Lec 20 jaundice LFTs Flashcards
Where is bilirubin primarily derived from?
mostly from breakdown of hemoglobin from old/injured RBCs or ineffective erythropoiesis
Where is bilirubin formed?
in liver and spleen
What are 3 causes of jaundice?
- increased bilirubin production
- impaired hepatic handling
- benign lab finding
AT what level of bilirubin do you see jaundice?
bilirubin > 2.5 mg/dL
What 2 enzymes involved in formation of bilirubin from heme?
- heme oxygenase
- biliverdin reductase
What is the reaction heme oxygenase catalyzes?
heme —> biliverdin
What is the reaction biliverdin reductase catalyzes?
biliverdin –> unconjugated bilirubin
Where are heme oxygenase/biliverdin reductase located in the body?
- spleen
- hepatocytes
- renal tubular epithelium
How is bilirubin primarily present in blood?
primarly present as unconjugated bilirubin bound to albumin
Why do you see greenish hue in resolving hematoma?
sign of biliverdin before it is converted to bilirubin
What is normal total bilirubin in plasma? % conjugated vs unconjugated?
1-1.5 mg/dl normal value
90% unconjugated
10% conjugated
Which type of bilirubin is soluble?
conjugated is soluble
unconjugated is insoluble –> must be bound to albumin
What are the 4 steps of bilirubin elimination via biliary tract?
- hepatocellular uptake
- intracellular binding
- conjugation
- excretion of conjugates into bile
What enzyme mediates bilirubin conjugation?
UDP-glucoronosyl transferase
What happens to bilirubin once it is secreted into small intestine?
- travels to ileum/colon where bacterial enzymes metabolize some of it to urobilinogen –> absorbed and recycled back to liver and to kidneys
- some converted to stercobilinogen –> excreted in feces
What is the rate limiting step in bilirubin metabolism?
excretion of conjugated bilirubin into bile canaliculus by MRP2 protein
What form of bilirubin excreted in feces?
stercobilin
What form of bilirubin excreted in urine normally?
urobilinogen
Does bilirubin in urine indicated conjugated or unconjugated hyperbilirubinemia?
indicated conjugated hyperbilirubinemia
unconjugated is bound to albumin so is not filtered by glomerulus
What percent of urobilinogen in gut is excreted as stercobilin vs reasbrobed?
80% secreted as stercobilin
20% reabsorbed
What are 3 possible causes of unconjugated hyperbilirubinemia?
- increased production of bilirubin
- reduced hepatic clearance of bilirubin
- inherited disorders of bilirubin metabolism
What are some potential causes of increased production of bilirubin leading to unconjugated hyperbilirubinemia?
- hemolysis
- inherited hemolytic anemias
- acquired hemolytic anemias
- ineffective erythropoiesis
What are 4 things you should think if unconjugated hyperbilirubinemia?
- hemolytic cause [inherited or acquired hemolytic anemia]
- physiologic
- crigler-najjar
- gilbert syndrome
What is mech of neonatal jaundice? What level/type of bilirubin
- occurs 2-5 days after birth –> have total bilirubin < 5-10 mg/dl
- due to hepatic immaturity
- unconjugated hyperbilirubinemia
What is treatment for neonatal jaundice?
phototherapy
What are 2 inherited disorders of bilirubin conjugation?
- gilbert’s syndrome
- Crigler-Najjar
thus have high unconjugated hyperbilirubinemia
What is pathology of GIlbert’s syndrome?
partial deficiency of UDP-glucoronosyltransferase
have asymptomatic or mild jaundice with high unconjugated bilirubin that increases with fasting or stress
What is pathology of Crigler Najjar syndrome type I?
no functional UDP-glucoronosyltransferase activity
have high indirect bilirubin 18-45 mg/dl
When does Crigler Najjar type I usually present?
presents in neonatal period
What are signs of Crigler-Najjar type 1?
- jaundice
- kernicterus [bilirubin deposition in brain] –> neuro impairment
- undetectable UDP-glucoronyltrasnferase
- normal liver histology
- often fatal w/in first 15 mos of life
What are total bilirubin levels in crigler-najjar type 1?
> 20 mg/dl
What are total bilirubin levels in crigler najjar type 2?
< 20 mg/dl
What is treatment for Crigler-Najjar type 1?
phototherapy
plasmapheresis
liver transplant
What is pathology of crigler-najjar syndrome type II?
associated with > 10 different mutations in gluconyl transferase
have very reduced by detectable enzyme activity
How does phenobarbital effect serum bilirubin in Gilberts vs Crigler type 1 vs Crigler type 2?
phenobarbital decreases serum bilirubin by A LOT in crigler type 2; has modest decrease in gilbert’s, and no change in crigler type 1
What are total bilirubin levels in gilberts?
< 6 [usually < 3]
What are 5 general causes of conjugated hyperbilirubinemias?
- genetic
- chronic liver disease
- intrahepatic cholestasis of pregnancy
- biliary obstruction
- drugs
What are two excretion defects of bilirubin?
- Dubin Johnson syndrome
- Rotor syndrome
What are two biliary tract diseases that can lead to conjugated hyperbilirubinemia?
- primary sclerosing cholangitis
- primary biliary cirrhosis
What is pathology of dubin johnson syndrome?
- mutation in gene encoding for MRP2 transporter of conjugated bilirubin
- leads to chronic intermittent jaundice with pigmented black bliver
What are clinical features of dubin johnson syndrome?
- asymptomatic direct jaundice in early adulthood
- hepatosplenomegaly
- black pigmented liver
What is pathology of rotor’s syndrome?
- due to unknown mutation
- have total bilirubin < 10
What is intrahepatic cholestasis of pregnancy? What lab values?
occurs in 2nd or 3rd trimester
- high ALT
- high conjugated bilirubin
- high serum bile acids
- high alk phosphatase
disappears after delivery
What are the 2 markers of hepatocyte damage?
- aspartate aminotransferase [AST]
- alanine aminotransferase [ALT]
What are the 3 markers of cholestasis?
- bilirubin
- alkaline phosphatase
- gamma glutamyl transpeptidase [GGTP]
What are the 2 markers of liver function?
- albumin
- prothrombin time [PT] / INR
What levels of ALT, AST, alk phos, GGTP, bilirubin, INR in acute hepatocellular injury?
- very high ALT
- very high AST
- normal or high alk phos, GGTP
- high bilirubin
- normal PT, albumin
What levels of ALT, AST, alk phos, GGTP, bilirubin, INR in chronic viral hepatitis?
- high ALT
- high AST
- normal or high alk phos, GGTP
- normal bilirubin, PT, albumin
What levels of ALT, AST, alk phos, GGTP, bilirubin, INR in NAFLD?
- high ALT
- high AST
- normal or high alk phos, GGTP
- normal bilirubin, PT, albumin
What levels of ALT, AST, alk phos, GGTP, bilirubin, INR in alcoholic hepatitis?
- high ALT
- higher AST
- high alk phos, GGTP
- high bilirubin
- normal PT, albumin
What levels of ALT, AST, alk phos, GGTP, bilirubin, INR in cirrhosis?
- normal or high ALT, AST, alk phos, GGTP, bilirubin
- increased prothrombin time
- decreased albumin
What levels of ALT, AST, alk phos, GGTP, bilirubin, INR in biliary obstruction / cholestasis?
- normal or high ALT, AST
- high alk phos, GGTP, bilirubin
- normal PT, albumin
