2.9 Liver clinical pathology

ALT species used and pattern of increase (4)

(alanine aminotransferase)

• Only dogs and cats

  • Hepatic ALT is low in large animals - use SDH/GLDH

• Increase within 12h injury

• Peak 1-2 days

• Decrease over next 2-3 weeks

How does rhabdomyolysis impact hepatocellular damage measurements?

AST and ALT can be derived from muscle - bad indicator for hepatocellular disease if that happens

• AST more prominent in muscles and also from haemolysis → therefore ALT used more often generally

List the 3 ways that ATP depletion or oxidation leads to release of liver enzymes from hepatocytes.

• Reversible damage → blebbing → blebosome

• Irreversible damage → blebbing → leakage

• Necrosis

SDH and GLDH names

• Sorbitol dehydrogenase

• Glutamate dehydrogenase

Most specific muscle damage indicator and patterns of elevation (4)

• Creatine kinase

• Increase within 1-2h muscle injury

• Peak at 6-12h

• Decrease next 24-48h

  • persistent elevation = ongoing damage

  • ALT > CK does not always mean liver damage → ALT may be rising while CK is falling

2 enzymes indicating cholestasis

• ALP (alkaline phosphatase)

• GGT (gamma glutamyl transferase)

Measure enzyme activity - enzyme conc is usually low (since recycled in body)

3 sources of ALP

• Bile duct epithelium irritated due to cholestasis

• Found in growing bone (young animals)

• Steroid induced isoforms in dogs

  • Endogenous - Cushing’s, exogenous - iatrogenic

Name the 2 causes of cholestasis leading to high ALP in cats and how you can distinguish them.

• Lipidosis compressing bile duct → cat is fat

• Hyperthyroidism → cat isn’t fat

How is induction different from leakage in ALP?

• Induction - normal bile flow - regular amount of bile duct stimulation → small amount of ALP regularly in blood

• Induction - steroids bind to surface receptor → transcription and translation of large amounts of ALP

What 2 steps of ALP increase are there during induction?

• Initial small increase

• Large increase 5-7 days later

Name 3 places GGT is found in.

• Bile duct epithelium

  • more sensitive VS ALP in large animals

• Colostrum - increased in nursing animals

• Renal tubular cells

  • Will not increase in blood

  • Changes conc in urine → affects osmosis

Describe the steps of bilirubin excretion into urine (8). How about the faeces?

• RBCs broken down by splenic macrophages

• Haemoglobin → unconjugated bilirubin (+ recycled iron)

• Unconjugated bilirubin binds to albumin in blood → transported to liver

• Unconjugated bilirubin endocytosed by hepatocyte

• Hepatocyte conjugates bilirubin

• Conjugated bilirubin in canaliculi →bile duct → intestine

• Intestinal bacteria convert bilirubin → urobilinogen

• Urobilinogen absorbed in portal veins → kidney → urine

  • gives urine colour

• If conjugated bilirubin processed by LI bacteria → stercobilinogen

  • gives faeces colour

How does haemolysis lead to bilirubinaemia? Which form of bilirubin increases first? (5)

• Excess number of RBCs broken down

• High levels of unconjugated bilirubin at liver

• Hepatocytes upregulate conjugation and excretion

• Excretion into intestine is rate limiting step → therefore unconjugated increases first

• Eventually conjugated that leaks back into blood competes VS unconjugated for hepatocyte binding → both increase

How does cholestasis lead to bilirubinaemia? Which form of bilirubin increases first?

• Obstruction in bile duct → conjugated bilirubin leaks into circulation

• Conjugated bilirubin goes into kidney → bilirubinuria (not seen in haemolysis)

  • Dogs can conjugate low levels of bilirubin in renal tubules - low levels of bilirubinuria normal

• Conjugated increases first since normal haemolysis

• Conjugated competes VS unconjugated → both increase

Why is albumin not a sensitive indicator of liver failure?

Other things (eg PLE/PLI) also decrease it

What does high and low urea levels suggest?

• High urea - renal excretion problem

• Low urea - liver conversion (urea cycle) problem

  • May see ammonium biurate crystals in urine

Why is looking at glucose levels not a sensitive indicator for liver failure?

Glucose production is highest priority of liver - glucose only really decreases with end stage liver disease

How does cholesterol increase or decrease with liver failure?

Synthesised in liver:

• Increase - liver excretion compromised (cholestasis)

• Decrease - liver production compromised

(if measure cholesterol - fast animal before taking blood since postprandial blood has lots of unprocessed cholesterol/lipid in blood)

How does cholesterol vary with hyperadrenocorticism, diabetes, and T4 levels?

• Increases with hyperadrenocorticism and diabetes

• Varies inversely with T4

Bile acid normal function (4)

• Conjugated bile acids in gall bladder

• Postprandial - gall bladder contracts → bile acids in gut

• Bile acids digest fat

• Body recycles via enterohepatic circulation → should be low levels in normal peripheral blood (if not postprandial)

How do you normally measure bile acid concentration? What 2 exceptions are there? (3)

• Measure fasting levels and postprandial

• Horse - do 1 sample (no gall bladder)

• Ruminants - do not use (wide range)

Name 2 potential pathologies suggested by increased bile acids in serum or plasma.

• Decreased liver functional mass → decreased bile acid clearance from portal blood

• Portosystemic shunt → blood bypasses liver → decreased bile acid clerance

• Obstructive cholestasis → decreased excretion via bile

  • Do NOT measure if you already know there is cholestasis - useless

Why is the bile acid challenge test done?

Liver can sometimes cope with base low levels (nonpostprandial) bile acids → feed the animal to see if it can cope postprandial

List 3 false increase reasons and 1 false decrease reason for ammonium.

Ammonium has poor stability:

• Haemolysis 

• Delayed sample analysis

• Measuring serum and not plasma

• Exposure to air

Name 6 pathologies potentially causing hyperammonaemia.

• Decreased liver functional mass → clearance

• Portosystemic shunt → clearance

• Postprandial → increased production

• Urea toxicosis (cow) → increased production

• Strenous exercise → increased production

• UTI → increased production (for some reason)