13-1: 2/9 - Bilirubin, Jaundice, Cholestasis

Front 1

What is jaundice?

Best places to detect?

Back 1

Yellowish discoloration of tissue resulting from deposition of bilirubin

Most apparents in sclera and underneath tongue

Front 2

RBC destroyed-->unconjugated bilirubin released from heme degradation-->liver (to make unconj'd bilirubin water soluble)-->bile duct-->intestine-->colonic bacteria metabolize-->excreted

Back 2

...

Front 3

What are the major sources of bilirubin?

Back 3

Senescent RBCs (70%)

Prematurely destroyed RBCs (20%)

Turnover of hemoproteins (myoglobin, cytochromes)--10%

Front 4

How is unconjugated bilirubin formed? Describe each step.

Where does this take place?

Back 4

During RBC breakdown, heme is catabolized to unconjugated bilirubin:

Heme-->Biliverdin (via Heme oxygenase) + CO
Biliverdin-->Bilirubin (via biliverdin reductase)--AKA unconj'd bilirubin

This occurs in liver, spleen.

Front 5

Describe the steps by which unconjugated bilirubin becomes conjugated.

Include transport of molecules, enzymes, receptors.

Back 5

Unconj'd bound to albumin-->liver-->UCB taken up by hepatocytes via OATP2 (albumin dissociates)-->UCB bound by ligandin (GST) to prevent efflux into liver sinusoids

Unconj'd Bilirubin-->bilirubin via UGT

Front 6

Why must bilirubin be conjugated?

Back 6

Unconj'd bilirubin isn't soluble.

Conjugated bilirubin is water soluble and facilitates rapid excretion into bile.

Front 7

Why are neonates often born with jaundice?

Back 7

Low physiologic activity of UDP (UDP-Glucuronosyl Transferase--GST) enzyme at birth (low levels of conjugation).

Inc'd intestinal reabsorption due to lack of gut flora to degrade bilirubin

Front 8

What becomes of conjugated bilirubin?

Begin in hepatocyte. Describe all steps.

Back 8

Enters bile canaliculus via MRP2
Drained into duodenum
Hydrolyzed by colonic bacteria to UROBILOGEN; excreted in feces

10-20% re-enters portal system and reexcreted by liver.
Small fraction filters across renal glomerulus and excreted in urine.

Front 9

Conjugated bilirubin AKA

Back 9

Direct bilirubin

Front 10

Conjugated vs Unconjugated Bilirubin:
Which is present in higher serum levels?

Back 10

Indirect bilirubin (unconjugated)

Front 11

Why is unconjugated bilirubin in urine always an abnormal finding?

Back 11

Unconj'd bilirubin always bound to albumin; shouldn't have a protein slipping through glomerulus!

Front 12

Causes of hyperbilirubinemia.

Back 12

Overproduction of bilirubin (hemolysis)

Impaired uptake, conjugation, excretion of bilirubin

Regurgitation of bilirubin from damaged hepatocytes/bile ducts

Front 13

Causes of indirect hyperbilirubinemia.

Back 13

Hemolytic disorder

Gilbert's Syndrome
Cringler-Najjar Syndrome

Rifampin
Probenacid

Front 14

Causes of direct hyperbilirubinemia.

Back 14

Dubin-Johnson Syndrome
Rotor's Syndrome

Front 15

What would cause an increased production of bilirubin?

Back 15

Hemolysis
Ineffective erytrhopoiesis
Hematoma

Front 16

Effect of hemolysis on bilirubin.

When does hemolysis occur?

Back 16

Modest increase in production of UNCONJUGATED bilirubin (<5 mg/dl)

Spherocytosis, G6PD deficiency, autoimune disorders

Front 17

Effect of ineffective erythropoiesis.

When does ineffective erythropoiesis occur?

Back 17

Increased production of UNCONJUGATED bilirubin.

Causes:
Fe deficiency
B12 deficiency
Folate deficiency
Pb poisoning

Front 18

Laboratory evidence of hemolysis.

Back 18

Schistocytes
Elevated retic count
Dec'd haptoglobin

Front 19

What drugs reduce hepatic clearance of bilirubin?

How?

Back 19

Rifampin, probenacid compete with bilirubin binding ligand (Ligandin--AKA GST) needed to prevent efflux of unconj'd bilirubin back into circuln.

Front 20

This syndrome exhibits no UGT activity.

What is plasma bilirubin like?

Back 20

Crigler-Najjar Type I Syndrome; plasma INDIRECT bilirubin 20-50!

Front 21

This syndrome exhibits markedly reduced UGT activity.

What is plasma bilirubin like?

Back 21

Crigler-Najjar Type II Syndrome

Plasma indirect bilirubin 6-25

Front 22

This syndrome exhibits decreased UGT activity.

What is plasma bilirubin like?

Back 22

Gilbert's Syndrome

Bilirubin <3-6

Front 23

These syndromes result in direct hyperbilirubinemia.

Back 23

Dubin-Johnson Syndrome
Rotor's Syndrome

These are both uncommon and benign.

Front 24

These syndromes interfere with UGT activity.

Back 24

Crigler-Najjar I, II
Gilbert's

Note: This results in indirect hyperbilirubinemia

Front 25

These syndromes interfere with MRP2 activity.

Back 25

Dubin-Johnson
Rotor

Note: This results in direct hyperbilirubinemia

(MRP2 = transport prot for conj'd bilirubin to bile canaliculus)

Front 26

Absolute height of ALT elevation does not ________.

Back 26

Height of ALT does NOT correlate with severity of clinical outcomes!

Front 27

Causes of elevated ALP.

Back 27

Bile duct obstruction
Intrahepatic cholestasis

Front 28

Causes of elevated ALT/AST.

Back 28

Viral hepatitis

Tylenol (predictable, dose-dependent)
EtOH
Isoniazid (unpredictable dose-independent)
Autoimmune hepatitis

Front 29

What is Budd-Chiari syndrome?

Back 29

Thrombosis of hepatic veins causing extreme blood retention in liver. Causes elevated AST/ALT.

Front 30

What is cholestasis?
Effects?

Back 30

Interruption of bile formation
Hepatic retention of products normally secreted into bile (bile salts)

Presentation:
Jaundice
hypercholesterolemia
If progressive, fibrosis, cirrhosis, liver failure

Front 31

Extrahepatic vs Intrehepatic Cholestasis:
Causes

Back 31

Extrahepatic: biliary obstruction--cholangiocarcinoma, panc ca, ampullary ca
choledocholithiasis (obstruction of CBD)
Primary sclerosing cholangitis
AIDS cholangiopathy
Chronic pancreatitis

Intrahepatic: transport protein defect;
Will not exhibit signs of obstruction;
Drug toxicity***--Abx
Nonhepatobiliary sepsis
TPN

ALP: >3x
ALT/AST: <5x

Front 32

PFIC1 vs PFIC2 vs PFIC3:
Gene defects
Effect
Symptoms

Back 32

PFIC1: FIC1 (defective phospholipid, bile salt transport)

PFIC2: BSEP (bile salt export pump)

PFIC3: MDR3 (phospholipid export)

All result in intrahepatic cholestasis

All exhibit PRURITIS, inc'd serum bile acid

Front 33

Bland cholestasis:
Presentation
Lab Values
Drug Causes

Back 33

Severe pruritis
Minimal rise in ALT

Causes; E2, anabolic steroids, tamoxifen

Front 34

Cholestasis with hepatitis:
Presentation
Lab Values
Drug Causes

Back 34

Abdominal pain
Jaundice
Pruritis

ALT>2-5x

Causes: Chlorpromazine, erytrhomycin, amox-clavulanate, NSAIDs

Front 35

Complications of retention of bile within liver.

Back 35

Pruritis
Bile acids destroy membranes, promote apoptosis, fibrosis
Lipid retention results in xanthoma, neuropathy

Front 36

Complicaitons of retention of less bile in bowel (due to retention in liver).

Back 36

Steatorrhea, weight loss
Low Vit A/D/E/K (night blindness, osteomalacia, neuropathy, easy bruising--respectively)

Front 37

Pruritis:
Treatment

Back 37

Cholestyramine--resin that sequesters bile acids; results in bad tase, bloating, constipation

Liver transplantation in severe intractable pruritis

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