1
Q
liver structure
A
-red brown color
-divided into lobes
-sharp edges (if soft edges something wrong
-composed of many hepatic lobules or acinus (same thing)
2
Q
liver blood supply
A
- Dual blood supply:
1. Portal vein (drains blood from
spleen, intestine and
pancreas)
2. Hepatic artery - Portal vein and hepatic artery
both drain into hepatic
sinusoids - Blood leaves the liver via the
hepatic vein.
3
Q
liver cell structure
A
-then layer of hepatocytes with hepatic and portal venule coming together and draining into sinusoids.
-sinusoids have holes which allow the interaction between liver and systemic circulation via the space of disse
-the space of disse: space between helatpcytes and sinusoids. contains stallate cells.
-liver filters blood
-in diseased cells the stellate cells with form firbous tissue. so fibrous tissue in space of disse so less blood filtering/ systemic circulation.
-any amount of liver firbosis is clinically relevent.
4
Q
Space of Disse
A
- Space of Disse: Fluid filled space
between endothelial cells and
hepatocytes - Interface for interaction between
liver and blood. - Contain “Stellate cells” which:
1. Store vitamin A (normally).
2. Can synthesize collagen and thus
cause hepatic fibrosis (in
diseased liver).
5
Q
Hepatic lobule (Hexagonal)
A
- Centre: Hepatic venule or
central venule - Periphery: Portal venule hepatic
arteriole bile duct, lymphatics,
nerves.
-least oxygenated in centerlobular area, and middle is midlobular area. most is periportal area
6
Q
Hepatic acinus (diamond shaped)
A
- Centre: Terminal afferent branches of the portal venule and the hepatic arteriole
- Periphery: Hepatic venules
-zone 1 most oxygenated (closest to hepatic arteriol) , zone 2 middle, zone 3 less oxygenated
7
Q
gallbladder
A
- Absent in horse, rat.
- Tubular organ
- Common bile duct empty into the
intestine
8
Q
function of the liver: bilirubin metabolism
A
-bilirubin comes from RBC, where they are filtered by spleen (heme) is phagocytozed by macrophages in spleen. splits into heme + globin
-heme converted to bilirubim. (production)
-bilirubin leaves spleen binds albumin in blood, taken up by liver where it is conjugated. (uptake)
- excreted in bile ( intestines) and is absorbed again
9
Q
Jaundice 3 causes? and clinical
A
Jaundice = Icterus
Yellow Discoloration Of Tissues
3 types:
* Prehepatic Jaundice=
Cause: increase break down
of RBCs (liver can’t keep up!) lots of conjugated bilirubin.
* Hepatic Jaundice=
Cause: decreased uptake of
bilirubin due to liver disease
(bilirubin accumulates
because the liver is not
removing it from the blood)
* Post-hepatic Jaundice=
Cause: decreased hepatic
excretion of bilirubin with bile
(cholestasis)
10
Q
common causes of jaundice in ruminants or horses
A
- In ruminants jaundice is most commonly prehepatic
(due to RBC hemolysis) - Icterus in other spps can occur to due prehepatic, hepatic, or post hepatic causes
- Horses develop physiologic icterus with starvation. NORMAL not disease.
Cause: Bilirubin uptake is energy dependent and is decreased during starvation. (This only occurs in
horses)
11
Q
functions of the liver
A
1 bilirubin metabolism
2 bile acid metabolim
3 carb metabolism: (everything to do with glucose, storage, formation ect.)
4 lipid metabolism: production and degradation of plasma lipids.
5 protein synthesis: 15% of proteins (albumin, clotting factors) and site for ammonia metabolism.
-ammonia is a toxic product of protein catabolism (in intestines), converted into urea in liver through urea cycle.
12
Q
Normal liver function
2. Bile acid metabolism
A
- Bile acids are major bile constituents
- Synthesized by the liver and secreted into the small intestine
- Most bile acids are reabsorbed by the intestine and taken up again by the liver (very efficient reabsorption and enterohepatic circulation)
- Usually only liver uptake of bile acids is reduced with hepatic disease (NOT production)
13
Q
Responses of the liver to injury
What can happen to the liver?
A
- Degeneration, Necrosis and Apoptosis
- Disturbances of Bile Flow and Icterus
- Regeneration
- Fibrosis
- Bile Duct Hyperplasia
- End Stage Liver
- Liver Failure
14
Q
Degeneration Necrosis and Apoptosis of liver 3 types
A
Patterns of distribution of degeneration and
necrosis:
1. Random= caused by bacteria or protozoa, brought from blood.
2. Zonal (5 types)
3. Massive
15
Q
zonal pattern of necrosis: centrilobular
A
-Most common type of zonal
change
-Hepatocytes are least oxygentaed
i.e. Prone to necrosis
-Hepatocytes contain greatest conc. of detoxyfying enzymes, aka mixed function oxidases or Cytochrome P450 enzymes.
-ex (nutmeg liver)
Common causes:
1. Toxins requiring metabolic
activation
2. Passive congestion in the liver
16
Q
zonal pattern of necrosis paracentral
A
- Involves only a wedge around
central vein (only one acinus is
affected)
-happens with severe acute anemia or hemorrhage (blood loss), loss of BS to liver
17
Q
Zonal pattern
3. Periportal (least common) 4 midzonal both rare
A
- Closest to blood supply
- Have high oxygen tension
- Affected first by toxins that
do not require activation - Have limited mixed function
oxidase enzymes i.e
generally, it is affected by
toxins that do NOT require
activation - Uncommon ex. Phosphorus
toxicity
18
Q
Zonal pattern
5. Bridging necrosis
A
- May link centrilobular
areas (central bridging) or
centrilobular areas to
periportal areas
19
Q
massive necrosis of liver
A
-The term describes
necrosis of an entire
hepatic lobule or
contiguous lobules
20
Q
Disturbances of bile flow =(cholestasis)-Two types
A
-Intrahepatic & Extrahepatic
-intrahepatic Cholestasis:
Affects bile caniliculi or
ductules within the liver
Causes:
- Liver injury (fibrosis)
- Inherited abnormality of
bile synthesis and secretion
-Extrahepatic Cholestasis:
Affects extrahepatic bile duct
Causes:
-obstruction due to a mass within or outside the lumen. Will lead to
intrahepatic cholestasis
-If prolonged leads to fibrosis &
bile duct proliferation in the liver
21
Q
liver regeneration
A
-Depends on the extent of damage
- If small: local proliferation of adjacent hepatocytes
- If extensive loss of hepatocytes and loss of extracellular matrix scaffold (basement membrane) (reticulin) occur:
You see regenerative nodules, disorganized regeneration.
-they don’t restroy hepatic function completely due to BF and bile flow is abnormal from firbosis.
22
Q
fibrosis due to liver injury
A
-reduced interaction from liver and systemic circulation
-examples: long standing R sided H failure, lack of flow causes liver firbosis
- Random areas of fibrosis are see when parasites migrate through the hepatic parenchyma.
-“Bridging fibrosis” indicates that
the fibrosis extends from one portal area to another or to
centrilobular area
-liver with firbosis will have irregular surface, pale & firm from collagen. mishaped (shrink)
23
Q
End Stage Liver (Cirrhosis)
A
3 processes all happening at same time:
-Degeneration and necrosis
-Regeneration,
-Fibrosis
These processes must be present almost diffusely throughout the liver to call it an end stage liver
24
Q
hepatic failure definition
A
“loss of adequate hepatic function as a consequence of either acute or chronic hepatic damage”.
25
Consequences of hepatic failure
hepatic encephalopathy
1. Hepatic encephalopathy:
-Accumulation of ammonia due to reduced uptake by the liver
-Ammonia is toxic to the brain
-Leads to abnormal neurotransmission in the CNS
and the neuromuscular system
26
Consequences of hepatic failure
2. Metabolic abnormalities: blood
a. Bleeding tendencies due to:
Decreased synthesis of coagulation factors
b. Decreased albumin synthesis edema, low albumin means liver is fried.
27
Consequences of hepatic failure
3. Vascular and Hemodynamic alterations
Example: Acquired portosystemic shunt
-An abnormal vascular communication between
the portal vein and the systemic circulation, firboris leads to PORTAL HYPERTENSION. and ascites.
-fibrosis reroutes blood flow: leads to serum bile acid and ammonia increases, get ammonia bicurate crystals (bladder/ urine), hepatic enephalopathy.
28
extrahepatic shunt in liver failure
-Blood coming to liver by portal vein, if we have hepatic fibrosis we have Uncomplient liver so increase hydrostatic pressure in portal vein--> ascites. Lots of tension in portal vein so portal hypertension. Forms new portal to the vena cava=
Extrahepatic shunt. So blood is being shunted away from the liver and not being filtered and instead
Going back into systemic circulation.
You can also have an intrahepatic shunt in the liver.
-these are acquired portosystemic shunts.
29
Consequences of hepatic failure
4. Cutaneous Manifestations
A. Superficial necrolytic dermatistis DOGS ONLY rare.
- crusting and ulceration of the epidermis
- muzzle, mucocutaneous areas of the face, footpads,
and pressure points of the skin in some dogs
- Unknown mechanism
- Also occurs with diabetes
30
Consequences of hepatic failure
4. Cutaneous Manifestations:
B. Photosenstization
B. this is secondary Photosenstization secondary to hepatic dysfunction
-ruminants
-they eat plants (chlorophyl) which is converted into phE absorbed in liver and excreted in bile. if you have liver failure phE will accumulate into skin and absord UV light and lead to photosensitization. (oxidative damage and necrosis)
31
cytsts in liver 2 causes
Congenital biliary cysts=
- Single or few cysts can be found
as an incidental finding, not significant.
Polycystic disease=
- Rare occurrence
- Reported in Cairn Terriers, West
Highland white Terriers and
Persian cats pigs and goats
- Extensive cysts within the liver,
kidney and pancreas
- Can be fatal
32
tension lipidosis
- Incidental finding
- Pale areas in the
livers of horses and
cattle
- occur adjacent to the
insertion of a
ligament (serosal)
attachment
33
hepatic lipidosis/ many causes
-metabolic disturbance
-yellow liver, float, round edges, enhanced lobular pattern.
-* When lipid accumulate within the liver we call
this “Hepatic Lipidosis”
* What accumulate is mainly triglycerides
* There are several mechanisms for hepatic lipidosis
-Increased mobilisation of FFA from adipose tissue (lactating/ preg animals -> ketosis--> tricglycerides)
-increased fat/ carb intake: diet leads to increased FFA--> triglycerides.
-decreased O2 & energy (anemia/ hypoxia: increased FFA & triglycerides are not being used to accumulate. no oxygen to convert FFA to other things.
-decreased protien intake (starvation) adipose tissue-> increase triglycerides
-hormonal (insulin): Low insulin will cause fat to be used as an energy source instead of glucose
& will increase the mobilisation of FFA.
-toxin induced fatty change: FFA increase triglycerides and stop other converting.
34
examples of hepatic lipidosis in vet med
Pregnancy Toxemia:
- Sheep
- Seen in late pregnancy
Bovine Fatty liver disease:
- Dairy cattle (lactation)
- Beef cattle (pregnancy)
-increased fat production and ketone bodies from mobilizing fat from adipose tissue.
Feline Fatty Liver Syndrome:
- Obese cats become anorectic for unknown reason and start mobilizing fat.
Hyperlipemia:
- A syndrome seen in ponies, miniature horses and donkeys
- Associated with increased demand on energy
- Occurs after an event causing anorexia
Endocrine disorders (diabetes and hypothyroidism):
- Insulin is an anabolic hormone
- Lack of insulin or in the response to insulin causes
increased mobilisation of fat
- Hypothyroidism causes hypercholesterolemia and
increased serum lipids
35
Glycogen Accumulation (Steroid
Hepatopathy)
* Dogs
* Two causes
- Prolonged administration of
corticosteroids
- Secondary to hyperadrenocorticism
Mechanism: increased
gluconeogenesis and glycogen
storage
* Liver is enlarged and bronze in
color
* Can cause elevation in liver
enzymes clinically
36
Circulatory disorders
Disturbances of outflow (blood can’t get out)
-Central Passive Congestion within the liver
- 2ndary to right-side heart failure
- Pressure within vena cava and central vein i.e. blood can’t
get out
37
liver in chronic right sided heart failure
1. Sinusoids at the centrilobular area become dilated (appear
red grossly)
2. Hepatocytes at the centrilobular areas undergo atrophy then
degeneration and necrosis
3. Hepatocytes at the periportal area undergo fatty change
(appear yellow grossly)
4. Grossly, the liver will be enlarged (rounded edges) and will
also have an enhanced lobular pattern
38
liver in acute right sided heart failure
- Acute heart failure:
1. Congestion at the centrilobular areas
2. Hepatocytes within centrilobular areas may undergo fatty
degeneration.
- Grossly: the lobular pattern of the liver might be slightly
enhanced.
39
Circulatory disorders
Disturbances of inflow: anemia
1. Anemia decreased Blood ( flow)
- Acute severe anemia can
cause centrilobular or
paracentral degeneration
of hepatocytes.
- Chronic anemia causes
atrophy of centrilobular
hepatocytes.
- Grossly the liver has
enhanced lobular pattern
40
Disturbances of inflow
2. Congenital portosystemic shunt
INTRAHEPATIC SHUNT- Failure of closure of ductus venosus, should close after birth. umbillical vein carriers O2 to fetus, half goes through liver half is shunted away (dustus venosis)
- Most commonly seen in large breed dogs
EXTRA HEPATIC SHUNT
- Connection between portal
vein & caudal vena cava or
azygus
-small breed dogs
-leads to liver atrophy, hepatic encephalopathy.
-neural signs, high bile and ammonia in both
Portal hypertension is ABSENT in congenital portosystemic shunts!!!
Only found in acquired shunts
41
Telangiectasis
- Dilated sinusoids
common in cattle,
horses and cats (older animals)
- Appear as red areas in
the liver
-not significant
42
liver infarction
-necrosis secondary to lack of BF
* Uncommon due to dual
blood supply
* Can occur secondary to
torsion of an individual
hepatic lobe.
* Can happen secondary to
thrombosis
43
Amyloid accumulation
- Primary: produced by plasma
cells that become cancerous
(amyloid light chain or AL)
- Secondary: to chronic
inflammation (amyloid A) MOST COMMON
* Misfolded amyloid accumulate
in a variety of tissues
* Liver orange in color
* Can cause hepatic failure and
rarely hepatic rupture (horses)
44
Copper accumulation/toxicity two forms and causes
* Primary poisoning is due to exposure to high amounts of copper (sheep is very susceptible)
* Secondary poisoning is due to decreased copper excretion
- Causes
- 1. Decreased excretion secondary to hepatic
damage (ruminants eating hepatotoxic plants)
- 2. Decreased excretion due to hereditary mutation (bedlington terrier, due to mutation in
COMMD1 gene
45
copper acumulaition path of chronic poisoning
-copper is an oxidizing agent--> leads to oxidative damage to the liver and damage to RBC-->
-leading to centrilobular to massive necorsis and intravascular hemolysis
-a decreased uptake of bilirubin leads to prehepatic and hepatic icterus.
-large spleen due to hemolytic crisis
46
primary copper poisoning path
-Liver has large capacity to store copper
-Once this is over reached you will have a massive Release of copper into systemic circulation from the
Liver. Causes intravascular hemolysis from oxidative damage to RBC so hemoglobin in vasculature then urine and you get hemoglobinuria. Also causes liver damage from oxidative damage to the liver and centrilobular and massive necrosis.
-usually brought on by stress such as lactation or pregnancy.
-suspected from BLACK KIDNEYS from hemoglobin. and urine.
47
Parasite hematin
- Liver flukes produce
dark excreta which
often stain the migratory tract within the liver.
-black multifocal lesions in liver
48
portals of entry to the liver
* Hematogenous
* Ascending from intestine through bile ducts
* Direct penetration
49
liver inflammation acute va chronic lesions
acute hepatitis: spots of necrosis and inflammation, no signs of chronic feature
chronic hepatitis: gross features= FIBROSIS, nodular regeneration, granulomas, absesses, severe lesoin.
If bile ducts & liver and involved: Chollangiohepatitis
50
infectious disease of liver: viral diseases
Herpes virus
Viral Diseases:
Herpesvirus infection:
- Bovine, equine, canine
feline herpsivirus-1
- Affect fetuses & neonates
- Fetal Abortion or neonatal
death (wont be able to see necrosis in fetus grossly in cattle)
- Liver of foal with EHV-1: Multifocal hepatic necrosis
51
bacterial diseases of liver Tyzzer’s disease
- Cause: Clostridium piliforme
- Affects neonates in almost all species
-bacteria in GI tract-> penetrate the intestine then portal vein then the liver.
-leads to Multifocal hepatic necrosis
- May also see colitis and myocarditis
- Most commonly foals
52
Bacterial Diseases
Fusobacterium necrophorum
-in adult feedlot cattle-> grain overload-> chemical rumenitis & mucusal injury-> bacteria enter the portal circulation-> liver absecces.
- is usually a mixed infection with other pathogens
-Trueperella pyogenes
-liver abscess usually incidental finding unless THEY OPEN INTO CENTRAL VEIN OR VENA CAVA and cause pulmonary thromboembolism, cause central vein thrombosis and occlusion causing hepatic passive congestion and portal hypertension.
53
Bacterial Diseases
Neonates umbilical infection:
- Causes multifocal hepatic necrosis or abscesses
- Multiple causes (mixed infections are common)
- Campylobacter (sheep)
- T. pyogenes, F. necroforum (calves)
- Rhodococcus equi (foals )
54
Hepatic granulomas causes
Tuberculosis
- Causes
Mycobacterium bovis'
-granulomas will be calcified
-zoonotic
Protozoa: histoplasmosis
55
bacterial disease of liver leptospirosis
- Causes intravascular hemolysis and you can
see hepatic necrosis
- The kidney is a good place isolate the organism
56
infectious (protozoal or fungal) diseases of liver
Protozoal Diseases:
- Toxoplasma and neospora can infect the liver
and causes necrosis.
Fungal Diseases:
- Aspergillus; Blastomyces; Coccidioides;
Histoplasma infection can cause liver granulomas
57
nematodes which cause lesions in the liver
Nematodes
- Ascaris suum: Larval stages
migrate through the liver of pigs
creating migration tracts
- Tracts heal by fibrosis producing
“milk spotted liver”
- Strongylus in horses produce
fibrous tags on the capsule
Dirofilaria immitis (vena caval
syndrome)
- D. Immitis in the vena cava in large number can cause DIC,
intravascular hemolysis and acute
hepatic failure
- Causes blockage of the vena cava
leading to severe passive
congestion within the liver
58
cestodes which cause lesions in liver
- Cysticercus cyst= (liver and other
organs)
- Food animal spp and wild
herbivores
- Adult stage Taenia (intestine of
canids)
- Hydatid cyst= (liver and other
organs)
- Food animal spp and wild
herbivores
- Adult stage is Echinococus
59
trematodes which leave liver lesions
- Fasciola hepatica= inhabits
the biliary system of
ruminants
- Fascioloides magna=
migrate through the
parenchyma of ruminants
- Metorchis= inhabits the
bile duct of dogs and cats
60
why the liver is so susceptible to toxin induced liver injury
-the liver is a target for toxicity: all substances delivered here via portal system, very metabolically active (more suseptable), liver uses CYP enzymes to metabolize chemicals which have active metabolites (toxic)
-random or zonal lesions
-centrilobular necrosis most common due to lowest O2 and highest CYP.
61
What are the major mechanisms through which toxicity occur? 6 causes
1. Production of injurious metabolites: phase I and II enzymes making compounds water soluable. produces toxic metabolites.
2. Formation of neoantigens: toxins + cellular proteins-> neoantigen on surface which are attacked by immune system leading to cell death and inflammation.
3. induction of apoptosis: by toxins or secondary to immune system.
4. Injury to cell membranes and activation of proteases
- increased influx of Ca+2 which activate cellular proteases
5. Disruption of bile secretion
6. Mitochondrial damage
- Toxins can affect mitochondrial membranes enzymes, and DNA Disrupt ECC
- Result is fatty degeneration or cell death by necrosis or apoptosis
62
hepatotoxic agents: blue green algae
1 microcystis: toxic algea on water in summer-> causes severe convulsions (neurotoxic) +/- liver damage
depending on the type of algae. diag: stomach content
63
hepatotoxic plants
1. Pyrrolizidine Alkaloid toxicity
- Alkaloid present in plants e.g.
Senico, Crotalaria
- CYP450 metabolism results in toxic metabolites
-icturus, ect.
-diagnosis: usually too late if there are signs.
64
mycotoxins as hepatic toxin
e.g. Aflatoxin
- Mycotoxins are metabolites of fungi
- Food stored at humid conditions allow fungi to
proliferate
- Toxicity is very similar to Pyrrolizidine Alkaloid i.e.
Usually chronic and can form megalocytes
- Diagnosis: Analyze the feed.
65
mushroom poisoning
-Acute, dogs and cats
- Centrilobular to massive hepatic necrosis
- Diagnosis: finding the mushroom in the stomach
66
copper and iron toxicity
- Usually chronic through feed
- Cause oxidative damage to the liver and necrosis
- Copper causes intravascular hemolysis
67
nodular hyperplasia
Raised nodules (not many) on the surface of the liver of
OLD DOGs
- Not significant, dog is
healthy
- No fibrosis, nodules are
yellow tan or red
- Different from regenerative
nodules (happens from trauma, has firbosis) they are different.
68
hepatocellular adenoma
- Somewhat large
solitary nodule on the
liver
- Need histology to
differentiate from
nodular hyperplasia
69
Hepatocellular carcinoma
- Friable grey white or
brown masses on the
surface of the liver.
- Can metastasize lung,
peritonium
70
bile duct neoplasia
Collangiocellular adenoma
- Uncommon
Chollangiocellular carcinoma
- Relatively common in cats, if it isnt chirosis
- Umbilicated raised lesions (depressed center) than look at bile duct and gall bladder. would also be effected.
- Metastasis is very common
Metastatic neoplams
- Metastatic neoplasma to the liver are more common than hepatic neoplasia
71
Equine Serum Hepatitis
(Theiler’s Disease)
- Acute centrilobular to
massive hepatic necrosis
- Occurs after an injection of
a biologic containing equine
serum (equine parvovirus)
- Hepatic failure and hepatic
encephalopathy
72
Bacillary Hemoglobinurea in ruminants
-caused by clostridium hemolyticum
-clostridial spores ingested and live in liver-> liver fluke migrates through causes injury and causes HYPOXIA -> spores germinate and bacteria release toxins. --> leads to acute liver necrosis, hemolytic anemia and hemoglobin urea.
73
Disorders Of Ruminants
Infectious Necrotic Hepatitis (Black Disease)
cause: Clostridium novyi type B
-Similar pathogenesis to bacillary hemoglobinurea
but NO INTRAVASCULAR HEMOLYSIS
-bacteria ingested, goes to liver, flukes migrate and leads to necrosis in the liver
74
Disorders Of Pigs
Hepatosis Dietetica
-Acute hepatic necrosis &
hemorrhage in young
rapidly growing pigs
(centrilobular to
massive)
Cause: Vitamin E and/or
Se deficiency
75
Disorders of Dogs
Infectious Canine Hepatitis
Cause: Canine Adenovirus 1
-Dogs less than 2years of age, unvacinated
-Virus has predilection for endothelial cells
-exposure through oral route -> viremia-> spreads to liver-> centrilobular hepatic necrosis inclusion bodies
76
Disorders Of The Cats
Lymphocytic Cholangitis
Slowly progressive disease of cat > 4 years
- unknown etiology
- Lymphocytic infiltration
centered on bile ducts with bile duct hyperplasia and fibrosis
77
Cholelithiasis (gallbladder stones)
- Bile concretions, bile duct obstruction
- Can block the extrahepatic
bile duct
- leads to Extrahepatic jaundice
78
Cholecystitis
-inflammation of gall bladder
-Usually associated with liver disease
- Ascending infection from the intestine
- Common causes Salmonella Dublin
(cattle) and Infectious canine hepatitis
(dog)
- Thickening of the wall with edema
79
Gallbladder Mucocele
- Gallbladder filled with mucous (dogs) lethargic, sick, non specific
- Can cause biliary obstruction
- If rupture occurs it causes severe bile peritonitis
80
Cystic mucinous Hyperplasia of gall bladder
- Mucosa thickened with
many surface cysts
- Incidental finding
veterinary systemic pathology
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