Bilirubin, Jaundice and Gallstones

Question 1

Describe bilirubin transport and liver absorption

Answer 1

Insoluble unconjugated bilirubn is transported in blood by binding to albumin.

At hepatocyte membrane, albumin separates allowing bilirubin absorption

Question 2

Describe process of bilirubin conjugation

Answer 2

Bilirubin is transported by ligandin in cytosol and is conjugated with glucorinade by UDP glucuronosyltransferase in ER

Question 3

Describe process of bilirubin secretion

Answer 3

Secreted mostly as diglucuronide (conjugated) into canaliculus against concentration gradient

Question 4

Bile formation process: what are the transporters for movement into canaliculi

Answer 4

MDR3 for phospholipids
MRP2 for glucuronides (bilirubin)
SPGP for bile salts

On basolateral membrane: ion exchangers and bile salt channels

Question 5

What are major components of bile?

Answer 5

Bile salts=66%
Phospholipids=22%
Protein=5%
Bilirubin= only 1%

Question 6

Conjugation produces what change in bilirubin?

Answer 6

Glucuronidation makes molecule more water soluble

Question 7

What is toxic effect of unconjugated bilirubin? How is this prevented?

Answer 7

Unconjugated bilirubin is a neurotoxic lipid

Protective mechanisms: Albumin binding, blood-brain barrier, conjugation, excretion in bile

Question 8

What is delta bilirubin

Answer 8

Conjugated bilirubin that is covalently bonded to albumin

It is only found in patients with protracted presence of conjugated bilirubin and its size prevents passage into urine

Question 9

What is effect of bacteria on bilirubin?

Answer 9

Bacteria convert bilirubin to colorless water soluble urobilinogen– some is absorbed and some reaches urine via serum

Bacteria act on urobilinogent o produce payrolls which are excreted

Question 10

What is the difference between indirect and direct jaundice?

Answer 10

Indirect: unconjugated hyperbilirubinemia– hydrogen bonding to albumin prevents passage into urine

Direct: mixture of conjugated/unconjugated bilirubin in serum– conjugated can pass into urine, may see delta bilirubin

Question 11

Describe difference in urine in unconjugtaed vs. conjugated jaundice

Answer 11

Unconjugated: yellow urine (negative on urine dipstick)
Conjugated: dark red urine (positive on dipstick)

Question 12

Main etiologies of unconjugated hyperbilirubinemia: (3)

Answer 12

Overproduction of bilirubin: hemolysis, extravasation into tissue, ineffective erythropoiesis
Reduced uptake of BR by liver: altered circulation or drug-induced
Defects of BR conjugation: inherited or acquired (drugs, hep, hyperthyroidism), newborns

Question 13

What is cause of jaundice in the newborn and how is it treated?

Answer 13

Jaundice in newborn is result of immature transport and conjugation of bilirubin as well as hemolysis

Treat with phototherapy (breaks hydrogen bonds allowing excretion) to prevent CNS injury

Question 14

What is Gilbert’s Syndrome?

Answer 14

A benign autosomal recessive defect in promoter gene for glucuronosyltransferase leading to elevated unconjugated bilirubin

Question 15

What is effect of fasting in Gilbert’s syndrome?

Answer 15

Exaggerated increase in unconjugated bilirubin that may cause jaundice

Question 16

How is Gilert’s Syndrome diagnosed

Answer 16

Exclusion: unconjugated bilirubinemia with no other uses

Normal LFTs, no bilirubine in urine

Question 17

What are main causes of conjugated hyperbilirubinemia? (3)

Answer 17

Inherited secretory defect
Disease of hepatocytes: necrotizing hepatocellular, cholestatic (intrahepatic cholestasis), mixed
Biliary obstruction (extrahepatic cholestasis)

Question 18

What are Dubin-Johnson & Rotor syndromes?

Answer 18

Inherited secretory defect– normal LFTs and normal bile salt excretion

Liver in Dubin-Johnson syndrome is black because of pigment

Question 19

What is necrotizing hepatitis?

What are some observations (3)

Answer 19

Acute disease associated with high serum transaminase and decreased synthetic function

Observe low serum prothrombin not corrected by intramuscular vitamin K as well as fatigue and anorexia

Question 20

What is chronic hepatitis?

Answer 20

Scarring and destruction of liver cells due to variety of causes (viral, alf, drugs, toxins, autoimmune)
Poor synthetic function (serum prothrombin not corrected by IM VitK)

Question 21

What is the difference between intrahepatic and extra hepatic cholestasis?

Answer 21

Intrahepatic: hepatocellular disease (i.e chronic hepatitis)

Extrahepatic: biliary obstruction ( can see dilated ducts)

Question 22

What is the histological appearance of cholestasis?

Answer 22

Canalicular bile plugging with little necrosis

Looks similar for both intrahepatic and extra hepatic causes

Question 23

What are biochemical findings of cholestasis? (2)

Answer 23

Alkaline phosphatase>3x normal 
Increased GGT (more specific)

Note: can have elevated alkaline phosphates or GGT without jaundice for partial biliary obstruction or intrahepatic cholestasis

Question 24

What are major symptoms in cholestasis? (3)

Answer 24

Pruritis (itchy skin)
Malabsorption of fat/fat-soluble vitamins (ADKE)
High serum cholesterol leading to xanthelasma (deposits in tissue)

Question 25

What are causes of extra hepatic cholestasis: both benign (3) and malignant (3)

Answer 25

Benign: gallstones, strictures, pancreatitis Malignant: Pancreas, bile duct or gallbladder

Question 26

What are intrahepatic causes of cholestasis (big list)

Answer 26

Alcohol, drugs, hepA, sepsis, pregnancy, estrogens, TB, primary biliary cirrhosis, malignancies, primary sclerosing cholangitis

Question 27

What is effect of ursodeoxycholic acid in cholestasis?

Answer 27

Prolongs life in primary biliary cirrhosis | May be useful in other forms of cholestasis

Question 28

Describe maximum serum bilirubin in following conditions: | Hemolysis, Gilbert's, complete obstruction, obstruction+hemolysis, obstruction+renal failure

Answer 28

Very high in complete obstruction Even higher in obstruction with hemolysis or renal failure

Question 29

What lab signs are visible in acute obstruction? Transaminase, bilirubin and alkaline phosphatase

Answer 29

Transaminase immediately dramatically increases and declines rapidly once stone passed Bilirubin increases then falls Delayed increase and fall in alkaline phosphatase levels

Question 30

What is etiology of gallstones? What are predisposing factors? (3)

Answer 30

Gallstones may form when cholesterol or BR precipitate from bile Predisposing factors: supersaturation, stasis, nucleation factors

Question 31

What are the different types of gallstones (2)

Answer 31

Cholesterol: >50% (form in gallbladder Pigment: unconjugated bilirubin

Question 32

What is the significance of black vs. brown pigment gallstones?

Answer 32

Black=form in gallbladder | Brown: form in bile ducts

Question 33

What are risk factors for cholesterol gallstones?

Answer 33

Female, age>30, multiparity, obesity, lack of exercise Rapid weight loss Family history, Native Americans, whites, blacks Drugs: estrogens, clofibrate, somatostatin Parenteral feeding

Question 34

Cholesterol Stone Composition

Answer 34

50-90% cholesterol with small amounts of mucin, Ca and bilirubin

Question 35

What is cholesterol supersaturation? What is result of it?

Answer 35

Supersaturation: low phophoslipid+bile salts/ cholesterol Supersaturation consistent with cholesterol stones (but not pigment stones)

Question 36

What is the medical treatment for cholesterol stones/sludge

Answer 36

Ursodeoxycholic acid or chenodeoxycholic acid may be effective for cholesterol stones (but not pigment stones)

Question 37

Black gallstones: What is composition? Where do they form and what are the risk factors (3)?

Answer 37

50-80% Calcium Bilirubinate (85% radio-dense) Form only in gallbladder; risk factors include old age, hemolysis and cirrhosis

Question 38

Brown gallstones: composition, formation and risk factors (2)

Answer 38

Brown gallstones are mostly calcium bilirubinate, but also contain fatty acids, bacteria Form mainly in bile duct Risk factors: old age, post cholecystectomy

Question 39

What are complications of gallstones? (6)

Answer 39

Intermittently obstructs cystic duct==>Intermittent biliary colic (20%) Impacts in cystic duct==>acute cholecystitis (10%) Compress common bile duct==>Mirizzi syndrome (.1%) Impact in distal common bile duct==>jaundice, colic pain, cholangitis/ acute biliary pancreatitis (5%) Erode thru gallbladder into duodenum==>cholesystenteric fistula (.1%) Chronic cholelithiasis==>gallbladder carcinoma (.1%)

Question 40

Describe the pathophysiology for acute cholecystitis

Answer 40

Persistent blockage of cystic duct by gallstone leads to increase in mucosal prostaglandins, which causes inflammation Superimposed infection can develop