Bile, Cholesterol, Bilirubin, Lipoproteins Flashcards
Criggler Najjar
Type 1
Complete absence of UDP-GT gene
Buildup of unconjugated bilirubin
Causes kernicterus in newborn
Criggler Najjar
Type II
Mutation in UDP-GT; allows for some activity
Buildup of unconjugated
Benign
Gilbert Syndrome
Reduction in transcription of UDP-GT
Buildup of unconjugated bilirubin
Appears in adolescence
See mild jaundice during periods of stress
Dubin-Johnson
Mutation in MRP2 (needed to move conjugated bilirubin from hepatocyte to canalicululs)
Deposits in hepatocytes
Appears at early adulthood
Jaundice
Rotor Syndrome
Mutations in OAT1B1 and OAT1B3 (needed move bilirubin from blood to hepatocyte)
Seen after birth or childhood
Unconjugated and conjugated hyperbilirubinemia
7-alpha hydroxylase
Function and feedback
Aka CYP7a
Only found in liver
Catalyzes rate limiting step needed to convert cholesterol to bile acids
Negative feedback by accumulation of bile acids
Activated when there is an accumulation of cholesterol
Primary bile acids
Chenodeoxycholic acid and cholic acid
Purpose of bile acid conjugation
Decrease the pKa so that more are present in ionized form, making them better detergents
Use glycine or taurine to produce glycohoilc acid and taurocholic acid, BILE SALTS
Production of secondary bile acids
Where are they found?
Done in colon by bacteria, which deconjugate and dehydroxylate primary bile acids
In feces
Secretion and reabsorption of bile acids
Channels
NTCP-sinusoidal space to hepatocyte
BSEP-hepatocyte to canaliculus
ASBT-absorption in ileum
OST-ileal cell to portal circulation
Morphological features with cholestasis
- Enlargement of hepatocytes
- Dilated canalicular spaces
- Apoptosis
- Kupffer cells with bile pigments
May see bile plugs
Pharmacological intervention with bile salts
Bile acid resins/sequestrates bind to bile acids to prevent reabsorption, to reduce cholesterol levels
Forces the liver to make more bile acids, which reduces cholesterol (takes away negative feedback mechanism
Can also use soluble fibers, which may also bind to bile acids to prevent reabsorption
Extravascular Erythrocyte Destruction
90%
Macrophages from reticuloendothelial system (spleen, liver, and bone) monitor RBCs to phagocytose them before they lyse
In macrophage, globin is broken down into AA, iron is recycled, and heme is broken down
SPHEROCYTES
Intravascular hemolysis
10%
Usually due to trauma
RBCs lyse in circulation, releasing hemoglobin into plasma
SCHISTOCYTES
Haptoglobin-hemoglobin: Hemoglobin binds to HAPTOGLOBIN, which takes into the macrophage, where it is then broken down into iron, heme, and globin
Hemopexin-heme: If haptoglobin saturated, free heme binds to hemopexin on macrophages of reticuloendothelial system to be engulfed
Heme degradation to bilirubin
Where and how?
Occurs in reticuloendothelial system (macrophage)
Heme converted to biliverdin by heme oxygenase; ONLY enzyme that produces carbon monoxide (here is cytoprotective)
Biliverdin converted to bilirubin by biliverdin reductase
Bilirubin released bound to albumin
Bilirubin fate in the liver
In circulation, bilirubin bound to albumin
Bilirubin enters the liver, and is bound to GST-b to prevent it from returning to circulation (which can happen when bilirubin is in its indirect form)
UDP-GT acts on bilirubin twice to make it direct (first time is the committed step to make BMG, second time is the rate limiting step BDG)
Direct bilirubin is excreted into small intestine
Acted on by bacterial enzymes to produce urobilinogen–>stercobilin (brown poop)
Some urobilinogen is reabsorbed and goes to kidney for excretion (stercobilinogen–>urobilin)
MRP2
Movement of bilirubin from hepatocyte to canaliculus for secretion
Defect causes Dubin-Johnson-buildup of direct bilirubin in hepatocytes
OAT1B1/3
Transporter of bilirubin from sinusoidal space to hepatocyte
Defect causes rotor syndrome (hyperbilirubinemia in both conjugated and unconjugated)
Hemolytic Jaundice
“Pre-hepatic”
Massive lysis of RBCs exceeds liver capacity to process bilirubin
Increase in indirect bilirubin
Urobilinogen in blood and urine also increased
Hepatocellular jaundice
Damage to liver cells causes increase in conjugated and unconjugated bilirubin
Regulation of Cholesterol Synthesis (positive, negative, short term vs. long term)
+ regulators:
Insulin dephosphorylates HMG receptor with HMGR phosphatase to activate it
-regulators:
Glucagon phosphorylates HMG receptor with AMPK to inactivate it
Long term regulation:
Decreased cholesterol causes SREPB2 (TF) to move into golgi and increase transcription of LDL receptors and HMG CoA reducatse. In presence of cholesterol, SREBP2 stays in endoplasmic reticulum
Statins
Inhibit HMG CoA reductase to reduce cholesterol synthesis
This then increases LDL removal from circulation by increases LDL receptors
Hypertriglyceridemia
Diagnostic
Causes
Clinical features
TAG over 150 due to abnormally high chylomicrons, VLDL, or both
Could be caused by lipoprotein lipase or CII deficiency
Can cause pancreatitis, eruptive cutaneous xanthomas, tuberous xanthomas, lipemia retinalis
Familial dysbetalipoproteinemia
Increased levels of IDL
(elevated VLDL:triglyceride)
Defective ApoE
Can cause xanthomas and atherosclerosis
