Hepatobiliary System

Terminology

o • Hepatitis = Inflammation of the liver tissue which may be acute or chronic; huge range – toxins,
infections…
o • Cholangitis = inflammation of the biliary tracts; primarily the bile ducts
o • Cholangiohepatitis = both biliary tracts and surrounding liver tissue is inflammed
o • Cholecystitis = gall bladder inflammation
o • Cholestasis = secretion of bile stops and/or decreases therefore bilirubin and bile acids accumulate
in blood. Causes include cancer, fasting, liver fluke, toxins, inflammation
o • Cirrhosis = final/end stage liver disease. This is chronic and irreversible. Hepatic fibrosis is present;
gross exam reveals the liver to be pale, small and hard. Results in liver failure with clinical signs and
blood changes.
o Hepatic encephalopathy = failure of function; can’t convert urea to ammonia, can’t covert toxic
metabolites → results in seizures, neuro signs, depression.
o • Jaundice (icterus) = yellow discolouration of sclera, visceral fat, MM’s due to increased bilirubin in
the blood. >50umol/L to see yellow.

Liver Disease Liver Failure/hepatic insufficiency

Blanket term for all acute and chronic (70-80% not functioning). Usually associated
processes (includes mild → severe). Somewhat with changes in CS and blood.
normal function so animal doesn’t always have
clinical signs or blood changes. Acute – rapid, no existing liver dz

Chronic – month/years of progressive

damage/dz

The hepatobiliary system

Colour: dark red-brown

Shape: divided into lobes with sharp tapering lobe edges - Lobe number and position differs between
species Texture: firm, but not too firm – you can put your finger through it with some force
FUNCTIONS

Bile formation
Carbs, fat and vit protein synthesis
and bilirubin
metabolism and secretion
metabolism -

detoxicatification
and storage immunity
Blood supply

o Portal vein drains from GIT and brings 75% of the liver’s blood
supply. High in nutrients, low in O2
o Hepatic artery blood provides the rest, high is O2
o The hepatic vein takes blood to central vein which drains
blood from liver to caudal VC.
o Note there are also lymphatic vessels despite this being portal
‘triad’
o 3 zones in each lobule → blood flows from outer portal area
to central vein within sinusoids
o Bile goes opposite way!

Immediate response to injury → degeneration or necrosis of hepatobiliary cells

Longer term response to injury → regeneration, fibrosis, biliary hyperplasia

A) Regeneration – this is a response to short-term or mild injury

- Amazing ability to repair itself → up to 70% can be surgically removed and it can grow back with normal
function to all parenchyma
- Includes all regions of the liver (bile ducts, hepatocytes ect)
- Gross appearance is nodular (often mistaken for neoplasia at PM)

B) Fibrosis – chronic or severe injury

- Extensive, non-resolving damage → replacement of normal cells with collagen

- Distribution of fibrosis may reflect nature of injury → Ie; facial eczema causes left lobe fibrosis and atrophy
whereas ragwort poisoning causes diffuse parenchymal fibrosis
- Gross appearance is small, pale and firm.

→ Liver with chronic ragwort toxicity

C) Biliary Hyperplasia – bile duct proliferation in portal triads

 - Bile duct injury due to obstruction, severe hepatocyte injury, portal inflammation
- Change only seen histologically
- Often in association with fibrosis

Outcome of Injury

1. Resolution – regenerates and normal function returns

2. Progress to end-stage disease – totally f****d; liver failure and death
3. Something in between – part of it might be too damaged to return to normal but other parts might be able to
function normally. Some regeneration and some fibrosis.

What happens when function is impaired?

Clinical signs of initial disease

Initially, due to the liver’s large functional reserve, clinical signs may be really mild and non-specific → anorexia, WT
loss, lethargy ect…

→ additional tests needed to confirm liver dz in early stages:

- CBC and biochem +/- urinalysis

- Imaging of liver (Ultrasound)
- Sampling FNA or biopsy

Clinical signs of more advanced disease

1. Oedema → due to hypoalbuminaemia (liver can’t produce enough albumin resulting in decreased colloid
osmotic pressure).
2. Neurological → limited conversion of ammonia to urea → toxic substance in blood build up and affect the
brain (hepatic encephalopathy)
3. Excessive bleeding → not producing enough coagulation factors (APPT and PT times may become elevated
and animal may become anaemic)
4. Photosensitisation → ineffective excretion of phytoporphyrins (build up in blood and dermis)
Evaluation of the Hepatobiliary system

Recap of 3rd year Pathology

Regenerative: anisocytosis, polychromasia + reticulocytosis:

- Haemorrhage – TPP usually low +/- evidence of bleeding
- Haemolysis – TPP usually normal +/- jaundice, spherocytes etc – what see depends on underlying
cause, severity and species

Non-regenerative: Usually normochromic + normocytic anaemia with no indicators of regeneration +

CHRONIC sounding Hx + clinical signs e.g.
- Chronic disease (or chronic inflammation) = really common
- Chronic renal disease = pretty common
- Chronic blood loss = often microcytic + hypochromic as body runs out of Hb
-
Pre-regenerative: <3-5 days since bleeding or haemolysis – looks non-regenerative but is actually just too
early to show regenerative changes.
- ACUTE sounding hx and clinical signs
Liver enzymes
Liver testing does not indicate how much functional liver is present → often only mildly increased in failure or
chronic dz. Only real worry is when liver enzymes are increased (don’t worry about decreases).

Two main classes of enzymes:

Leakage - ALT, AST and GLDH Induction – ALP, GGT

Leak into the blood when hepatocyte Increase as a result of bile retention. Often
damage or death occurs; become elevated indicators of cholestasis. Take longer to be
quickly after an event of damage (hrs) ‘induced’ (days)

Predict; hepatocellular damage (HC) Predict; cholestasis

1. ALT

Liver specific = acute HEPATOCELLULAR damage indicator in cats and dogs. ^ within 12 hrs of injury/event and
returns to reference ranges within 1-3 weeks unless injury ongoing.

▪ Marked increase = acute and severe necrosis (infections, toxins, trauma)

▪ More variable = occurs with a wide range of diseases (diabetes mellitus, hyperthyroidism, pancreatitis…)
▪ No/mild increase = chronic progressive liver disease/failure

Note: Many primary and secondary diseases can cause hepatocellular damage and increased ALT. Further
diagnostics are needed to differentiate.

2. AST
 Non-liver specific = hepatocellular or muscle injury/necrosis in LARGE animals (but can be used in cats and dogs
too). Because it could also be increased due to cardiac, haemolysis or muscle disease – need to analyse CK and
PCV at the same time.

▪ If BOTH AST and CK are high, mm damage is more likely

▪ If AST is high but CK and PCV normal, LIVER damage is more likely. But AST has longer half-life than CK
so AST will remained elevated after CK has gone back to normal → Clinical signs and history help rule
this out.

3. GLDH

Liver specific = LARGE animals. Acute hepatocellular damage. (large animal version of ALT).

4. ALP

Non-liver specific = mainly cats and dogs. Many different causes of increased ALP due to isoforms. Tests to separate
not used in NZ so likely cause of elevated by hx and CS. But → ^ ALP and ^ bilirubin indicates cholestasis.

Hepatic isoform sensitive but non-specific indicator of cholestasis in cats and dogs. Increases vary from mild to
marked.

- Dogs = increases in ALP seen before jaundice

- Cats = increases in ALP seen after jaundice (any increase in cats is significant). May be increased with
hyperthyroidism in cats too.

Bone isoform seen in rapidly growing animals.

- Rapidly growing animals

- Bone diseases

Drug induced isoforms glucocorticoids mainly.

5. GGT

Fairly liver specific = LARGE animals. Cholestasis is the major cause of increased GGT. (however, in neonates the
most common cause is colostrum intake ie; a good thing!).

Liver function tests

Why? – liver enzymes are not great at predicting loss of liver function → these tests evaluate liver’s ability
to perform normal functions.

- Can be markedly abnormal despite enzymes being normal. These tests measure the compounds in serum
that are either:

1. Normally removed by a functioning liver from the blood = INCREASE with liver dysfunction
2. Normally made by a functioning liver = DECREASE with liver dysfunction

Bilirubin

HYPERBILIRUBINAEMIA
 Hyperbilirubinaemia only becomes clinically evident as jaundice when serum bilirubin concentration >50μmol/L

1. Fasting → Fat metabolism which interferes with bilirubin uptake. More common in horses.
Unconjugated and usually mild.

2. Pre-hepatic/haemolytic 3. Hepatic 4. Post-hepatic/cholestatic

Acute haemolytic diseases (IMHA eg) =
marked hyperbilirubinaemia with
jaundice. Rate of RBC breakdown
exceeds the capacity of hepatocytes to
conjugate and excrete. Liver enzymes
usually normal.
Acute or chronic liver dz.
Extensive liver damage reduces
uptake and conjugation. See
jaundice if concurrent
cholestasis. Liver enzymes
usually normal. Sometimes ALT
increased mildly and ALP
increased if concurrent
cholestasis.
Regurgitation of bilirubin back into circulation.
Obstruction may be intra (hepatocyte
necrosis) or extra (neoplasia) hepatic.
Often marked and with jaundice. Increased
induction enzymes (but bilirubin increases
before ALP increase seen) and bilirubinuria.

5. Sepsis-associated → Inflammatory mediators reduce transport proteins for bilirubin → decreased excretion.
In dogs with severe infections. Inflammatory leukogram usually seen. Mechanism unknown in cats.

Bilirubinuria

Conjugated bilirubin is water soluble - freely filtered by the glomeruli. Can be detected by dipstick. Clinical
significance of bilirubinuria depends on the species the USG:

▪ 1+ bilirubin in the concentrated urine of a dog (USG>1.029) probably not significant unless the urine is
dilute.
▪ 1+ (or greater) bilirubin in the urine of a cat (regardless of USG) is always significant and suggests
cholestatic liver disease.

Bile Acids

Synthesised and conjugated in liver → excreted in bile

→ 95% reabsorbed in GIT and go back to portal blood
→ removed and recycled back into the bile again.
Increases may result from:
- Decreased clearance of bile acids from portal
blood → mod to severe reduction in functional
liver mass.
- Portosymstemic shunts → shunt blood away
from liver
- Decreased excretion of bile acids: cholestasis –
regurgitation into the peripheral blood.
Most useful to Dx: PS shunts or hepatobiliary dz.

Increased acids indicate disease and reduced function

but not cause or severity – other tests needed.

When should we test for bile acids? – (this is not part of routine biochem or liver tests)
 Liver dz is suspected but:

- There is ^ ALP and normal bilirubin

- There is ^ bilirubin but normal ALP
- Normal enzymes but other ‘liver-ish’ signs

Red top tube

- 1 samples – horses and ruminants = easier but less accurate

- 2 samples – dogs and cats = more specific and sensitive (pre-prandial and post-prandial)

Normal liver Damaged liver

Pre-prandial → low BA’s: post-prandial → usually Pre-prandial → increased BA’s: post prandial→
mild increase usually marked BA’s

Albumin

Synthesised in liver → when liver can’t make enough (hepatic failure or insufficiency) = hypoalbuminaemia (half-life long
so only see with chronic) Note: usually note seen in horses ‘cause they are weird.

- Ca is bound to it so see low Ca simultaneously.

- Hyperglobinuria is often seen too in liver failure. (Don’t need to know why just that A:G ratio is often decreased
with chronic dz).

Urea

Ammonia converted to urea in the liver then urea is excreted via the kidney in urine. Impairment means blood ammonia
levels go up, but hard to measure so use LOW UREA instead. Ammonia bitrate-crystals mostly present in animals with
portosystemic shunts.

Cholesterol

Synthesised in liver. cholesterol metabolism is impaired →hypocholesterolaemia. . Bile is the major route for cholesterol
excretion → biliary excretion also reduced so can see normal cholesterol too.

Glucose

Metabolised by liver. Significant impairment of hepatic function can result in EITHER:

- Hypoglycaemia (due to reduced hepatic gluconeogenesis and glycogen breakdown)

- Hyperglycaemia (due to decreased glucose uptake by the liver after eating)
- Normoglycaemia

Coagulation factors

Produced in liver. Impaired = reduction of production resulting in:

- Elevations in prothrombin time (PT)

- Activated partial thromboplastin time (APTT)
- Activated clotting time (ACT)
- Clinical signs of haemorrhage may be seen but do not always occur
Key points: Albumin, urea and cholesterol DECREASE with poor function. Glucose
is very variable. Usually 70-80% loss of function is needed before decreases are
seen on biochem.

Liver Sampling

1. Cytology
- Trans abdominal FNA (guided with US or blind)
- Good for diffuse processes
- Cheap and quick but not as accurate/diagnostic as histology

2. Histology
- Biopsy sample taken by tru-cut needle (or big chunk in ex.lap)
- Placed in formalin and sent to lab
- Good for local and diffuse
- Slow, expensive and more risky that cytology (may need GA, Haemorrhage risk, check clotting times)

3. PM
- Samples should be taken at PM
- For histo and cyto: <1cm thick, no more than 1:10 tissue to formalin ratio
- If you suspect infectious or toxic cause then take bigger samples (>3cm squared)
Specific disease examples
Incidental lesions

Nodular hyperplasia

Common in older dogs – multiple, firm, rounded nodules on surface and extending into parenchyma. OF NO
CLINICAL SIGNIFICANCE.

Telangiectasis

Multiple dark red spots = blood filled cavities

- Especially common in cats and cows

- ONLY SIGNIFICANCE = DDx for haemangiosarcoma metastases

Major post mortem changes seen after death

Due to its abundant nutrient content and close proximity to GIT bacteria, the liver rapidly undergoes post mortem
decomposition. Common post mortem changes (non-lesions) seen include:

• Putrefaction: irregular PALE foci +/- gas bubbles on the capsular surfaces.

• Autolysis: diffuse softening of the liver which becomes like putty.

• Pseudomelanosis: green-black pigmentation of tissues in contact with the GIT (staining from sulphur leaking from GIT
bacteria and reacting with iron from Hb)

• Bile imbibition: yellow -brown staining of tissues in contact with the gallbladder. haemoglobin from haemolysed
erythrocytes.

• Haemoglobin imbibition: red staining of blood vessel endothelium and adjacent liver by

→ These changes are really easy to mistakenly interpret as lesions when inexperienced

→ If you’re in doubt about whether an abnormality is a true lesion or just a post mortem change, take a sample in
formalin: histology will confirm which it is.
Circulatory disease

1. Atrophy of liver due to decrease blood flow

2. Hypertrophy of liver due to increased flow

Passive congestion → deoxygenated blood backs up in the liver.

- Usually due to RIGHT sided heart failure (RSHF)

- Occasionally due to hepatic or caudal vein obstruction

Acute Due to acute RSHF. Gross appearance = distension of central veins and centrilobular sinusoids with dark red
blood. Bloody cut surface, diffusely enlarged and dark red liver.

Chronic Due to chronic RSHF. Rounded margins and distension. Hypoxic centrilobular hepatoctyes start to die. VERY
MARKED lobular pattern = ‘nutmeg’ liver (see above).

Anaemia

Centrilobular hepatocytes get blood first so if acute severe anaemia they become hypoxic.

Dx changes: +/- mild to moderate increase in LE’s (ALP due to cholestasis) Causes = IMHA, Parvo, brassica
toxicity, theileria.

Portosystemic shunts

Abnormal vascular connection/s from portal vein to systemic circulation →

- Caudal VC (most common)

- Hepatic vein
- Azygous vein

Sequalae; blood from GIT bypasses liver => decrease in nutrients, liver atrophy in adults/doesn’t develop
in babies. Smaller liver → decreased function → hepatic encephalopathy. Can’t recycle bile ^^ BA’s in
serum.

Types:

INTRA-hepatic PSS’s

- Abnormal vessel WITHIN liver

- Sometimes due to ductus venosus failure to close at birth
- Large dogs

EXTRA- hepatic PSS’s

- Abnormal vessel OUTSIDE the liver

- Small dog breeds and cats
 1. CONGENITAL PSS’s

- Animal born with PSS (ductus venosus failure to close)

- SINGLE abnormal vascular connection – these are often really difficult to locate PM

Clinical signs: poor growth, neuro, lethargy, weakness…

Clinical presentation: small liver (but otherwise normal). +/- late stage ascites only (hypoalbuminemia).

2. AQUIRED PSS’s

- Animal develops after birth (older dogs with severe chronic dz)
- Usually due to portal vein hypertension → blood can’t get through liver so creates escape valve to
give itself a way back into systemic circulation
- Caused by chronic severe liver dz or failure (fibrosis and compression of BV’s)

PM: LOTS OF TORTUOUS/twisted abnormal BV’s surround connection to mesentery. Portal veins
distended. SMALL FIBROTIC liver.

Clinical signs: ascites (from portal vein hypertension) and neurological signs.

Clinpath:

- liver enzymes usually normal or mildly increased

- BA’s elevated pre and post eating.
- Other tests are abnormal (albumin and urea decreased)
- Increased coagulation times
- Ammonia – biurate crystalluria
- Mild microcytic non-regenerative anaemia

Metabolic and nutritional diseases

Hepatic lipidosis

Normally = lipids to liver as FFA’s → esterified to TG’s → complexed with lipoproteins and enters circulation
→ energy!

Pathologically = ‘fatty liver’ → presence of ^ lipids in hepatocytes due to altered metabolism (often results
in dysfunction)

Gross changes: pale/yellow/orange, enlarged and rounded → greasy, soft and friable
 Predisposition Dz associated with hepatic lipidosis

- Obese - Ketosis
- Pregnant/lactating - Diabetes
- Starvation - Feline fatty liver
- Equine hyperlipaemia
- White liver dz

Ketosis

→ diet not meeting metabolic needs → Results in: ^^^ fat mobilisation from tissues, hepatic lipidosis,
ketone production = ketosis

Sheep = late gestation Cows = mainly dairy → late gestation, post-partum/lactation

Clinical signs: weakness, recumbency, death Dx test: urine ketones, serum ketones

Diabetes Mellitus

Dogs and cats with decreased insulin production by pancreas → hyperglycaemia +/- glucosuria.

→ usually gradual onset of signs including PU/PD

- Altered fat + carbohydrate metabolism:

- ^ fat metabolised from tissues
- ^ hepatic lipidosis
- ^ ALT, AST + ALP + cholesterol

Feline Fatty Liver Syndrome

→ obese cats after long period of anorexia.

- Often acute hepatic failure and death

- Biochem: MARKED ^ ALT, AST, ALP + bilirubin

Equine Hyperlipaemia

Overweight or lactating ponies, minis,

Shetlands after a period of anorexia
→ hepatic lipidosis develops
→ often acute hepatic failure + death

Biochem: ^^ GLDH, GGT, bilirubin +

hyperlipaemia

White Liver Dz

→ Sheep with cobalt deficiency = decreased fat exiting liver due to decreased activity of cobalt-dependant
enzymes. Clinical signs: ill thrift, scungy wool, +/- photosensitisation

Glycogen accumulation
 Swollen hepatocytes with extensive
cytoplasmic vacuolation from
glycogen accumulation

^^ glycogen compared to normal hepatocytes due to altered glucose metabolism

a) Diabetes often in combo with excess lipids

b) Hyperadrenocorticism – excess steroids due to:

1. Endogenous = cushings
2. Exogenous = prednisone ect…

→ steroids induce glycogen synthase activity which causes more glycogen to be stored in hepatocytes

Clinical signs: PU/PD, Polyphagia, muscles wasting, pot belly, alopecia

Clinpath: ^ ALP, stress leukogram, low USG, hyperglycaemia, hypercholesterolaemia

Gross changes: pallor, patchy and swollen liver (looks like hepatic lipidosis)

Infectious Diseases

Bacterial Disease
3 main routes of entry:
1. Blood
2. Bile ducts
3. Direct extension
Variable gross appearance:
- No obvious gross changes
- RANDOM and small multifocal white spots
- Larger and RANDOM abscesses, granulomas or foci or necrosis (well-demarcated-trueperella
pyogenes; granulomas-mycobacterium)

Liver abscess (or necrosis) in post-partum period

Lambs or calves with inadequate colostrum (<24hrs) + navel ill – occur in first 2-6w of life
- Lack of maternal Ab & immunosuppressed
- Open umbilicus → umbilical v. (septicemia) → liver → spine, lungs & joints

How to check adequate colostrum intake? = GGT should be markedly elevated (20-30x)

Mixed environmental bacteria → not worth culturing

- Fusobacterium necrophorum ~ necrotic foci – multifocal areas of green-yellow coagulative
 necrosis
- Trueperella pyogenes ~ abscesses (pus)

Dx: signalment, hx of colostrum intake, PM lesions. These babies have poor prognosis (euth or die)

Liver abscess in older animals

Cattle (+/- sheep) following GIT bacterial infection → prior reticulitis or ruminitis (e.g. following hardware
disease or lactic acidosis)
- or through haematogenous spread via the portal vein (e.g. following bacterial enteritis).
common pathogen: Trueperella pyogenes
FATAL sequalae:

Invasion and rupture of the abscess in vessel (hepatic vein or caudal vena cava) causing dissemination of
bacterial emboli around the body →
Bacterial septicaemia → secondary infection of various other organs – vegetative valvular
endocarditis and lung abscesses →
Bacterial proliferation within these lung abscesses with ultimate invasion of pulmonary vessels
causing pneumonia, vessel rupture, hemoptysis (coughing blood) and epistaxis → +/- death.
o PEA = pulmonary embolic aneurysm
o CVC = caudal vena cava syndrome

Leptospirosis

Young calves (and lambs) Adult dogs

Serovar L.pomona L.copenhageni

Syndrome Haemolytic anaemia Concurrent acute severe liver

and renal failure
RBC changes Regenerative anaemia, WNL TPP WNL

Urine Haematouria Variable

Azotaemia +/- prerenal Severe renal and

hyperphosphataemia
Leakage enzymes WNL, unless hypoxia in ^^^ ALT + AST
hepatocytes
Induction enzymes WNL ^^^ ALP

Jaundice Pre hepatic Hepatic, cholestatic & sepsis

Clinical Signs Sudden death – group usually Severely and acutely ill →
lethargy, pyrexia, abdominal
pain, death

Dx: serology → samples taken @ 2 and 4 weeks for rising Ab titres. (PCR is possible but takes ages)
With dogs, usually just tx symptoms on presumptive dx before sampling.

PM : get good idea of dz via signs of acute renal and liver damage: enlarged, reddened, friable and
jaundice. But DEFINITIVE via histo and culture + PCR

Viral Disease
Most of the viruses primarily affecting the liver don’t occur commonly in NZ
 - Herpes, neonatal or fetal abortion and death
- Infectious canine hepatitis

FIP
Mutated form of enteric feline coronavirus → causes chronic and fatal disseminated vasculitis throughout
all organs.
- Young purebreds + multi-cat environments
Clinical signs: jaundice and increased enzymes, +/- neuro; +/- abdominal distension
Lab results:

1. Hyperglobinaemia = most consistent change

2. Abdominal effusion → high protein and low cellularity (degen. Neutrophils,
NO bx)
3. Non-regenerative anaemia due to chronic dz
4. Inflammatory leukogram: neutrophils with L-shift & toxic changes
5. ↑AST + normal ↑CK = hepatocellular damage
6. ↑ALT = acute hepatocellular damage
7. ↑ALP (likely liver isoform) = due to cholestasis
8. ↑bilirubin likely to be a combination of hepatic & post hepatic (cholestasis)
causes
+/- ↑ mild
Dx:9.Cytology of glucose
abtap, serum protein↑ electrophoresis
= transient due to stressed cat in the
(expect clinic
polyclonal gammopathy), PCR, PM, Serology .

Parasitic disease

Nematode migration
Tracts of necrosis + inflammation → fibrosis (~ firm white foci) → Usually clinically insignificant!

Cestodes
Cysticercus
Larval Taenia cestodes – usually Cysticercus tenuicollis

Liver encystation common = fluid-filled cysts

(left) & firm fibrotic nodular foci (right) →

Echinococcus – ZOONOTIC
Hydatid disease – Echinococcus granulosus
Eradicated from NZ 2002
Large, multiple, thick-walled fluid-filled cysts
Liver (+/- lungs)
Usually sheep or cattle (but other animals too)

Tremtodes: liver fluke (Fasciola hepatica)

COMMON + IMPORTANT in sheep in parts of NZ (+/-
cattle + goats)
 - Ingest larvae → migrate to liver
→ liver damage → enter bile
ducts
Early: cholangitis + bile duct obstruction →
cholestasis
Chronic: gross dilation + fibrosis of bile ducts
(“hosepipes”) →
Ill-thrift +/- anaemia + mild ↑GGT & bilirubin
(much milder than sub- acute FE
Toxic diseases

The liver is subjected to toxin-induced damage more often than any other organ, as almost
all ingested substances absorbed from the GIT end up in the liver via the portal blood. If
these substances are directly hepatotoxic, liver injury obviously results.
Hepatic biotransformation: transforming substances into excretable metabolites, intermediate
reactive compounds are produced which are much more hepatotoxic than the original compound
– most commonly via the cytochrome p450 enzyme system.

FE: sporidesmin
Occurs in late summer and autumn when warm humid conditions – ideal conditions for
fungal growth Cause: fungus Pithomyces chartarum → spores release mycotoxins =
sporidesmin
Pathogenesis:
1. Ingestion of spores in pasture litter
2. Uptake in bloodstream
3. Removed by liver & excreted in bile
4. Damaging bile ducts = cholangitis, cholestasis, jaundice & +/- hepatic necrosis
a. Ruptured bile duct bile leakage hepatic necrosis
5. Inadequate secretion of phytoporphyrin from plan
6. ↑ phytoporphyrin in blood
7. Deposit into unpigmented hairless areas
8. Phytoporphyrin activated by sunlight
9. Photosensitization
Ragwort: Pyrrolizidine alkaloids
Cause: Pyrrolizidine alkaloids (PAs) in ragwort both fresh & hay are
toxic Spp. affected:
- Cattle and horses are most commonly and severely affected
- Sheep and goats are more resistant to intoxication and so seldom develop clinical signs
- Pigs are highly susceptible they don’t often ingest ragwort – they are not exposed to it
Pathogenesis:
- Indirect liver damage: ingested PAs are converted to hepatotoxic metabolites by hepatic
enzymes
- Ingestion to clinical sign development is variable (1 week to several months)
Clinical signs: weight loss, D+, jaundice, with neurological signs due to hepatic encephalopathy
including hyperexcitability, aimless wandering and ataxia sometimes seen

Ewe @ PM → chronic toxicity showing cirrhosis – white

bands of fibrosis separating multiple regenerating nodules of hepatic tissue.

Copper
High concentrations of copper = hepatotoxic free radical production & oxidative damage
→ hepatocellular necrosis

1. Sheep are most susceptible (inability to excrete copper in bile)

2. Breed predisposition: Bedlington terriers → : )
o Familiar Cu accumulation in many dog breeds: WHWT,
Dalmatians Metabolism affected:
o → Canine chronic hepatitis gene deletion with
3. Vitamin E, Se or Mo deficient animals are more susceptible
copper transport
proteins

3 mechanisms of toxicity:
1. Defective Cu metabolism

Altered Cu excretion in bile: Lower ability to excrete Cu in

2. Decreased Cu excretion
bile → retention in liver
3. Dietary Cu excess – ruminants
only A combo of these 2 causes in sheep
 Dietary Cu excess: Over-supplementation – acute or chronic
- Acute: single dose → gastroenteritis & hepatic necrosis → death (48hrs)
- Chronic toxicity: PKE supplementation
o Combination effect: decreased Cu excretion, ↑dietary Cu → ↑Cu absorption
o Concurrent hepatic damage – predispose Cu toxicity & damage
o 2 stage process:
1. Chronic Cu accumulation within liver (weeks to months)
• Dietary excess & no CS
2. Acute release of stored Cu (hours to days)
• Initiated by crisis: stress, transport, etc.
• Massive/sudden release → hepatic necrosis
• Oxidative damage to RBC – severe
intravascular haemolysis & Heinz body
anaemia
PRESENTS ACUTE BUT MECHANISM IS CHRONIC

Clinical signs: jaundice, haemoglobinurea and death

Clinpath:
- Regen (or pre-regen) haemolytic anaemia
- Heinz bodies
- Red urine
- Hyperbilirubinaemia
- Marked ^^^ GLDH and GGT

Dx: fresh liver and kidney (Cu levels) or fixed for histo

Therapeutic drugs in cats and dogs

Cats are more susceptible than other species.

Usually indirect hepatic damage → biotransformation of hepatotoxic metabolites
- Can be acute damaged Ie; a high dose of a drug

Drugs that cause potential toxicity:

1. Paracetemol (Panadol, acetaminophen) in cats; Heinz bodies & significant acute
liver necrosis – elevated ALP & ALT
o Cats have a low activity of a key hepatic detoxification enzyme: glucurynoltransferase
2. Carprofen (Rimadyl) hepatic necrosis in dogs – esp. Labradors
3. Diazepam (valium) acute hepatic necrosis in cats
4. Anticonvulsants chronic liver damage in dogs

Other diseases/miscellaneous
Canine chronic hepatitis “chronic-active hepatitis”
Persistent hepatitis in middle age – older dogs >6mo
Dx: liver biopsy – prognosis typically poor by time of Dx (weeks-
months)
Pathogenesis:
1. Initiating cause unknown due to time of dx – any damage to the liver did not resolve
• Cu storage defect (Bedlington terreir), previous lepto, previous toxic
hepatopathy
2. Early progression: non-specific, mild intermittent signs +/- ↑ALT + ↑ALP
3. Later progression: enzymes often normal (+/- mild ^) but more clear signs of liver
failure +/- characteristic clinical pathology changes
4. +/- portal hypertension → acquired PSS

Clinical path: non-regen anaemia (chronic dz) = decreased → urea, hyperbilirubinaemia & jaundice,
albumin, clotting factors (coagulopathy). + cholesterol & glucose variable

Grossly: varying degrees of cirrhosis (can sometimes looks like tumors)

Liver rupture
Fetal → significant trauma during birth when pulled rapidly or roughly
through canal.
Normal/adult → VERY SIGNIFICANT trauma
= fatal death due to blood loss (haemoabdomen)

Image of horses liver after rupture and death →

Diseases of the bile ducts

Lymphocytic Cholangitis
Older cats → immune mediated

Clinical signs: sometimes ill, sometimes not (wax and wane) – lethargy, V+/D+

Pathophysiology: Inflammatory lymphocytes destroy bile duct

Dx: liver biopsy → enzymes and bilirubin mildly ^

Acute Suppurative Cholangitis

Cats and dogs

Pathophysiology: GIT bx inx tracts up into ducts +/- liver → sphincter of oddi stops working

Clinical signs: SEVERE – V+, pyrexia, lethargy, ab.pain, anorexia

Dx: Inflam. Leukogram, increased enzymes and bilirubin (variable in magnitude)

Neoplasia

Primary Liver Neoplasms: originates in liver and seen across all species
 Benign
- Usually single, smallish, and well
demarcated
- Not normally clinically significant
a) Hepatocellular adenoma -> hepatocytes
b) Cholangiocellular adenoma -> bile duct
epithelium
Malignant
- Larger, poorly demarcated with
multifocal masses throughout liver +
mets to other organs
a) Hepatocellular adenocarcinoma
b) Cholangiocellular adenocarcinoma

Secondary Liver Neoplasms

Spread to liver from another body site (more common) → multiple masses and diffuse enlargement

1. Lymphoma

All animals but especially cats and dogs

Grossly: pale, white and creamy due to e xtra lymphocytes. Diffusely large, pale liver OR multifocal masses

2. (Splenic) Hemangiosarcoma

Mainly dogs but also cats

Blood vessel endothelial cell neoplasia that spreads to liver from the spleen
Grossly: multiple dark and varying sized bloody masses
Rupture is common.
DDX – telangiectasis
 Dietary Cu excess: Over-supplementation – acute or chronic
- Acute: single dose → gastroenteritis & hepatic necrosis → death (48hrs)
o Combination effect:  Cu excretion, ↑dietary Cu & Mo & Se → ↑Cu absorption
o Concurrent hepatic damage – predispose Cu toxicity & damage
o 2 stage process:
3. Chronic Cu accumulation within liver (weeks to months)
• Dietary excess & no CS
4. Acute release of stored Cu (hours to days)
• Initiated by crisis: stress, transport, etc.
• Massive/sudden release → hepatic necrosis
• Oxidative damage to RBC – severe
intravascular haemolysis & Heinz body
anaemia
Liver = large, soft, pale ORANGE
 CS: & death

Clinical pathology:
- Regenerative (or pre-regen) haemolytic anaemia
- Heinz bodies
- Marked ↑↑↑ GLDH & GGT

- Fresh liver & kidney = Cu

levels
Dx: - Fixed liver & kidney =
histology