Lecture 18 - Hematoxicology 2 Flashcards
- What plant is pictured below?
- Where can this plant be found?
Red Maple (Acer rubrum)
Found in the entire eastern US
and Canada
Red maple (Acer rubrum) is a deciduous tree native to eastern North America
but is found as far west as Texas.
Red maple is planted as an ornamental because of its vibrant fall colours, and
it thrives better in altered environments and has outcompeted rival species.
Red Maple (Acer rubrum)
Toxic principles: ___________
○ ______ acid and ______
oxidants, Gallic, tannins
Red Maple (Acer rubrum)
Species affected?
: equine (horses, ponies, Grevy’s zebra) following ingestion of wilted or dried leaves. Bark also is toxic
Red Maple (Acer rubrum) ADME
_______ acid is metabolized to ________ acid in equine ileum by ___________ ______ or ____________________-
_______ acid is further metabolized to ________ in equine ileum also by ___________ ______ or ____________________
___________ is absorbed in equine ileum and
interacts with ____ (Fe) to form _____ ________
leading to the oxidation of ____ to ____ in Hb to form ________
Tannic acid is metabolized to gallic acid in equine
ileum by Klebsiella pneumoniae or Enterobacter
cloacae
Gallic acid is further metabolized to pyrogallol in
equine ileum also by K. pneumoniae or E.
cloacae
Pyrogallol is absorbed in equine ileum and
interacts with iron (Fe) to form free radicals
leading to the oxidation of Fe2+ to Fe3+ in Hb to
form methemoglobin
What is the MOT of Red Maple Toxicosis?
Oxidative damage of Hb → precipitation of
oxidized Hb as ______ _____ in the RBCs →
RBCs are then removed by the ______
(extravascular hemolysis)
Damage to RBC membranes → altered
_________ → intravascular ________
Both processes result in severe progressive
_______
In addition, hemoglobin is filtered in _____ →
________ in renal tubules → renal ________
Mechanisms of Toxicity
Oxidative damage of Hb → precipitation of
oxidized Hb as Heinz bodies in the RBCs →
RBCs are then removed by the spleen
(extravascular hemolysis)
Damage to RBC membranes → altered
permeability → intravascular hemolysis
Both processes result in severe progressive
anemia
In addition, hemoglobin is filtered in kidney →
precipitation in renal tubules → renal failure
What are the clinical signs of red maple toxicosis?
Poisoning is more likely in fall/late summer or
after a storm when fallen red maple leaves/tree
branches are accessible to horses. Poisoned
animals display:
Depression, anorexia, acute hemolytic anemia
with weakness, increased respiratory and heart
rates, cyanosis, icterus, and a red-brown
coloration of the urine, decreased PCV, Heinz
bodies, proteinuria, weakness, coma and death
Abortion may occur in pregnant mares
Paracute death from tissue anoxia may occur
How do you Dx Red Maple Toxicosis?
History of ________ to red maple leaves
Poisoning occurs primarily between ____ and _____
________ signs
Rule out other causes of _______ ______
History of exposure to red maple leaves
Poisoning occurs primarily between July and October
Clinical signs
Rule out other causes of hemolytic anemia
What are your DDx for Red Maple Toxicosis?
Causes of hemolytic anemia
Equine infectious anemia
Piroplasmosis
Ehrlichiosis
Onion toxicosis
Nitrate/nitrite toxicosis
Brassica toxicosis
Naphthalene toxicosis
How do you Tx Red Maple Toxicosis?
Allium (?)
Herbaceous plants with bulbs
Domesticated and wild varieties
Found throughout North America
Toxic principle: ?
Allium (Onion, Garlic, Leek, Chives)
Herbaceous plants with bulbs
Domesticated and wild varieties
Found throughout North America
Toxic principle: n-propyl disulfide and other disulfides
List the exposure and risk factors for allium toxicity?
What is the toxic dose of allium toxicosis?
What is the MOT of Allium toxicosis?
Affects the enzyme ______-__-_______________ _________ thereby impairing the hexose monophosphate pathway in RBCs
Oxidation of Hgb results due to insufficient
________ or _________
The oxidized Hgb precipitates in the RBCs to
form _______ ________
RBCs with _______ _______ are removed in the spleen or undergo hemolysis → ________
______ are highly sensitive because their Hb is
more sensitive to oxidative damage
Affects the enzyme glucose-6-phosphate dehydrogenase thereby impairing the hexose monophosphate pathway in RBCs
Oxidation of Hgb results due to insufficient
NADPH or glutathione
The oxidized Hgb precipitates in the RBCs to
form Heinz bodies
RBCs with Heinz bodies are removed in the
spleen or undergo hemolysis → anaemia
Cats are highly sensitive because their Hb is
more sensitive to oxidative damage
What are the clinical signs of allium toxicosis?
Anorexia, vomiting, salivation, lethargy, ataxia or
recumbency, rapid breathing and heart rates,
pale or icteric mucous membranes, onion odor
in breath and onion flavor in milk
Pregnant animals may abort
Hemoglobinemia, hemoglobinuria (dark red-
brown urine), reduced PCV and hematocrit,
Heinz bodies may be seen in RBCs, elevated
WBC count
How do you Dx Allium toxicosis?
Dx
Hematological parameters and urine appearance
History, clinical signs and examination of pasture
or property for Allium spp.
How do you treat Allium toxicosis?
Tx
Decontaminate: emesis (within 1 h), gastric
lavage (within 2-4 h), activated charcoal plus
cathartic (e.g., sorbitol)
Maintain cardiovascular support
IV fluids
Oxygen
Whole blood transfusion or Oxyglobin
Bracken Fern (
Pteridium aquilinum)
Native perennial herb
Occurs throughout the US
Young plants and rhizomes
are the most toxic
Toxic principles:
Thiaminase
Ptaquiloside
Cyanogenic glycoside
What is the Mechanisms of Toxicity of
Ptaquiloside
Causes death of __________ cells in bone marrow
Causes urinary tract _______
Ptaquiloside causes DNA _______ and induction of _________
Ptaquiloside is secreted in ____ (the milk causes
__________ in mice)
Causes death of precursor cells in bone marrow
Causes urinary tract neoplasia
Ptaquiloside causes DNA alkylation and induction of
protooncogenes
Ptaquiloside is secreted in milk (the milk causes
neoplasia in mice)
Disease Syndromes Caused by Bracken Fern
Clinical signs of bracken fern toxicosis?
Suppression of bone marrow activity occurs
after >3-4 weeks of exposure
There is severe pancytopenia with acute
onset of fever, lethargy and loss of appetite
Hemorrhaging via natural orifices: vulva,
mouth, conjunctiva and anterior chamber of
the eye
Bloody stool and urine
What can happen as a result of prolonged consumption of bracken fern?
Enzootic Hematuria
Red Water disease
Intermittent blood loss in urine from
hemorrhages and tumors in the urinary
bladder
Occurs after prolonged (2 years) consumption
of low levels (<10g/kg/d) bracken fern
Results in anemia, elevated heart rate,
weakness
○ Death from anemia
GI tract tumors result in:
Choking, coughing, bloat, emaciation
Regurgitation of greenish fluid and extended neck
posture
How do you Dx Bracken Fern toxicosis?
History of exposure to bracken fern over
several weeks to months
Compatible clinical signs and lesions
How do you Tx Bracken Fern toxicosis?
Blood or platelet transfusion in cattle for
aplastic anemia
Antibiotics to prevent secondary infections
List the sources of Brassica.
Sources: Cabbage, kale, broccoli, turnips,
mustards, etc. Often used as winter feed for
cattle and sheep
What are the toxic principles of Brassica?
Toxic principles
S-methyl cysteine sulfoxide (SMCO)
Others: glucosinolates, goitrin, nitrile and nitrates
What species are susceptible to brassica toxicosis?
poultry, swine, cattle,
sheep
Brassica toxicosis - ADME
SMCO is reduced to toxic dimethyl disulfide
by microbial fermentation in the GI tract
Absorption and metabolism take <1 day
What is the MOT of brassica toxicosis?
Dimethyl disulfide is an oxidant
Oxidizes hemoglobin to form Heinz bodies →
hemolytic anemia
Glucosinolates give rise to isothiocyanates
which cause gastroenteritis
Goitrin is goitregenic
Nitrate is converted to nitrite in rumen →
oxidation of Hgb → methemoglobinuria
Nitrile causes pulmonary emphysema, hepatic
necrosis and blindness
What are the clinical signs of brassica toxicosis?
Anemia and GI upset are the most common signs
Hemoglobinuria(emia), tachycardia, polypnea,
cyanosis and jaundice may be observed
Scouring, colic, rumen stasis
Poor conception rate, reduced milk production
and growth retardation
Goiter
How do you Dx Brassica toxicosis?
Presence of Brassica, evidence of
consumption and appropriate clinical signs
How do you treat brassica toxicosis?
Mostly supportive
Blood transfusion
Diuresis with fluids to reduce occurrence of
hemoglobinuric nephrosis
What species are susceptible to Cu toxicosis?
all
List the different Cu toxicities.
Acute copper toxicosis in sheep
Enzootic icterus in sheep (South Africa)
Genetic canine copper toxicosis in Bedlington
terriers, West Highland white terriers, Skye
terriers, Dalmatian, Doberman pinschers
○ In Bedlington terriers it is due to an autosomal
recessive disorder of biliary Cu excretion
Wilson’s disease in humans
What are the causes of acute copper toxicosis?
–> Causes: ingestion or administration of Cu-
containing formulations or material:
Anthelmintics, footbaths, pesticides, dietary
additives, copper salts, environmental
contamination, poultry litter, coins
Feeding of calf, horse, poultry or swine food to
sheep
What are the risk factors of acute copper toxicosis?
Feeding ionophores (e.g.,
monensin) increase Cu absorption and toxicity
Which species are sensitive to acute copper toxicosis?
What is the MOT of acute copper toxicosis?
Necrotic hepatocytes release Cu to blood
circulation → Cu damages RBCs →
intravascular hemolysis and release of Hgb
Lysis of RBC causes anoxia → centrilobular
hepatic necrosis and more release of Cu, which
accumulates in other tissues such as the kidney
What is the MOT of acute copper toxicosis?
_________ hepatocytes release Cu to blood
circulation → Cu damages _____ → intravascular _______ and release of ____ –> Lysis of RBC causes _____ → ________ hepatic necrosis and more release of Cu, which accumulates in other tissues such as the kidney
Necrotic hepatocytes release Cu to blood
circulation → Cu damages RBCs →
intravascular hemolysis and release of Hgb
Lysis of RBC causes anoxia → centrilobular
hepatic necrosis and more release of Cu, which
accumulates in other tissues such as the kidney
What is the MOT of acute copper toxicosis?
Necrotic hepatocytes release Cu to blood
circulation → Cu damages RBCs →
intravascular hemolysis and release of Hgb
Lysis of RBC causes anoxia → centrilobular
hepatic necrosis and more release of Cu, which
accumulates in other tissues such as the kidney
–> Inactivation of proteins
Displacement of other essential metals e.g. Zn
from their proteins
Oxidation of –SH groups and depletion of
antioxidants (e.g., GSH) → oxidative stress →
oxidation of biomolecules (membrane lipid,
proteins and DNA)
What are the clinical signs of acute copper toxicosis in sheep?
Sheep (and cattle)
Rarely show signs until stressed → massive liver
necrosis → Cu release → RBC damage →
hemolysis → hemoglobinuria, icterus, anoxia and
death
Hemolytic crisis: dark-red (port wine) urine,
swollen gunmetal-blue kidneys, swollen spleen
with dark brown-black parenchyma
stress: ↓Food intake
* Transportation
* Handling, shearing
* Extreme weather
* Exercise
What are the clinical signs of acute copper toxicosis in swine?
generally resistant
Young swine are more susceptible than adults
Anorexia, depression, poor weight gain, icterus,
hemoglobinuria and bloody feces are observed
- Acute Cu toxicity is rare in cats and dogs
- Commonly associated with ingestion of pennies
Canadian pennies minted up to 1997 contain 98.5% Cu
Some US pennies minted up to 1983 contain 95% Cu
Note: Canadian penny was discontinued in 2013 - Typical signs include depression, dehydration,
anorexia, intermittent vomiting, mild abdominal
pain and diarrhea
Describe copper storage disease in dogs
Subacute Cu Poisoning
Occurs in lambs in Cu-deficient areas like FL,
other south-eastern coastal areas, and west of
Rockies
Toxicosis results from administration of Cu
compounds (even at normal dosage!)
Signs include GI tract hemorrhage, pulmonary
edema and ascites. There is liver damage but
no icterus or hemolytic crisis
How do you Dx subacute cu poisoning?
History
Evidence of blue-green ingesta
Elevated serum & liver/kidney Cu concentrations
CBC and serum panel
Check for evidence of hemolysis, elevated liver
enzymes and other indicators of liver dysfunction
Abdominal radiographs: foreign objects e.g., coins
Liver histopathology
Breed of dog
How do you Tx subacute cu poisoning in small animals?
Surgery to remove foreign body
Supportive care, e.g., IV fluids
D-penicillamine to chelate Cu and promote its urinary
excretion
How do you Tx subacute cu poisoning in ruminants?
Treatment of acute Cu toxicosis often not successful
Ammonium molybdate, sodium thiosulfate or
ammonium tetrathiomolybdate to reduce liver [Cu]
Dietary supplementation with zinc acetate to reduce
Cu absorption
List the sources of Zinc
Consumption of zinc sources or zinc-
containing foreign bodies
Pennies: US pennies after 1982: 97.5% Zn.
Canadian pennies 1997-2001: 96% Zn
Galvanized metal, pennies, diaper rash
ointment, zinc oxide sunscreen, feed mixing
error, forage close to industries etc
Which species are at risk of Zinc toxicosis?
all, dogs (small breeds, younger
dogs) mainly, caged birds
Zn is an ?
Essential trace mineral
Zinc ADME
Small intestine is the main site of absorption
Absorption is affected by several factors:
Dietary components (Cu2+, Ca2+, Mg2+, phytate,
protein), age, growth rate
Excretion
In bile via feces, intestinal mucosal secretions
and pancreatic fluid. Some chelated Zn is lost via
urine
What is the MOT of Zinc toxicosis?
- Direct irritation of GI tract → GI signs
- Zinc causes hemolytic anemia due to:
Direct damage to RBC membranes
Inhibition of RBC enzymes
Increased RBC susceptibility to oxidative damage - Competitive interactions with Cu & Fe (causes
enemia) and Ca
What are the clinical signs of Zinc toxicosis?
Depression, vomiting, diarrhea, anorexia,
abdominal pain
^ number of nucleated RBCs, ^basophilic
stippling (aggregation of ribosomal RNA in
RBCs)
Icterus, hemolytic anemia, decreased PCV,
hemoglobinemia, hematuria, weakness and
death
Cu deficiency may occur in sheep
How do you Dx Zinc toxicosis?
Zinc analysis in serum, kidney, liver and urine
Collect serum in royal blue-top tubes (have plastic
stoppers). Syringes used to collect blood should
not have rubber (rubber is contaminated with Zn)
Radiography
DDx: Onion, copper, mothballs, nitrate/nitrite,
and acetaminophen toxicoses, propylene
glycol toxicosis, naphthalene toxicosis
How do you Tx Zinc Toxicosis?
- Symptomatic and supportive
IV fluids, electrolytes, blood transfusion
Diuresis with a balanced crystalloid solution - Remove zinc foreign body: endoscopic or
surgical (gastrotomy or enterotomy) - Proton pump inhibitors, H2-blockers and
sucralfate - Chelation therapy: Ca-EDTA, BAL or D-
penicillamine
