
* PHW took decision to reduce reference range in children <18 yrs to <0.25 µmol/L (<5µg/dL)
* Adults <0.48 µmol/L
* New discussion at <0.1µmol/L for children
42
Lead- laboratory measurement
* Whole blood lead for inorganic lead
* Urine for organic lead
* ZnPP helpful to see if chronic or acute toxicity
* Urine porphyrins not routinely used to assess Pb exposure
43
What is the third major environmental poison?
Where does it occur and what is it used in?
* After lead and mercury, **arsenic** is the third major environmental poison
* **Occurs naturally** in the environment
* Used in industry- ores of smelting gold, copper and zinc
* More recently used in semiconductor industry
* Used in insecticides, herbicides, feed additive and wood preservatives
44
What are the different forms of arsenic?
Organic and inorganic
45
Tell me about inorganic arsenic and rice
* Inorganic arsenic contamination in groundwater
* Important to know as contaminates rice and workers from rice fields
* Different concentrations in groundwater and hence rice depending on where it is grown
* Rice absorbs more arsenic than any other cereal
* Legislation in UK on concentrations of As in rice
* Issues has been with products such as rice milk if given to children
* FDA now state that rice milk should not be given to children <5 years as a substitute for either cows, breast, or formula milk
46
What are the other sources of exposure for arsenic?
* Arsenic trioxide as ‘Fowlers solution’ (1% K Arsenide)
* Arsenic trioxide trialled more recently as a cancer treatment
* As also found in Ayuverdic treatment with other heavy metals
47
Tell me about the absorbtion of arsenic?
* Ingested inorganic salts well absorbed
* Inorganic salts have different solubility
* Very soluble salts absorbed via inhalation or through skin
* Organic arsenic almost completely absorbed
* Once absorbed rapidly distributed to lungs, liver, kidney, and spleen
* Then distributed to skin, nails, and hair where it binds tightly to keratin
48
Arsenic is present in different oxidation states, have different toxicities
49
Tell me about exposure to Arsine gas
* Arsine gas, rapidly absorbed by lungs and disrupts erythrocyte Na/K pumps cause haemolysis
* Exposure is rare and often accidental
* Arsenite most important toxic agent (As(II)O3)
* Adverse effects widespread
o GI
o CV
o Renal syndrome
o Long term get peripheral and CNS adverse effects
50
Tell me about the metabolism of arsenic in the pharmacokinetics
* Metabolism via reduction and methylation varies between species
* In humans, metabolism is in the liver to produce less toxic daughters Monomethylarsonic acid (MMA) and Dimethylarsinic acid (DMA)
51
How is arsenic excreted?
Urine excretion 10-15% inorganic As, 10-15% MMA and 60-80% DMA
52
In fish, what further stage occurs?
What is produced?
* In fish get further metabolism to arsenobetaine
* Arsenobetaine is a stable and non-toxic compound
53
Tell me what happens when humans ingest fish which contain arsenic?
* In fish get further metabolism to **arsenobetaine **
* Arsenobetaine is a stable and non-toxic compound
* It is rapidly absorbed in humans through ingestion of fish/ seafood containing As
* Inorganic As are large ligands
* **As (III) toxicity** binding to sulphydryl groups on proteins
* **Inhibition of enzymatic systems i.e. pyruvate dehydrogenase **
* As (V) resembles structure of SO4 and PO4 ion and can enter mitochondria
*** Competes with PO4 **to form high energy compounds which are not stable
* Uncouple oxidative phosphorylation
* Endothelial damage, loss of capillary integrity, capillary leakage, volume loss, shock
54
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
55
What are some symptoms to chronic exposure to arsenic?
o Occupational exposure- dermatitis, skin and nasal ulcers
o Increased incidence of peripheral neuropathy, cardiovascular disease, cirrhosis, and renal tubular impairment
o Living in areas with contaminated groundwater develop hyperkeratosis, pigmentation, and ulcers after 2 to 3 years exposure
o Known human carcinogen to skin and lungs
56
Arsenic- symptoms Palmer Keratosis
57
Refer to lecture for arsenic cases
58
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
59
Arsenic- summary
* Arsenic can be measured in blood- inorganic
* Also measured in urine
* Most ICPMS measure total urine As
* Can refer these samples to HSL Buxton for speciation
* Will need to exclude fish and seafood from the diet for 5 days before a collection
60
What is the second major environmental poison?
Tell me about its use?
**Mercury** is the second major environmental poison
Long history of use
o Cinnabar- HgS- used in embalming antibacterial
o Calomel (Hg2Cl2 Mercurous chloride)- used until 1953, for nappy rash and teething powders
61
Past cases of mercury use
* 1978 case described of fatal poisoning of child due to mercurochrome for a large omphalocele
* 1984 fatal Hg poisoning irrigation of peritoneal cavity with mercuric chloride
62
What does more recent exposure to mercury come from?
o Small photographic or hearing aid batteries (mercuric oxide)
o Ethnic remedies
o Skin lightening creams (mercuric iodide)
o Mercury vapour from dropped thermometers
o Vaccinations (MMR) and autism
o Dental amalgams
63
What is the toxicity of mercury dependent on?
o Organic vs inorganic
o Oxidation state
64
How is organic mercury produced?
65
Organic mercury
66
How long does methylmercury take to equilibrate in the blood?
About 30 hours
67
Why is the blood ratio in humans of mercury 5:1?
Equilibration with tissues quicker than excretion so brain: blood ratio in humans is 5:1
68
What is the target organs for methylmercury?
CNS target organ for methylmercury
69
Why is the Foetus 5-10 more sensitive to same dose as adults?
Crosses the placenta freely
70
Elemental mercury
71
Mercurous mercury salt
72
Mercuric Mercury salts
73
Is Hg (II) reactive?
Highly reactive
74
What are the effects of Hg (II)?
* Disrupts membranes
* Combine with sulphydryl groups to inhibit enzymes and damage DNA
* Kidney major target organ for Hg (II)
o Concentrated in proximal tubule
o Causes mitochondrial, lysosomal in proximal tubules
75
Refer to lecture for mercury cases
76
What is the treatment for mercury?
* Chelation
* Toxbase advises discuss each case
* Consider if patient symptomatic and/or
o Blood >25 nmol/L
o Urine >6 nmol/mmol
* Choices same as DMPS or DMSA
* Again DMPA marginally favoured
77
Mercury- laboratory measurement
* Blood Hg for organic mercury
* Urine Hg for inorganic Hb
* Generally advise both as type of mercury unknown
78
Tell me about **Thallium** what is it often used in?
* Not commonly but highly toxic
* Tasteless, colourless and odourless- a poisoners poison
* Ingestion of more than 10/15 mg/kg is lethal
* Used in optical glass for transmission of long wavelength radiation
* Used in electronic industry as a dopant for semi-conductors
* Used as a catalyse in organic synthesis
* Many countries use thallium salt as rodenticides
79
Whats the pharmacokinetics of thallium?
* Closely resembles potassium in size and charge
* Volume of distribution is large
* Within 48 hours enter CNS and other tissues
* Elimination starts after 25 hours
* 2/3rds excreted in intestine but re-absorption occurs
* Remaining third excreted in urine
80
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
81
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
82
What are the symptoms of chronic thallium poisoning?
o Symptoms can be more insidious in onset:
Alopecia
Distal neuropathy (initially sensory then motor loss) then spread proximally
Respiratory paralysis
Personality changes and severe loss of intellectual function
83
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
84
Refer to lectures for thallium cases
85
How is metal analysis performed?
Metal analysis performed by either **atomic absorption or ICPMS**
86
Tell me about Atomic absorption
87
What is the main treatment for metal analysis?
Pre ICPMS
88
What are the disadvantages of the pre-ICPMS technique?
* Disadvantages
o Single element
o Lacks sensitivity of dynamic range than ICPMS
o Larger sample volume required for some elements
* Large number of trace element laboratories moved to ICPMS
89
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 **
90
ICPMS
91
What samples can be analysed by ICPMS?
What is the general approach to this technique?
* sample analysed can by whole blood, plasma, urine, fluids, tissues
* General approach is to dilute the sample in diluent
* Dilution factors can vary from 1 in 15 to 1 in 100 for example
* Internal standard usually added
* Try to match internal standard by mass/ ionisation potential
* Use microwave digestion to digest tissue pre dilution
* Commonly aqueous standards
* ICPMS allows multielement analysis on one run
* UHW approach to batch elements commonly requested together
o Plasma: Cu, Se, Zn
o Whole blood: Pb, Cd, Hg, As, Tl
o Urine: lots of elements
* Semi quant scan- scanning mass spectrum and gives semi quant of each element
* Confirm any elevations on quantitative assay
* Speciation uses LC coupled to ICPMS
* Chromatographic separation of arsenic species prior to analysis of As by ICPMS
92
Refer to lecture for ICPMS case for heavy metal exposure
93
Outcomes of talk
* Clinical and forensic toxicology of important metals including **As, Pb, Tl and Hg **
* **Pharmacokinetics and metabolism** of important heavy metals and relationship to acute and chronic toxicity
* **Laboratory technique for detection and measurement** of heavy metals in biological fluids and tissues
