Bilirubin, Jaundice and Gallstones Flashcards
Describe bilirubin transport and liver absorption
Insoluble unconjugated bilirubn is transported in blood by binding to albumin.
At hepatocyte membrane, albumin separates allowing bilirubin absorption
Describe process of bilirubin conjugation
Bilirubin is transported by ligandin in cytosol and is conjugated with glucorinade by UDP glucuronosyltransferase in ER
Describe process of bilirubin secretion
Secreted mostly as diglucuronide (conjugated) into canaliculus against concentration gradient
Bile formation process: what are the transporters for movement into canaliculi
MDR3 for phospholipids
MRP2 for glucuronides (bilirubin)
SPGP for bile salts
On basolateral membrane: ion exchangers and bile salt channels
What are major components of bile?
Bile salts=66%
Phospholipids=22%
Protein=5%
Bilirubin= only 1%
Conjugation produces what change in bilirubin?
Glucuronidation makes molecule more water soluble
What is toxic effect of unconjugated bilirubin? How is this prevented?
Unconjugated bilirubin is a neurotoxic lipid
Protective mechanisms: Albumin binding, blood-brain barrier, conjugation, excretion in bile
What is delta bilirubin
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
What is effect of bacteria on bilirubin?
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
What is the difference between indirect and direct jaundice?
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
Describe difference in urine in unconjugtaed vs. conjugated jaundice
Unconjugated: yellow urine (negative on urine dipstick)
Conjugated: dark red urine (positive on dipstick)
Main etiologies of unconjugated hyperbilirubinemia: (3)
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
What is cause of jaundice in the newborn and how is it treated?
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
What is Gilbert’s Syndrome?
A benign autosomal recessive defect in promoter gene for glucuronosyltransferase leading to elevated unconjugated bilirubin
What is effect of fasting in Gilbert’s syndrome?
Exaggerated increase in unconjugated bilirubin that may cause jaundice
How is Gilert’s Syndrome diagnosed
Exclusion: unconjugated bilirubinemia with no other uses
Normal LFTs, no bilirubine in urine
What are main causes of conjugated hyperbilirubinemia? (3)
Inherited secretory defect Disease of hepatocytes: necrotizing hepatocellular, cholestatic (intrahepatic cholestasis), mixed Biliary obstruction (extrahepatic cholestasis)
What are Dubin-Johnson & Rotor syndromes?
Inherited secretory defect– normal LFTs and normal bile salt excretion
Liver in Dubin-Johnson syndrome is black because of pigment
What is necrotizing hepatitis?
What are some observations (3)
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
What is chronic hepatitis?
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)
What is the difference between intrahepatic and extra hepatic cholestasis?
Intrahepatic: hepatocellular disease (i.e chronic hepatitis)
Extrahepatic: biliary obstruction ( can see dilated ducts)
What is the histological appearance of cholestasis?
Canalicular bile plugging with little necrosis
Looks similar for both intrahepatic and extra hepatic causes
What are biochemical findings of cholestasis? (2)
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
What are major symptoms in cholestasis? (3)
Pruritis (itchy skin)
Malabsorption of fat/fat-soluble vitamins (ADKE)
High serum cholesterol leading to xanthelasma (deposits in tissue)
What are causes of extra hepatic cholestasis: both benign (3) and malignant (3)
Benign: gallstones, strictures, pancreatitis
Malignant: Pancreas, bile duct or gallbladder
What are intrahepatic causes of cholestasis (big list)
Alcohol, drugs, hepA, sepsis, pregnancy, estrogens, TB, primary biliary cirrhosis, malignancies, primary sclerosing cholangitis
What is effect of ursodeoxycholic acid in cholestasis?
Prolongs life in primary biliary cirrhosis
May be useful in other forms of cholestasis
Describe maximum serum bilirubin in following conditions:
Hemolysis, Gilbert’s, complete obstruction, obstruction+hemolysis, obstruction+renal failure
Very high in complete obstruction
Even higher in obstruction with hemolysis or renal failure
What lab signs are visible in acute obstruction? Transaminase, bilirubin and alkaline phosphatase
Transaminase immediately dramatically increases and declines rapidly once stone passed
Bilirubin increases then falls
Delayed increase and fall in alkaline phosphatase levels
What is etiology of gallstones?
What are predisposing factors? (3)
Gallstones may form when cholesterol or BR precipitate from bile
Predisposing factors: supersaturation, stasis, nucleation factors
What are the different types of gallstones (2)
Cholesterol: >50% (form in gallbladder
Pigment: unconjugated bilirubin
What is the significance of black vs. brown pigment gallstones?
Black=form in gallbladder
Brown: form in bile ducts
What are risk factors for cholesterol gallstones?
Female, age>30, multiparity, obesity, lack of exercise
Rapid weight loss
Family history, Native Americans, whites, blacks
Drugs: estrogens, clofibrate, somatostatin
Parenteral feeding
Cholesterol Stone Composition
50-90% cholesterol with small amounts of mucin, Ca and bilirubin
What is cholesterol supersaturation? What is result of it?
Supersaturation: low phophoslipid+bile salts/ cholesterol
Supersaturation consistent with cholesterol stones (but not pigment stones)
What is the medical treatment for cholesterol stones/sludge
Ursodeoxycholic acid or chenodeoxycholic acid may be effective for cholesterol stones (but not pigment stones)
Black gallstones: What is composition? Where do they form and what are the risk factors (3)?
50-80% Calcium Bilirubinate (85% radio-dense)
Form only in gallbladder; risk factors include old age, hemolysis and cirrhosis
Brown gallstones: composition, formation and risk factors (2)
Brown gallstones are mostly calcium bilirubinate, but also contain fatty acids, bacteria
Form mainly in bile duct
Risk factors: old age, post cholecystectomy
What are complications of gallstones? (6)
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%)
Describe the pathophysiology for acute cholecystitis
Persistent blockage of cystic duct by gallstone leads to increase in mucosal prostaglandins, which causes inflammation
Superimposed infection can develop
