Hepatobiliary & Muscle Disorders Flashcards
What are the general functions of the liver?
- metabolizes carbohydrates, lipids, proteins, hormones, and vitamins
- detoxifies and excretes waste products and toxins
- digests fats and forms triglycerides and cholesterol
- excretes bilirubin and bile acids
- produces clotting factors
- synthesizes proteins
- converts ammonia into urea (BUN)
- glucose homeostasis and glycogen storage
What are the 3 supplies of blood to/from the liver?
- HEPATIC ARTERY: receives oxygenation blood from systemic circulation
- PORTAL VEIN: receives blood from the GIT and spleen
- HEPATIC VEIN: returns blood to systemic circulation
What makes up the portal triad? What zone is most susceptible to necrosis under hypoxia?
- hepatic artery
- portal vein
- bile duct
ZONE 3 - furthest away from the portal triad
How does bile flow in the liver? What species lack gallbladders?
- hepatocytes secrete bile into the sinusoids
- drains into interlobular ducts
- hepatic ducts
- gallbladder
- cystic duct and hepatic duct join to form the common bile duct that terminates at the major duodenal papilla
horses
What are the main categories of tests for liver disease/failure?
- hepatocellular injury - serum enzymes detect sublethal injury or necrosis (normal biochem)
- cholestasis - serum enzyme assays detect obstructed bile flow (normal biochem)
- liver function - evaluates hepatocyte functionality detected at 70-80% of hepatocyte loss (special tests)
What is important to remember about liver enzymes?
NOT A LIVER FUNCTION TEST —> hepatic disease has inconsistent lab findings and may overlap with enzymes of specific conditions
What are the 5 major leakage liver enzymes? What are they found? When are they elevated?
- alanine aminotransferase (ALT)
- aspartate aminotransferase (AST)
- sorbitol dehydrogenase (SDH)
- lactate dehydrogenase (LDH)
- glutamate dehydrogenase (GDH)
cellular cytoplasm and organelles - cell membrane disrupts and leaks from the cell into the blood, seen in sublethal injury and necrosis (hepatocellular injury)
What are the 2 major inducible liver enzymes? Where are they found? When are they elevated? How do results compare to leakage enzymes?
- alkaline phosphatase (ALP)
- γ-glutamyltransferase (GGT)
cell and organelle membranes - stimulus must induce the production and release, seen in cholestasis
produced in much smaller numbers and increased serum activity is detected much slowly over several days
What typically accompanies hepatocyte injury? How does this make reading biochemistry results difficult?
cell swelling, inflammation, and necrosis, which may alter bile flow and lead to cholestasis
increased activity of BOTH leakage and inducible enzymes
Where is alanine aminotransferase (ALT) found? What is it not helpful for detecting?
hepatocyte cytoplasm —> highest in dogs and cats, so it is often the only test used to detect hepatocyte injury or necrosis in these animals
hepatocyte injury in horses and ruminants
Why is alanine aminotransferase not considered a liver-specific enzyme? How can this be evident on biochemistry?
also found in smaller amounts in skeletal and cardiac muscle
ALT can also increase with severe muscle damage —> increases in 12 hr and will return to normal in 2-3 weeks
What are 5 common causes of elevated alanine aminotransferase (ALT)? What drugs can also cause an increase? What would a mild increase indicate?
- hypoxia
- metabolic alterations that cause intrahepatocyte lipid accumulation (hepatic lipidosis)
- bacterial toxins
- primary or metastatic neoplasia
- trauma (HBC)
corticosteroids and phenobarbital
hepatocyte injury after injury
What affects the magnitude of alanine aminotransferase (ALT) increase? How do chronic injuries affect its activity?
greater with acute hepatocellular injury —> increases within 1-2 days and decreases over several weeks after the injury resolves
periodic flares of increased activity
What 2 things are not affected by the magnitude of liver enzyme increase?
- differentiate cause or severity
- make a prognosis
Where is aspartate aminotransferase (AST) concentration highest? How does its half-life compare to ALT? In what species is it preferred for detecting hepatocyte injury?
cytoplasm and mitochondria of hepatocytes and skeletal/cardiac myocytes
shorter half-life compared to ALT
horses and ruminants
Aspartate aminotransferase (AST) increase can be caused by the same factors as ALT. What additional condition can increase ALT?
in vivo or in vitro hemolysis (pink/red serum) —> contained in RBC cytoplasm
Where is sorbitol dehydrogenase found (SDH)? How does its diagnostic use compare to AST? Why is it not commonly detected in labs?
hepatocyte cytoplasm in high concentrations in all species (liver-specific!)
much more specific than AST for detecting hepatocyte injury in horses and ruminants (preferred)
low in vitro stability - must be refrigerated or frozen
Where is lactate dehydrogenase (LDH) found? What are 3 causes of increased levels?
NOT LIVER-SPECIFIC —> found in the cytoplasm of most cells
- hemolysis
- muscle damage
- hepatocellular injury
What is glutamate dehydrogenase (GDH)? In what species is its levels used? What is a major caveat?
cytoplasmic leakage enzyme that increases with hepatocellular necrosis
liver-specific in bird, but has low sensitivity
What is alkaline phosphatase (ALP)? Where is it found?
inducible enzyme found on cell membranes in liver, bone, kidney, intestine, pancreas, and placenta
What 3 isoenzymes of alkaline phosphatase (ALP) are incorporated into total ALP measurements on biochemistry panels? What isoenzyme is not included?
- liver ALP (L-ALP) - hepatocytes, biliary epithelial cells
- bone ALP (B-ALP) - osteoblasts
- corticosteroid ALP (C-ALP) - canine hepatocytes ONLY (contributes 10-30% of canine ALP activity)
intestinal ALP (I-ALP) - very short half-life, unlikely to cause an increase in activity
How does the half-life of alkaline phosphatase (ALP) compare in dogs and cats? What does this mean?
- DOGS = 3 days
- CATS = 6 hrs
typically do not see marked elevations in ALP activity in cats, so if this is observed it is clinically significant
How is alkaline phosphatase (ALP) at detecting cholestasis in horses and ruminants? Why?
inferior to GGT —> has a wide reference interval
What causes elevated liver alkaline phosphatase (L-ALP)? What are 6 examples?
intrahepatic or posthepatic (gallbladder) cholestasis
- degenerative diseases - necrosis, hepatocyte swelling impairs flow
- metabolic diseases - hepatic lipidosis, DM, hyperadrenocorticism, cholelithiasis, feline hyperthyroidism
- neoplasia
- inflammatory disease - cholangiohepatitis, pancreatitis
- toxins
- drugs - corticosteroids and phenobarbital in dogs
What 2 toxins cause elevated liver alkaline phosphatase (L-ALP) levels?
- pyrrolizidine alkaloid - Crotalaria, Heliotropium, Senecio
- clovers
What causes increases in bone alkaline phosphatase in young and adult animals?
YOUNG - growing with increased osteogenesis, causing an increase 3x adult ALP RI
ADULT - bone lysis/remodeling, feline hyperthyroidism, canine hyperparathyroidism, osteosarcoma, fracture repair, rickets
What 2 causes of elevated corticosteroid alkaline phosphatase (ALP) levels?
- ENDOGENOUS: hyperadrenocorticism (Cushing’s)
- EXOGENOUS: corticosteroid treatment
marked increases up to 200x —> dogs only
What is γ-glutamyltransferase (GGT)? How does it compare to ALP?
inducible enzyme found on cell membranes of hepatocytes, biliary epithelial cells, renal tubular epithelial cells, and mammary epithelial cells (also found in colostrum from dogs, sheep, and cattle)
more sensitive indicator of cholestasis in horses, ruminants, and avian species
What else (other than cholestasis) can cause an increase in GGT in horses and ruminants?
severe hepatic necrosis, which leads to necrosis of biliary epithelium and blockage of bile flow
What are the 3 major tests of hepatic intake, conjugation, and secretion?
- bilirubin
- bile acids
- ammonia
What is bilirubin? What are the 4 steps of its metabolism?
pigment produced in macrophages by the degradation of heme from RBCs
- heme is converted into biliverdin, then unconjugated bilirubin
- unconjugated bilirubin circulates bound to albumin and is taken up by hepatocyte membranes
- hepatocytes conjugate bilirubin
- conjugated bilirubin is secreted in the bile canaliculi, reaches the intestine, is converted into urobilinogen, and eliminated in feces
Other than feces, where can bilirubin be excreted?
urine —> hyperbilirubinuria precedes hyperbilirubinemia
What 3 measurements of bilirubin may be available on analyzers? What can each tell us?
- total BILI - unconjugated and conjugated (need to determine source of bilirubin if elevated)
- unconjugated (free/indirect) BILI - pre-hepatic hyperbilirubinemia
- conjugated (direct) BILI - intrahepatic or post-hepatic cholestasis
What gross finding is common in hyperbilirubinemia?
- icterus (jaundice) when concentration is > 3.0 mg/dL, specifically in sclera, skin, and gingiva
- icteris plasma or serum
What are the 3 categories of hyperbilirubinemia? What are causes of each?
- pre-hepatic - hemolysis
- hepatic - loss of hepatic function, anorexia in horses, sepsis
- post-hepatic - neoplasia, hepatic lipidosis, corticosteroid hepatopathy, colangitis, cholelithiasis, cholecystitis, pancreatitis
What are 2 causes of pre-hepatic hyperbilirubinemia? What does this result in?
- extravascular hemolysis
- severe internal hemorrhage
increased bilirubin production overwhelms hepatic uptake, conjugation, and secretion capabilities —> increase unconjugated (indirect) bilirubin
What are 3 causes of hepatic hyperbilirubinemia? What does this result in?
- loss of hepatic function
- anorexia in horses - bilirubin conjugation requires glucose
- sepsis
increased unconjugated (indirect) BILI
What is the most common cause of post-hepatic hyperbilirubinemia? What are some causes? What doses this result in?
cholestasis by decreased secretion of bilirubin into the bile or physical obstruction
- neoplasia
- hepatic lipidosis
- corticosteroid hepatopathy
- cholangitis, cholelithiasis, cholecystitis
- pancreatitis
increased conjugated (direct) BILI
What is the typical pattern on biochemistry profiles of cholestatic and hepatic necrosis?
CHOLESTASIS: elevated ALP, GGT, and bilirubin
HEPATIC NECROSIS: elevated ALT, AST, and/or SDH wth normal ALP, GGT, and bilirubin
How can feline hepatic lipidosis be differentiated from other diseases causing cholestasis?
ALP will be more increased compared to GGT
Where are bile acids produced? How are they metabolized?
in the liver from cholesterol
- conjugated and secreted into the bile
- once in the intestine, they solubilize lipids and aid in fat digestion
- reabsorption into the blood from the GIT, where they are removed from portal blood by hepatocytes and recycled for re-excretion into bile (enterohepatic circulation)
What is bile acid testing a good indicator of? What also causes an increase? When is it especially helpful to measure bile acids?
hepatobiliary function (not specific to underlying disease process)
diseases that secondarily affect liver function
when liver enzymes are increased, but bilirubin is normal —> liver disease is suspected, but can be proven (unhelpful in icteric patients, will always be increased)
What 2 measurements of bile acids are done in dogs and cats? When is this done? When is hepatobiliary disease suspected?
baseline (testing) and postprandial
sample taken 2 hours after feeding
the greater of the 2 values higher than > 25 µmol/L
What can cause a falsely increased bile acid concentration? How does the bile acid test differ in horses?
lipemia in postprandial sample interferes with light transmission
only a single sample is taken
Interpreting serum bile acid results in dogs and cats:
How are serum bile acid results interpreted in horses and ruminants?
- single sample taken
- HORSE: marked increases in SBA 40-100 µmol/L is indicative of hepatic necrosis, hepatic lipidosis, neoplasia, or cirrhosis
- CATTLE: variable, can still detect hepatobiliary disease
What are 4 causes on increased bile acid concentrations?
- portosystemic shunts - portal blood bypasses the liver and enters systemic circulation
- liver failure - decreased bile acid uptake from portal circulation
- cholestasis - decreased bile acid excretion
- premature gallbladder contraction - falsely increases fasting BA concentration
What is decreased bile acid concentration indicative of?
small intestinal disease (NOT liver disease, BAs are efficiently recirculated and recycled)
- difficult to recognize due to low RIs for BA
Where is ammonia produced? How does it move in the body? What are the main 2 results once it reaches its destination?
GIT microflora from metabolism of amino acids and urea
GIT —> portal vein —> liver
- 85% converted into urea in the liver by hepatic urea cycle enzymes
- 15% enters systemic circulation
What is preferred for running baseline ammonia testing? Why can testing be problematic?
plasma
ammonia is very volatile and unstable —> must be kept on ice and analyzed ASAP (< 30 mins)
When is ammonia tolerance testing contraindicated? How is this done? What are the 2 main results?
patients who are hyperammonemic on baseline testing
baseline measurement is performed, followed bu second measurements within 30 mins of giving oral ammonia chloride solution
- ADEQUATE LIVER FUNCTION = second measurement is equal to or 2x higher than baseline
- HEPATIC INSUFFICIENCY = second measurement 3-10x higher than baseline with possible formation of ammonium biurate crystals on urine sedimentation
What are 3 causes of hyperammonemia?
- hepatic insufficiency - decreased liver uptake and conversion of ammonia to urea
- portosystemic shunt
- ruminants fed excess urea or soybean meal
What are hepatic pseudo-function tests? What 4 analytes are included?
testing of other analytes affect by alterations in hepatic synthesis, typically seen when at least 70% of hepatic functional mass has been lost
- hypoglycemia
- hypoalbuminemia +/- hypoglobulinemia
- decreased BUN
- hypocholesterolemia
(confirm suspicion of liver insufficiency with BA or ammonia testing)
How does hepatic insufficiency affect hemostasis?
decreased production of coagulation factors —> prolonged PT and PTT
What is the most common liver disease that alters CBC and blood smear findings? What is seen on each?
portosystemic shunts
- CBC: microcytic and/or hypochromic anemia (decreased MCV and MCHC)
- BLOOD SMEAR: acanthocytes, codocytes, hypochromasia may be visible
What enzyme is measured to detect muscle injury? Where is it not found? What is its half-like life?
creatine kinase (CK) in the cytoplasm of skeletal and cardiac myocytes, with a small amount in smooth muscle
hepatocytes —> muscle-specific
short (< 2 hr in dogs) —> increased activity = ongoing muscle damage
What are 6 causes of elevated creatine kinase (CK) activity?
- degenerative muscle disease - exertion, seizure, exertional rhabdomyolysis, saddle thrombus
- neoplasia
- nutrition - vitamin E or selenium deficiency
- inflammatory muscle disease (myositis) - Toxoplasma, Neospora, bacteria, immune-mediated
- toxins - monensin, castor beans, possypol
- trauma - HBC, recumbency in horses and cattle
(mild increases often not clinically significant)
How is muscle injury differentiated from hepatocellular injury?
MUSCLE = elevated CK, LDH, and AST without elevated ALT, ALP, GGT, or bilirubin
HEPATOCELLULAR = elevated ALT, AST, ALP, GGT and bilirubin with normal CK
