B2.069 Liver Case Flashcards
when does jaundice/icterus occur?
when the equilibrium between the production of bilirubin and the metabolism and excretion is disturbed
bilirubin > 2.5 mg/dL
how is bilirubin formed?
senescent erythrocytes release heme
heme oxygenase catalyzes production of biliverdin
biliverdin reductase catalyzes formation of bilirubin
what type of cell carries heme oxygenase and biliverdin reductase
macrophage (mononuclear phagocytic cell)
what protein carries bilirubin to the liver?
albumin
what are sources of unconjugated hyperbilirubinemia?
hemolytic anemia
resorption from internal hemorrhage
ineffective erythropoiesis
why does bilirubin complex with albumin?
it is insoluble and can’t be secreted otherwise
what can cause reduced uptake of bilirubin by the liver resulting in jaundice?
drug effects
what is the process of conjugation
hepatocytes take in bilirubin and form bilirubin glucuronides using UGT1A1
what are some sources of impaired conjugation?
neonatal jaundice (decreased UGT1A1 Activity) breast milk jaundice Crigler-Najjar syndrome Gilbert syndrome viral hepatitis drugs
Crigler Najjar syndrome
type 1: absent UT1A1
type 2: reduced UGT1A1
Gilbert syndrome
have about 30% of typical UGT1A1
presents jaundice under stress
what are some sources of impaired canalicular transport of bilirubin?
Rotor syndrome
Dubin-Johnson syndrome
Drugs
what structure transports bilirubin from the hepatocytes to the bile ducts?
bile canaliculus
what are some sources of obstructive jaundice?
bile duct obstruction
gallstones
carcinoma biliary
carcinoma pancreatic
what enzyme catalyzes the formation of urobilinogen?
bacterial b-glucuronidase
unconjugated bilirubin
indirect (can’t be directly measures)
insoluble
complexes tightly with serum albumin
cannot be excreted
conjugated bilirubin
direct water soluble nontoxic loosely bound to albumin can be excreted in urine when in excess
reasons for increase in unconjugated bilirubin levels
excessive production
reduced hepatic uptake
impaired conjugation
reasons for increase in conjugated bilirubin
decreased hepatocellular excretion
impaired bile flow
conjugated: total bilirubin < 0.4
unconjugated hyperbilirubinemia
conjugated: total bilirubin > 0.4
conjugated hyperbilirubinemia
how do you evaluate hepatocyte integrity?
cytosolic hepatocellular enzyme levels
AST (aspartate aminotransferases)
ALT (alanine aminotransferases)
what is the typical presentation of apoptotic hepatocytes on IHC?
“dead red”
no nucleus
how do AST and ALT change with massive necrosis in hepatocytes?
rises and then falls once all hepatocytes are dead
how do you evaluate biliary excretory function?
serum bilirubin secreted in bile
plasma membrane proteins of bile ducts:
serum alkaline phosphatase
serum gamma-glutamyl transpeptidase (GGTP)
what makes up the portal triad?
hepatic artery
portal vein
bile duct
lab studies associated with acute liver disease
increased AST and ALT
lab studies associated with acute liver failure
increased AST, ALT, ammonia
prolonged PT
lab studies associated with obstructive/biliary liver disease pattern
increased alk phos, bilirubin, GGTP
lab studies associated with cirrhosis pattern
decreased albumin and platelets
prolonged PT
how is the prothrombin time related to liver function?
coagulation factors in extrinsic pathway are produced by the liver
how do you evaluate hepatocyte function?
serum albumin
prothrombin time
serum ammonia
why is serum ammonia relevant to liver function?
the liver converts nitrogen to usable products
ammonia is the biproduct
what are clinical findings of hepatic encephalopathy?
alterations in mental status
disordered sleep
asterixis
coma and death
characterize hepatic failure
80-90% of functional capacity gone
mortality = 70-95% without transplant
what are two ways to get hepatic failure?
sudden massive destruction
end point of progressive damage to liver as part of chronic liver disease
what accounts for 50% of acute liver failure cases in the US?
acetaminophen overdose
what are some general causes of acute liver failure?
viral infection drug induced autoimmune ischemia mushroom poisoning
what is ascites?
a decrease in albumin causes a decrease in oncotic pressure
water pools in the belly
what are the 3 main results of cirrhosis?
decrease in detox
portal hypertension
decrease in protein synthesis
results of decrease in protein synthesis in liver
less coag proteins
PT time lengthened
bleeding tendency
results of portal hypertension
ascites
esophageal varices:
hypovolemia
hepatorenal syndrome
results of decrease in detoxification in liver
hyperestrinemia: due to less breakdown of estrogen
-gynecomastia, testicular atrophy
ammonia toxicity
-encephelopathy
causes of cirrhosis
viral hepatitis alcoholic liver disease NAFLD biliary disease primary hemochromatosis wilson disease A1AT deficiency cryptogenic cirrhosis
pathogenesis of cirrhosis
progressive fibrosis and reorganization of vascular microarchitecture of the liver
types 1 & 3 collagen
what do activated Kupffer cells do?
release cytokines
activate stellate cells
how are Kupffer cells activated?
apoptosis of hepatocytes
what is the function of activated stellate cells?
myofibroblasts
secrete type 1 collagen and form irreversible fibrous bands
what parts of your body can be affected by cirrhosis induced shunting of blood flow?
esophageal varices spider angiomata splenomegaly hemorrhoids periumbilical caput medusa
why does spenomegaly occur?
blood pools in the spleen
platelets are sequestered
which zone of the liver acinus has the most oxygen?
zone 1 (outside)
which zone of the liver acinus has the most cytochrome p450
zone 3 (inside)
what pattern of necrosis in the liver lobule is associated with APAP?
centrilobular
how do centrilobular necrosis zones appear on IHC?
pale
what is the toxic metabolite of APAP?
NAPQI
what compound neutralizes NAPQI?
gluthathione
what happens when glutathione stores are depleted in the liver?
NAPQI covalently binds to cell proteins
triggers mitochondrial permeability transition
leads to necrosis
what are the 3 possible metabolites of APAP?
sulfate moiety (nontoxic) glucuronide moiety (nontoxic) NAPQI (toxic)
what is the antidote to APAP overdose?
NAC
replenishes glutathione stores
most effective in 1st 12 hours
characterize cytolytic acute liver injury
spotty necrosis
submassive necrosis
massive necrosis
APAP, psychotropic drugs, herbal medicines, cocaine, carbon tetrachloride
characterize cholestatic acute liver injury
intrahepatic cholestasis- mostly in centrilobular hepatocytes, formation of canalicular plugs
anabolic or contraceptive steroid use
steatosis
fat deposition in liver
what causes steatosis in alcoholic induced liver disease
excess reducing equivalents (NADH and H+)
shunting of normal substrates away from catabolism and toward lipid biosynthesis
dysfunction of membranes
hypoxia
oxidative stress
what is the progression of alcohol induced liver disease?
steatosis
steatohepatitis
cirrhosis
what are some features of steatohepatitis?
liver cell necrosis
inflammation
Mallory bodies
fatty change
can you reverse alcohol induced liver disease?
steatosis -yes
steatohepatitis- yes
cirrhosis - no
how do fat droplets appear on IHC?
cytoplasm replaces with white instead of pink
what is Mallory hyaline?
ubiquinated cytokeratin intermediate filaments
appears dark purple in ballooned hepatocytes
what contributes to non alcoholic fatty liver disease?
obesity
dyslipidemia
hyperinsulinemia
insulin resistance
what is the most likely cause of increased AST and ALT?
non alcoholic fatty liver disease
what is metabolic syndrome
one of: DM impaired glucose stuff insulin resistance AND two of: high BP dyslipidemia central obesity microalbuminuria
