liver Flashcards

1
Q

Pathologies that are associated with
significant hepatocellular injury- Primary hepatic disorders

A
  • Necrosis
  • Inflammation due to infectious or non-
    infectious background
  • Toxic insult (drugs, chemicals plants)
  • Neoplasia (hepatocellular, biliary)- level of increase can be variable; absence
    of increase does not excluded neoplasia.
  • Biliary obstruction
  • Extensive trauma
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2
Q

Pathologies that are associated with
significant hepatocellular injury- Secondary hepatic effec

A

Ischaemic injury (circulatory, severe anaemia,
cardiovascular)
* Metabolic (endocrine disease, often as a result
of lipidosis or steatosis, negative energy
balance – same mechanism of lipidosis)
* Toxic effect of thyroid hormones in
hyperthyroidism
* Neoplasia, metastatic cancer
* Acute severe injury can be reversable and
hence would not necessarily result in impaired
function.

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3
Q

Main tool for evaluation of hepatocellular
damage is

A

measuring of leakage enzymes

Leakage enzymes : Enzymes which are present in high concentration within hepatocytes
and leak to serum when cells are damage

Most specific to Liver
 Alanine Aminotransferase (ALT)- Small animal only

Less specific to the liver, present in liver
and muscle
* Aspartate Aminotransferase (AST)
* Lactate Dehydrogenase. (LDH )

lare animal-
Sorbitol Dehydrogenase (SDH)
 Glutamate Dehydrogenase (GLDH)

Correlation with muscle specific
enzyme: CK can help assess
significance in terms of
hepatocellular injury

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4
Q

ALT

A

Most specific parameter for hepatocellular damage
* Main tool in small animals
* Acute stage: severity of increase is proportionate to no. cells affected – but not whether lethal/sub
lethaL

In a repeatable injury, concurrent increased levels from regeneration
* ALT half-life is 17-60 hours but may not return to normal level as quickly as expected based on
its serum half-life
* Persistent high levels imply ongoing damage and/or concurrent regeneration

In advanced severe liver disease, there is decrease in no. functional hepatocytes – may be minimal
ALT inc.
* There are several toxins (aflatoxin, microcystin) which interfere with transaminase production;
massive acute hepatic necrosis may occur with minimal increases in ALT (or AST).
* Steroid hepatopathy – ALT will go up (endocrinopathy, GC tx or severe sustained metabolic stress)

  • Rapid elevation (no synthesis de novo but release of accumulating enzymes)
  • Mild (2-3 folds)
  • Moderate (4-5 folds)
  • Marked, higher, up to 10 and over is considered marked
  • Severity does not correlate with reversibility
  • Acute severe injury can be reversable and hence would not necessarily result in impaired function.
  • End stage liver disease may have only slight increase in leakage or induction enzymes, or none at all.
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5
Q

AST

A

Not organ specific
* Skeletal muscle&raquo_space; Liver & Cardiac muscle
* Can be useful when confirmed as liver only in absence of elevation of CK
* Erythrocytes contain enough to raise activity in serum when intravascular or invitro hemolysis occurs

AST has cytosolic and mitochondrial isoenzymes. Reflected in two-tiered pattern of elevation.
* Mild elevation, mild reversable injury
* Marked elevation, severe irreversible injury

The expectation is for the elevation to lag behind the elevation in ALT and recovery to be slower.
* AST is more sensitive marker for liver injury in cats, particularly with granulomatous hepatitis in FIP where you can
see mild AST elevation with normal ALT

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6
Q

Hepatic torsion in rabbit clinical indications

A

Presentation: Anorexia, lethargy, jaundice and
abdominal pain
.
Lab results: Anaemia elevated liver enzymes
ALT, AST and GGT should prompt US where
diagnosis is established.

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7
Q

Cholestasis

A

Any pathology, hepatic or extra
hepatic which decrease bile flow
result in the following

Increase in induction and/or
release of enzymes
 ALP (induction)
 GGT (induction and/or release)

Increase in bilirubin concentration,
specifically conjugated bilirubin- functionality of liver ramins intact however this is an obstructive issue

  • Hyperbilirubinemia (conjugated higher then unconjugated )
  • Bilirubinuria - low renal threshold of the conjugated (soluble bilirubin)
  • Disproportionate increase of cholestatic/inducible enzymes
  • Increase in bile acid concentration (clearance function vs cholestasis)
    Additional relating changes:
  • Abnormal Vitamin K absorption resulting in coagulopathy
  • Hyper cholesterolemia reflecting decrease clearance of cholesterol in bile
  • Impact on lipoproteins and lipid metabolism
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8
Q

Pathologies resulting in cholestasis

A

structural cholestasis-
Intra hepatic obstruction
* Hepatocellular swelling
* Severe cellular infiltrate
* Solid hepatic biliary or metastatic tumours
* Fibrosis around biliary tree
* Parasites
*
Extra hepatic obstruction
* Tumours adjacent to the liver
* Pancreatitis
* Fibrosis

Functional cholestasis-
Defects in the transporters needed for
active transport of bile acids into the
canaliculi
* Endotoxins
* Inflammatory cytokines

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9
Q

γ-glutamyl transferase (GGT)

A

Transmembrane protein ,expressed on the cell membrane, with expression
being restricted to the luminal surface
* Solubilization of the membrane with bile acids and increased synthesis
result in increased activity in serum
* NOT liver specific BUT elevation in serum activity is almost always of
hepatobiliary origin

  • Present in high concentration in kidney, mammary tissue, pancreases BUT typically secreted to
    luminal surface of these organs and hence do not result in elevated serum levels
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10
Q

Interpretation of increased GGT activity in dogs and cats

A

Hepatobiliary Disease Detection:
* Cholestasis, cholangiohepatitis, hepatitis, and liver necrosis.
* GGT activity can often increase before other liver enzymes, valuable for early detection.

Biliary Hyperplasia:
* Biliary hyperplasia, a response to increased biliary pressure (e.g.) extrahepatic bile duct obstruction and
structural cholestasis.

Sensitive marker with differentiating value in cats
* May increase before alkaline phosphatase (ALP) and can be a more sensitive indicator of various liver
disease; minimal and/or or delayed increase is expected in hepatic lipidosis.

Drug-Induced Changes:
* Certain medications, like corticosteroids and phenobarbitone, can lead to increased GGT activity in
dogs.
* Understanding the potential drug-induced effects on GGT levels is important for accurate diagnosis and
treatment.

Hyperadrenocorticism:
* Dogs with Cushing’s often exhibit elevated GGT levels - useful marker for both diagnosis and monitoring
of treatment response.

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11
Q

interpreting GGT results in large animals

A

Neonates will have high levels from colostrum ingestion

Significant in liver complications of gastrointestinal diseases-
Colonic Displacement:
* GGT elevation observed in horses with right and left colonic
displacement and direct compression of bile duct

Proximal Enteritis:
* GGT increase linked to hepatic cell swelling from ascending
bacterial infections or toxin absorption.
* Histologic evidence of biliary hyperplasia or cholestasis.

Parvovirus-induced Hepatitis:
* increases in horses with parvovirus-induced hepatitis. Lag in
peak GGT activity compared to other liver enzymes

Plant Toxicity:
* Pyrrolizidine Alkaloids: marker for pyrrolizidine alkaloid toxicity in
ruminants.

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12
Q

Alkaline Phosphatase (ALP)

A

Tissue Sources
Liver:
* Hepatocytes & biliary tract epithelium.
* L-ALP isoform (all species) & C-ALP (corticosteroid induced isoform) in dogs
* Induced by cholestasis or corticosteroids

Bone:
* Produced by osteoblasts.
* Increases with osteoblastic activity.
* Elevated in osteosarcoma.

Others (Intestinal, Renal, Mammary, Placental):
* Usually not major sources.
* Exceptions in late pregnant queens, mares, and dogs with mammary tumours

dogs-
Cholestatic diseases can result in
marked increases in serum ALP
activity in dogs (greater than 10-fold
URL)
* Diff. cholestatic ALP from
stress/steroid – bilirubin…. may not be
increased if only partial biliary tree
obstruction
* Steroid hepatopathy does not
normally affect hepatic function
(bilirubin) although can if severe
* ALP and neoplasia – liver, bone and
mammary

cats-
* Shorter half-life & lower concentration- smaller increase more significant
* Smaller magnitude of serum ALP
activity increases compared to dogs
* ALP is less sensitive but more clinically
specific for feline cholestatic liver
disease (2–3× URL) can be significant
* Pancreatic + intestinal lesions can
sometimes be the primary cause of
cholestasis due to extrahepatic bile
duct obstruction.

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13
Q

Pre-hepatic Bilirubin/icterus

A

Immune-mediated hemolytic
anemia
Infectious (e.g., Mycoplasma spp.)
Toxins (e.g., paracetamol)
Hypophosphatemia
Hereditary defects (PK deficiency)

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14
Q

Hepatic Bilirubin/icterus

A

Inflammatory hepatopathies
Hepatotoxicity (e.g., diazepam)
Neoplastic
Cirrhosis/hepatic fibrosis
Hepatic lipidosis
Amyloidosis
Bacterial (cholangiohepatitis)
Protozoal (toxoplasmosis)
FI{

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15
Q

Post-hepatic Bilirubin/icterus

A

Bile duct obstruction (cholelithiasis,
biliary tree neoplasia,
inflammation)
Bile duct extraluminal compression
(pancreatitis, neoplasia, duodenal
disease)
Cholangitis/cholangiohepatitis

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16
Q

icterus and urinalysis

A

Renal threshold for bilirubin is low ,
bilirubinuria will proceed bilirubinemia
and/or icterus

Additional findings in urine :
* SG can be low, hyposthenuria ( low tonicity of
renal medulla due to low urea )
* Assess sediment

17
Q

Hyperthyroidism liver markers

A

ALP, AST, ALT elevated.
GGT, bilirubin normal.

18
Q

Hepatic lipidosis liver markers

A

ALP elevation early
Bilirubin increase follows
GGT elevation in later stages

19
Q

Necro inflammatory Disorders liver markers

A

very very high ALT

GGT > ALP increase when there is
biliary structures or pancreas
involvement.

Healing Phase after Necrosis:
*Sustained ALT ALP, GGT increase.

20
Q

Biliary proliferative
Diseases liver markers

A

GGT > ALP without
cholestasis
*e.g., biliary
carcinoma & biliary
hyperplasia

Cushing’s Disease
ALP significant increase
GGT variable increase,
ALT/ bilirubin variable

21
Q

Parameters
of Liver synthetic
function

A
  • Albumin
  • Glucose
  • Urea
  • Cholesterol
  • Coagulation factors
  • Coagulation inhibitors
  • Lipoprotein – impact lipid metabolism
  • Iron/hem metabolism
22
Q

Parameters
of liver clearance capacity

A

Endogenous
* Bile acids
* Ammonia
* Bilirubin

Exogenous
* Caffeine

23
Q

causesof liver dysfunction

A

low albumin, urea, cholesterol (or high)

low coagulation factoe and coagulation inhibitoes

llipoproteans
heamoglobin synthesis

clearance capacity-
Endogenous
* Bile acids
* Ammonia
* Bilirubin (non-conjugated)
all elevated
Resulting in hyper lipidaemia
Elevated triglycerides and/or
cholestero

Coagulopathies
intrinsic & extrinsic
pathways (PT &PTT
impacted)
* Different from
coagulopathies of
cholestasis which is
impacting the extrinsic
pathways only (PT) as a
result of decreased
vitamin K absorption

May be reflected by microcytosis

Between 70-75 of liver
parenchyma need to be
lost before there is
notable compromise to
liver function

24
Q

Different conditions with hepatic insufficiency

A

Chronic hepatitis
* infectious background: Leptospirosis, bacillus piliformis, helicobacter, bartonella spices, etc

Toxic injury
* Hepatic copper excess
* Any breed, but particularly those overrepresented (Bedlington Terrier , Dalmatian, Labrador
Retriever, Doberman Pinscher, and West Highland White Terrier)

Metabolic conditions
* Alpha-1 antitrypsin deficiency, American and British Cocker Spaniels

Immune mediated
* Immunological diagnostic tool, enzymology, IgG, and autoantibodies including antinuclear
antibodies, anti-mitochondrial antibodies, and anti-liver and kidney microsomal antibodies

25
Q

Enzymology progression of chronic hepatitis

A
  1. Early Indicator of Chronic Hepatitis (CH):
  2. Alt activity is the earliest and best indicator of CH.
  3. Later Stage Indicator in CH:
  4. ALP activity increases later in CH.
  5. When ALT&ALP activities are increased, ALT ̺ ALP increase.
  6. Progression of CH:
  7. As CH progresses and hepatic parenchyma decrease
  8. ALP and GGT activities increase compared to ALT.
  9. Fluctuations and Late-Stage Cirrhosis:
  10. Considerable variation in serum ALT activity can occur throughout the course of the disease, indicating fluctuations in
    necroinflammation over time.
  11. In late-stage cirrhosis, transaminases (including ALT) may decrease due to parenchymal loss.
  12. Prognostic Application and Histologic Injury:
  13. Serum ALT activity does not have a prognostic application but is associated with the severity of histologic injury.
  14. Other Enzymes:
  15. Serum Aspartate Aminotransferase and GGT activities tend to mirror ALT and ALP activities, respectively, but are less
    sensitive
26
Q

Enzymology progression of
chronic hepatitis

A

Early Indicator of Chronic
Hepatitis
ALT activity is the earliest and
best indicator of CH

ALP increases
later in CH
When ALT&ALP
are both
increased,
ALT»ALP

As CH progresses and
hepatic parenchyma
decrease
ALP&GGT >ALT

  1. Fluctuations and Late-Stage Cirrhosis:
  2. Considerable variation in serum ALT activity can occur throughout the course of the disease, indicating
    fluctuations in necroinflammation over time.
  3. In late-stage cirrhosis, ALT may decrease due to parenchymal loss.
  4. Prognostic Application and Histologic Injury:
  5. Serum ALT activity does not have a prognostic application, but trend can be informative.
27
Q

Monitoring of liver function throughout the course of
Chronic liver disease

A

TSBA
Consistent increase in the presence of portosystemic shunting, effective in detecting cirrhosis
Specificity is a challenge when cholestasis is linked to hepatic disease

Low urea nitrogen and cholesterol
Seen in about 40% of cases and more frequently in those with
cirrhosis

Hypoalbuminemia
Typically appears late in the
course of hepatic synthetic
failure

Hyperammonaemia
Sensitive CH, cirrhosis, and APSS like
TSBA, and more specific but difficult
to measure

Hyperbilirubinemia
Common in around 50% of dogs
with chronic hepatitis
Negative prognostic indicator

28
Q

What Causes Increased Bile Acid Concentration in Serum or Plasma?

A

Decreased biliary excretion of bile
acids
 Decreased functional hepatic mass
 Congenital or acquired
portosystemic shunts

Obstructive or functional
cholestasis
* Decreased biliary excretion of bile
acids
* Obstructive or functional cholestasis

29
Q

Interpretation of bile acid challenge

A

Increased post prandial bile acid in patient with
concurrent icterus /bilirubinaemia, cannot
differentiated True Liver insufficiency from cholestasis

Increased post prandial bile acid in patient
with no concurrent icterus/bilirubinaemia,
supports True Liver insufficiency

30
Q

Cytology of the liver

A

 When used appropriately, can guide the approach for more invasive diagnostic approach
 Decision to review cytology should be heavily rely on diagnostic imaging

Good reasons for cytology :
* Initial investigation of
hepatomegaly
* Assess the nature of diffuse
change in echogenicity
* Obvious focal lesions
* Staging
* Suspected cholangio
hepatitis
* Investigation of infectious
diseases

Bad reasons to do cytology
* Increased enzymes activity,
particularly if incidental
* Suspected reduced liver function

31
Q

Diffuse change in
echogenicity or
mottled appearance

A

Steatosis, lipidosis
* Cytoplasmic refraction
* Steatosis
* Infiltrative process- Inflammation, Neoplasia
* Extra medullary haematopoiesis

32
Q

Cytoplasmic rerfraction

A

Reflects accumulation of glycogen or water
(hydropic change) within hepatocytes and it is a
nonspecific sign of reversible cellular injury.
Glycogen accumulation may result from
administration of glucocorticoids or excess
endogenous glucocorticoids
(hyperadrenocorticism, chronic stress associated
with illness)
Hydropic change may be caused by a variety of
insults such as hypoxia, inflammation, some drugs
and hepatotoxins.

Cytoplasmic rerfraction must be interpreted
within the clinical context , laboratory data and
imaging (nodular diffuse sonographic changes).
* Cytoplasmic refraction is often
seen in nodular lesions, such as
nodular hyperplasia or
regenerative nodules,
* Post copper chelation
* Cytoplasmic rarefaction could
account for the presence of
hepatomegaly
* Mottle or heterogenous
ultrasonographic appearance.
* Elderly dog

33
Q

Lipidosis, fatty liver and steatosis

A

Must be a diffuse change, general consensus is
80% of hepatocytes affected
Definitive diagnosis requires correlation with
appropriate history, diagnostic imaging,
comprehensive haematology and biochemistry

Enzymes :
* ALP elevation early
* Bilirubin increase follows
* GGT elevation in later stages
Synthetic function
* Decreased blood urea
* Hypoalbuminemia
Other laboratory changes
Hyperglycaemia
Hypokalaemia,
Hypophosphatemia
Hypomagnesaemia

Full blood count is often normal,
* There may be a predisposition to Heinz
body formation (oxidative damage).
Bleeding tendency is observed in 45-
73% of patients.
* Histological biopsy may be considered
depending on the clinical picture (e.g. a
concurrent liver disease is suspected)
* Generally not recommended, given the
possible complications and the
increased fragility of steatotic liver
parenchyma.

34
Q

STEATOSIS-
LIPIDOSIS

A

Two types (but NO prognostic value):
* Macrovescicular: globules larger than nucleus)&raquo_space; accumulation of triglycerides
* Microvescicular: globules smaller than nucleus&raquo_space; accumulation of lipoprotein (more difficult
to differentiate from glycogen accumulation, but even in microvescicular types, you can find
some sharp larger globules)

35
Q

Macroglobular
eosinophilic bodies

A

Protein droplets are variably sized
eosinophilic (hyaline) droplets in the
cytoplasm of hepatocytes
* possibly engulfed serum proteins
represent a non-specific and variable
finding associated with shock,
ischemia, or other acute
hepatocellular injury.
* Eosinophilic cytoplasmic bodies of
variable size may be the result of
phagocytosis of apoptotic bodies by
hepatocytes

36
Q

Common Pigment in
Hepatocytes include :

A

Lipofuscin
Bile
Haemosiderin
Copper
Ceroid pigment is often noted
in macrophages

37
Q

lipofuscin

A

Most common pigment that is noted in
hepatocytes
* Part of aging process of the cells
* Lysosomes with indigestible lipid rich residues blue
green granules different from yellow coloration in
histology
* Colouration is similar to bile, difficult (essentially) to
tell apart when intercellular
* Pragmatism :
* With the understanding that there is often a mixture
* Intercellular – lipofuscin
* Extra cellular. Bile

38
Q

Copper

A

is the most common toxic injury causing
chronic hepatitis in dogs
* Copper plays a critical role in development, progression and
morbidity of chronic hepatitis
* Genetic in some breeds (Bedlington Terrier, Labrador, Dalmatian,
Labrador Retriever, Doberman Pinscher and West Highland White
Terrier.)
* In others on the spectrum between a cause and a consequence ( high
dietary content, result of cholestasis)
* Elevated enzymes could be the only sign, silent progression