Transcript Thallium intentional intoxication Pelclova et al

INTENTIONAL THALLIUM
POISONING – VERIFICATION
AND TREATMENT
Pelclová D (1), Šenholdová Z (1), Lukáš E (1), Urban P (2), Lacina L (3), Vlček K (1),
Fenclová Z (1), Kitzlerová, E (4).
1. Department of Occupational Medicine, Charles University, Prague
2. National Institute of Public Health, Prague
3. Department of Dermatology;
4. Psychiatric Department,
General University Hospital and First Medical faculty,
Charles University, Prague, Czech Republic
THALLIUM
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discovered in 1861 by Sir Williams Crooks
1862 by French chemist Claude-Auguste Lamy
In Greek, thallos "green twig."
Using spectroscopy, the brightest lines in the spectrum of
thallium are green
melting point 300º C (576º F)
boiling point 1480º C (2,655º F)
elementary thallium non-toxic
monovalent and threevalent salts very toxic
LD about 900 mg
THALLIUM
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rather uncommon element
world production 12 tons/year semiconductors,
photocells, optic glass, thermometers
in medicine – Tl201radioactive tracer in heart
scintigraphy to detect myocardial ischaemia
occurrence in minerals
emissions 1500 tons/year granite, coal
THALLIUM – IN THE PAST
Tl2SO4 has long been used as
rodenticide, insecticide
 Colorless and tasteless
 Tl acetate : treatment of
 veneric diseases, ringworm
 Depilatory agent
 Low therapeutic index
 Banned in the 1970ies in most countries
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Toxicokinetics – inorganic salts
absorption by all ways, oral about 90%
 distribution to all tissues
 greatest concentration in the intestines, liver,
kidney, heart, brain and muscles
 excretion by faeces and urine,
 the proportion 2:1
 enterohepatic circulation
 half-lives 1-30 days
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Pathophysiology - 1
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Similarities in charge and ionic radius between K+ and Tl+
ions), Tl substitutes for K:
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1. blocks energy utilization by Na-K-ATPase channel =
(active transport of monovalent ions - K+ across cell
membrane)
Thallium disturbs maintaining of a resting potential across
the membrane of active cells - Tl has 10-fold greater affinity.
Neuronal, cardiac and skeletal muscle cells
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2. blocks energy production from glucose: ADP to ATP by
pyruvate kinase = K requiring enzyme - links anaerobic
glycolysis to the Krebs cycle)
inhibition by binding with 50-fold affinity comparing to K.
Pathophysiology - 2
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3. damages riboflavin, precursor of FAD forming an
insoluble complex and intracellular sequestration of vit. B6
decrease of riboflavin disrupts metabolism by reducing
activity of Krebs cycle
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4. binds to SH groups and interferes with formation of
disulphide bonds in keratin - structural damage to hair, nails
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5. causes activation or inhibition of other enzymes (ALA
synthetase, B12 metabolism…)
2 Case reports
2 patients, mother and daughter, living in the
same household
 Very probably intentional poisoning by one
member of the family
 Oral intake
 Chronic
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Patient A
mother
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44years old
PH: no serious disease
OH: super-market manager
1. poisoning
November 2004 sudden strong chest pain, following 3
days severe pain with paresthesias in both lower limbs
Symptoms disappeared within 3 weeks, following 3 weeks
persisted mild paresthesias and discomfort in the lower
limbs
2. poisoning
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In March 2005 she developed suddenly a strong muscular
pain in the lower limbs. The gait was painful „as on a broken
glass“.
within 5 days she became bald.
In April – one month stayed at neurology dept. With
suspicion on LI syndrome and posttraumatic stress disorder
(anxious, depressive, had work overload and home conflict
environment)
EMG, evoked potentials, MRI normal
In June improvement, returned to work
3. poisoning
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August 2005
Progressive pain in lower limbs with paresthesias
Blurred vision – she could differentiate only dark
and light spots in the periphery of the visual field
After 3 weeks her condition improved a little
Mild pain in the feet and knees persisted several
weeks
Vision difficulties persisted
Eye fundus : n. opticus atrophy
Hospitalization
Dept. Occupat. Medicine
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Admitted on January 31,2006
5 months after last intoxication
1) attempt to prove the poisoning
2) attempt to improve vision damage – she still could not
read
EMG: mild motor and sensoric damage, EEG borderline
Visual evoked potentials: severe damage with visus
BIOLOGICAL HALF-LIFE of thallium
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broad range of 1-30 days
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Hoffman RS. Toxicol Rev 2003
Patient B: History
daughter
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22years old woman
PH: no serious disease
OH: high school,1 year maternity leave
FH: mother treated for symptoms of unknown etiology,
father probably psychopathic personality, no treatment,
daughter 1 year old, healthy
1 poisoning
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In December 2005 suddenly strong pain in lower limbs,
maximum in the stockings distribution, ache in the skin of
lower extremities
Anorexia
3rd week symptoms deteriorated, treated with analgesics
(tramadol)
4th week lost all body hair (except eyebrow and eyelashes)
She developed blurred vision, weakness of lower limbs,
unable to walk
Hospitalized at neurology dept.
Hospitalization
at Neurology Dept.
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Blood and urine sent to toxicology screening (drugs, metals
incl. Cd, Pb, Hg, Se, Zn, Tl,)
5th week: vision damage with maximum in the central area,
right and left eye
Shortly also speaking difficulties and feeling of heavy tongue
Positive results for thallium in blood and urine
Hospitalization at
Dept. Occup. Medicine
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Admitted on January 26, 2006
7th week of symptoms
On admission:
On a wheel chair, paraparesis, motor weakness
Bald (only eyebrow and lashes left)
Could distinguished fingers from 30 cm complained of
strong pain in lower limbs
Altered mental status, depressive, anxious
Slow speech, low voice
Antidote
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Prussian blue - Fe4[Fe(CN)6]3 (ferric hexacyanoferrate),
Radiogardase, Heyl
CAS 14038-43-8
discovered 1704 by a Berlin color maker Diesbach
since the 1960s used to treat Cs and Tl poisonings
Binds thallium by ion exchange, adsorption and
mechanical trapping within the crystal structure
Specific treatment
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Insoluble, low absorption from the GIT (?)
stops enterohepatic circulation of thallium
Increases elimination both to faeces and urine
Advantage: rare side effects, bluish sweat and
tears
Reduces half-life from 8 to 3 days
First dose after arrival 6g /12 hours
Continued with 12 g/day in 4 doses
Supportive therapy
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10% mannitol as cathartic
Charcoal (Carbosorb) 2x 25 g/day
Analgesics
Vit. B12, B6
Topical dermatological treatment supporting hair growth
Thallium concentration in urine µg/l in the daughter
Total excretion 8.4 mg in 32 days, further Tl in faeces
Antidotal treatment 22 days
Toxicological analysis in daughter
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Thallium found in all biological materials –
blood, urine, faeces, hair
Examinations
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Neurological (incl. needle EMG, VEP, BAEP, EEG, MRI of
the brain)
Ophthalmological (visus, fundus, perimeter)
Dermatological
Further:
ECG, psychiatric, blood biochemical analysis, urinalysis,
kidney functions
January 2005
2nd month
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Unable to walk
Severe polyneuropathy
Verified by needle EMG
sensory, motoric and autonomic
Symmetrical
Low extremities only
April 2006
5th month
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Able to walk with a walker leg support.
Severe motor polyneuropatie. Mild improvement,
esp. Sensitive and autonomic nerves.
MRI of the brain: normal finding incl. optic nerves,
tracts, chiasma and visual cortex
Atrophy of both optic nerves on the ocular fundus
August 2006
9th month
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Still severe motor polyneuropathy
She could walk without support
Unstable gait
Pathology in EEG, VEP, BAEP
Vision of fingers from 0.75 m
EEG, BAEP
VEP
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Slightly abnormal
entrance findings
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Control: slow
improvement
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2nd month: no
response due to severe
vision damage
5th month: Low peak at
right side, no response
left side.
9th month: Bilaterally
abnormal finding low
reproducibility and low
VEP, worse left side
FURTHER FINDINGS
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ECG – non-specific ST segment and T wave
changes during a febrile state with tachycardia
Transthoracic echocardiography – diffuse
hypokinesis of the left ventricle, markers normal
Psychiatric examination
Neuropsychological testing not possible – visual
problems
USG of the abdomen normal
Kidney functions normal
Total alopecia
daughter
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Reversible
Highest value 36.1 μg/g (5th week)
Sequential analysis of 1.5 cm hair segments = 6 months
Thallium 5.61- 6.24 – 7.41 – 7.81 – 6.67 μg/g hair
New hair 6th week of poisoning and 8th day of antidote
treatment– drop to 1.6 μg/g) Daniel J Am Acad Dermatol 2004
Trichological analysis of the acute hair
loss of the daughter
Normal hair
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Light microscopy The proximal end hair fibre tapered and distorted.
Rough surface of the proximal end
Amorphous cuticular and cortical cells as a sign of the
pathological keratinisation. (Metter and Vock 1984)
Trichological analysis of the acute hair
loss of the daughter
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Under transmitted-light microscopy the cortex dark
discolorisation and disorganized on the widened clubshaped end.
Gaseous inclusions under the phase contrast microscopy.
Trichological analysis of the new
hair of the mother
Hair of the acute loss not available
 Recent hair – normal finding, smooth surface
of keratinocytes
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Thallium in urine (μg/l)
Optical Emission Spectrometer - Inductively Coupled Plasma (OES-ICP)
daughter
Initial
measurement
urine
mother
580.00
8.50
Jan.15
Jan. 25
normal range
0.018-0.021
Thallium in urine (μg/l)
daughter
before antidote
voltammetry
mother
control subject
580
neg.
neg.
maximum after
antidote/
12 h sample
urine
1170.0
21.0
4.0
end of treatment
12 h sample
urine
2.0
5.4
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after 6 months
urine
neg.
neg.
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Thallium in blood and faeces
Optical Emission Spectrometer - Inductively Coupled Plasma (OES-ICP)
μg/l
daughter
mother
normal range
(OES-ICP)
First
measurement
blood
mg
770.00
0.30
Jan. 15
Jan. 21
daughter
mother
0.049-0.013
Voltammetry
maximum with
antidote
faeces
13 mg/250g
0.25 mg/40g
?
3 days after the
end of treatment
faeces
0.1mg/100g
0.05 mg/70g
neg.
CONCLUSION - mother
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Treatment with Prussian blue produced a higher
excretion of thallium in urine
And a measurable amount in faeces
In mother the clinical effect was negligible –
1¼ year after last poisoning:
EMG: Residual mild axonal sensory neuropathy,
mild improvement after 6 months. Autonomic fibers
without damage.
Opthalmologic examination: scotomas of upper and
central parts of both visual fields
Visual evoked potentials: prologed latency, lower
amplitude
CONCLUSION - daughter
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1 year after intoxication
EMG examination - Severe damage in motor and
sensory fibers, autonomic normalized already
Ophthalmologic examination – mild improvement
right eye - scotomas in central and medium
periphery
left eye – scotomas in central area
SUMMARY
Thallium typically causes damage of
peripheral nerves of lower extremities,
vision and hair.
 Combination of these symptoms suggests
thallium poisoning
 Late treatment has low effect
 Prognosis of hair loss is good
 Polyneuropathy improves within months till
years
 Vision damage has the worst prognosis
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THANK YOU
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3rd victim – dog of the family