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Causes Of Jaundice

Bile Formation
Unconjugated →  bound to albumin →  never excreted in urine
Conjugated →  soluble →  urine (bilirubinuria)
  1. Prolonged hyperbilirubinemia:
    1. Production of circulating bilirubin becomes covalently bound to albumin
    2. Bilirubin - brilliant yellow       
    3. Cholestasis- ↑ bilirubin, bile salt and cholesterol       

A. Predominantly Unconjugated Hyperbilirubinemia

1. Excess production of bilirubin Q

  1. Hemolytic anemias
  2. Resorption of blood from internal hemorrhage (e.g, alimentary tract bleeding, hematomas)
  3. Ineffective erythropoiesis syndromes (e.g., pernicious anemia, thalassemia) 

2. Reduced hepatic uptake Q           

  1. Drug interference with membrane carrier systems
  2. Some cases of Gilbert syndrome

3. Impaired bilirubin conjugation Q

  1. Physiologic jaundice of the newborn (decreased UGT1A1 activity decreased excretion)
  2. Breast milk jaundice (β-glucuronidase in milk)  
  3. Genetic deficiency of UGT1A1 activity (Crigler Najjar syndrome types I and II)
  4. Gilbert syndrome (mixed etiologies)
  5. Diffuse hepatocellular disease (e.g. viral or drug-induced hepatitis, cirrhosis)

4. Predominantly conjugated Hyperbilirubinemia Q       

  1. Deficiency of canalicular membrane transporters (Dubin-Johnson syndrome, Rotor syndrome)
  2. Impaired bile flow

5. Neonatal Jaundice Q (physiological jaundice of newborn)

  1. Transient
  2. Conjugating / excretory mechanism matures at 2 wks of age
  3. Breast milk contains 13 glucuronidase, which de conjugates bilirubin in intestine

B. Hereditary hyperbilirubinemia

Unconjugated Hyperbilirubinemia

1. Crigler Najjar syndrome Type IQ

  1. AR
  2. Absent UGTIA1 activity
  3. Fatal (within 18 months of birth)
  4. (N) Liver morphologically      

2. Crigler Najjar syndrome Type IIQ

  1. AD
  2. UGT AI-less severe, non fatal activity ( signal activity)
  3. Liver (N) Q

3. Gilbert's syndrome? ADQ

  1. Benign: mild fluctuating hyper bilirubinemia
  2. UGTA1 activity (to 30% of (n))
  3. Liver - (n) - typically detected in adolescent / adult life in association with stress, strenuous exercise
  4. 6% of population
Conjugated Hyper Bilirubinemia
  1. Dubin Johnson syndromeQ
    Impaired excretion of bilirubin glucuronides (canalicular membrane carrier protein MRP2 absent)
    1. Liver: Darkly pigmented (coarse pigmented granules within cytoplasm of hepatocytes)
    2. Electron microscopy: ? Epinephrine metabolite within lysosomes
    3. Asymptomatic / chronic & recurrent jaundice
    4. AR
  2. Rotor syndrome Q
    1. AR             
    2. Multiple defects in hepatic uptake and excretion of bilirubin
    3. Liver (N)               
    4. Jaundice, Asymptomatic
  3. Cholestasis:
    causes ­-
    1. Hepatocellular dysfunction         
    2. Intrahepatic biliary obstruction
    3. Extrahepatic biliary obstruction
      (Pruritus, Skin xanthomas. ↑ S alkaline phosphates ↑Gamma-glutamyl transpeptidase ,
      ↓bile flow => malabsorption Q
  4. Familial intrahepatic cholestasis
    2 groups of disorders
Group I - Disorders with ↓GGTQ
  1. ↓Bile salts and bile acids, ↓cholesterol and ,↓ phosphatidylcholine secretion 'in bile
  2. ↑S. bile acids pruritis
    ↑S. Cholesterol
    ↓Gamma- glutamyl transpeptidase (GGT)
  1. Benign recurrent intrahepatic cholestasis Q
    1. Intermittent attacks of cholestasis over life
    2. No progression to chronic liver disease
  2. Progressive familial intra hepatic cholestasis 1
    1. Cholestasis in infancy
    2. Liver failure by adult hood
    3. Also known as Byler syndrome (family members affected) or Byler disease (unrelated individuals)
    4. Mutation in ATP8 B1 gene on chromosome 18q21 encodes canalicular P-type ATPase
  3. Progressive familial intra hepatic cholestasis 2 (PFIC-2) Q
    1. Cirrhosis by 1st decade of life
    2. Mutation in canalicular bile salt export pump (BSEP) encoded by ABCB11 gene on chromosome 2 q24,
Group II -   GGT levels Q
  1. Progressive familial intrahepatic cholestasis 3 (PFIC-3)
  2. Mutation in ABC B4 gene on chromosome 7q21
  3. Encodes MDR3- canalicular transport protein responsible for flipping phosphatidyl choline from internal to external leaflet of canalicular membrane
  4. No phosphatidylcholine in bile  
  1. H/P:
    1. Bile in hepatocytes, canaliculi, Kupffer cells
    2. Feathery /foamy degeneration (wispy appearance)        
    3. Parenchymal destruction => Bile lakes obstruction => Bile stasis ↑ back pressure
    4. Proliferation of duct epithelial cell =>looping and reduplication => bile lakes PT fibrosis => Biliary Cirrhosis
(Bile stained cirrhotic liver)
Extrahepatic cholestasis curable by surgery, intrahepatic cholestasis requires liver transplant

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