Heme Catabolism and Bile Salts Flashcards
Jaundice caused by Extravascular hemolysis/ineffective erythropoiesis
- why is urine dark?
- increased risk for what complication?
- increased urine urobilinogen (not conjugated bilirubin)
- increased risk of pigmented bilirubin gallstones
Gilbert syndrome
- mech
- symptoms
- lab findings
- reduced UGT
- jaundice only clinically significant during stress (eg infection)
- increased UCB
Hyperbilirubinemia, conjugated
- disorders, mech
- what happens to liver grossly?
- Dublin-Johnson syndrome (MOAT defect)
(multi organic anion transporter)
- Liver turns pitch black
2. Rotor syndrome - liver does not discolor
Rotor syndrome
- mech
- symptoms
- lab findings
- unknown mech, but similary to Dublin-Johnson (MOAT transporter mutation)
- jaundice, no liver discoloration
- increased CB
Heme catabolism in hepatocyte:
- what enzyme conjugates bilirubin?
- what is the bilirubin transporter?
-UGT1
Uridine glucuronyl transferase
-MOAT
multiorganic anion transporter
Familial Hypercholesterolemia
- mech
- symptoms
- mutation in gene encoding LDL receptor (pts have difficulty increasing LDL receptor expression, so cholestyramine does not work as effectively)
- high LDL
- xanthomas, atheromas (LDL cholesterol depositions)
Familial Hypercholesterolemia
- prevalence
- genetic inheritance pattern
- Auto dom
- 1 in 500 are heterozygote, affected
- 1 in 1 million are homozygotes–have CAD at birth
Familial Hypercholesterolemia
-tx
- Use both HMG-CoA reductase (statin) and bile acid binding resin (cholestyramine)
- Cholestyramine removes bile acids through gut, which increases bile acid formation–through upregulating HMG CoA reductase (which creates cholesterol) and through increased LDL uptake through LDL receptors.
- Therefore, you also need to block HMG CoA reductase to force LDL uptake from blood.
Heme catabolism in hepatocyte:
-what keeps bilirubin from returning back into circulation after entering hepatocyte?
-Ligandins (cytosolic proteins) bind to bilirubin
Dublin-Johnson syndrome
- mech
- symptoms
- lab findings
-MOAT mutation
(multiorganic anion transporter)
- jaundice, pitch black liver
- high CB
Obstructive jaundice
-clinical findings (5)
- dark urine (high CB)
- pale stool (no bile)
- steatorrhea with malabsorption of D,E,A,K
- cholestatic pruritis (plasma bile acids deposit in skin)
- xanthomas (hypercholesterolemia)
Neonatal jaundice
- mechanism (3 factors)
- what % of newborns are clinically jaundiced during first 5 days of life?
- low UGT activity
- decreased excretory capacity of hepatocytes
- increased bilirubin production secondary to accelerated destruction of fetal erythrocytes
- 50%
Hyperbilirubinemia, unconjugated
- disorders
- mech
-Crigler-Najjar syndrome (no UGT)
Gilbert syndrome (reduced UGT)
Overview of Heme catabolism:
-steps by location (5 locations)
- Macrophage–Heme ring opening (heme -> biliverdin -> bilirubin)
- Blood (bilirubin carried by albumin from macrophage to liver)
- Liver hepatocytes (conjugation with glucronic acid, excreted to GB)
- GI tract (converted to urobilogen by deconjugation by bacteria)
GI tract: urobilogen -> stercobilin (brown feces)
urobilogen enters blood
- Kidney: Urobilogen -> Urobilin (yellow urine)
Jaundice caused by viral hepatitis:
- mechanism
- lab findings:
- CB/UCB
- urine bilirubin
- urine urobilinogen
- inflammation of hepatocytes and bile ductules
- high CB and UCB
- high urine CB (cause of dark urine)
- low or normal urine urobilinogen
Heme catabolism inside Macrophage:
intermediates and steps
Heme -> Biliverdin
(Heme oxygenase, requires NADPH)
Biliverdin -> Bilirubin
(biliverdin reductase, requires NADPH)
Why does ineffective erythropoiesis cause jaundice?
-macrophages inside bone marrow eat erythrocyte precursors, breaking Hb down
Crigler Najjar syndrome
- mech
- symptoms
- lab findings
- tx
- no UGT
- jaundice
- high UCB
- daily phototherapy throughout life
Jaundice:
-3 general categories of mechanism
- Hemolytic
- Hepatocellular
- Obstructive
Bile acids vs bile salts
-what are they and why the difference?
Bile salts are bile acids conjugated to glycine or taurine
-this lowers the pKa value of the molecules, making them more soluble in gut
Kernicterus
- what brain parts are damaged?
- symptoms
- Tx
- Basal ganglia, specifically
- athetoid (writhing) cerebral palsy, hearing loss
- phototherapy (bile can be excreted without conjugation)
Obstructive jaundice
- lab findings:
1. UCB/CB
2. urine urobilinogen
3. ALP
- high CB
- low urine urobilinogen
- high ALP
