Jaundice& BilirubinLecture 29Metabolism
JAUNDICEThe common causes of jaundice are1. Bilirubin overproduction,2.Hepatitis,3.Obstruction of the flow of bile.
Hepatic bile serves two major functions:(1)The emulsification of dietary fat in thelumen of the gut through the detergenta...
Alterations of bile formation become clinicallyevident asyellow discoloration of the skin and sclera(jaundice and icterus,...
The metabolism of bilirubin by the liver consists offour events: USCE1.uptake from the circulation;2. intracellular storag...
Bilirubin and Bile FormationBilirubin is the end product of hemedegradation.• The majority of daily production (0.2 to 0.3...
• Most of the remainder (15%) of bilirubin isderived from the• turnover of hepatic heme or hemoproteins(e.g., the P-450 cy...
• Intracellular heme oxygenase oxidizes hemeto biliverdin (step 1 ), which is immediatelyreduced to bilirubin by biliverdi...
• Bilirubin thus formed outside the liver isreleased and bound to serum albumin (step2).
• Albumin binding is necessary to transportbilirubin because bilirubin is virtuallyinsoluble in aqueous solutions at physi...
• Hepatic processing of bilirubin involvescarrier-mediateduptake at thesinusoidal membrane (step 3),
•conjugationwith one or two molecules of glucuronic acid bybilirubin uridine diphosphate (UDP)–glucuronyltransferase (UGT1...
• Most bilirubin glucuronides aredeconjugated in the gutlumen by bacterial β-glucuronidases anddegraded to colorlessurobil...
• The urobilinogens and the residue of intactpigment are largely excreted in feces.
• Approximately 20% of the urobilinogensformed are reabsorbed in the ileum andcolon, returned to the liver, and re-excrete...
• A small amount of reabsorbed urobilinogenis excreted in the urine.
Bilirubin metabolism and elimination.(1) Normal bilirubin production from heme (0.2–0.3gm/day) is derived primarily from t...
Pathophysiology of Jaundice• Both unconjugated bilirubin and conjugatedbilirubin (bilirubin glucuronides) mayaccumulate sy...
• Unconjugated bilirubin is virtuallyinsoluble in water at physiologic pH andexists in tight complexes with serum albumin....
• Normally, a very small amount ofunconjugated bilirubin is present as analbumin-free anion in plasma. This fraction ofunb...
• The unbound plasma fraction may increase insevere hemolytic disease or when protein-binding drugs displace bilirubin fro...
• In contrast, conjugated bilirubin is water-soluble, nontoxic, and only loosely bound toalbumin. Because of its solubilit...
• With prolonged conjugatedhyperbilirubinemia, a portion of circulatingpigment may become covalently bound toalbumin; this...
• Serum bilirubin levels in the normal adultvary between 0.3 and 1.2 mg/dL, and• the rate of systemic bilirubin production...
• Jaundice becomes evident when the serumbilirubin levels rise above 2.0 to 2.5 mg/dL;levels as high as 30 to 40 mg/dL can...
Jaundice occurs when the equilibrium betweenbilirubin production and clearance is disturbed byone or more of the following...
• The first three mechanisms produceunconjugated hyperbilirubinemia, and thelatter two produce predominantlyconjugated hyp...
Neonatal JaundiceBecause the hepatic machinery for conjugating andexcreting bilirubin does not fully mature untilabout 2 w...
• This may be exacerbated by breastfeeding, asa result of the presence of bilirubin-deconjugating enzymes in breast milk.N...
CholestasisCholestasis denotes a pathologic condition ofimpaired bile formation and bile flow,leading to accumulation of b...
It can be caused by extrahepatic orintrahepatic obstruction of bile channels, orby defects in hepatocyte bile secretion.
• Patients may have jaundice, pruritus, skinxanthomas (focal accumulation ofcholesterol), or symptoms related tointestinal...
• A characteristic laboratory finding is elevatedserum alkaline phosphatase and γ-glutamyltranspeptidase (GGT), enzymes pr...
HCC
L29 jaundice
L29 jaundice
L29 jaundice
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L29 jaundice

  1. 1. Jaundice& BilirubinLecture 29Metabolism
  2. 2. JAUNDICEThe common causes of jaundice are1. Bilirubin overproduction,2.Hepatitis,3.Obstruction of the flow of bile.
  3. 3. Hepatic bile serves two major functions:(1)The emulsification of dietary fat in thelumen of the gut through the detergentaction of bile salts, and(2) The elimination of bilirubin, excesscholesterol.
  4. 4. Alterations of bile formation become clinicallyevident asyellow discoloration of the skin and sclera(jaundice and icterus, respectively) due toretention of bilirubin.
  5. 5. The metabolism of bilirubin by the liver consists offour events: USCE1.uptake from the circulation;2. intracellular storage;3.conjugation with glucoronic acid;4.biliary excretion.
  6. 6. Bilirubin and Bile FormationBilirubin is the end product of hemedegradation.• The majority of daily production (0.2 to 0.3gm, 85%) is derived from breakdown ofsenescent red cells by the mononuclearphagocytic system, especially in the spleen,liver, and bone marrow.
  7. 7. • Most of the remainder (15%) of bilirubin isderived from the• turnover of hepatic heme or hemoproteins(e.g., the P-450 cytochromes) and• from premature destruction of red cellprecursors in the bone marrow
  8. 8. • Intracellular heme oxygenase oxidizes hemeto biliverdin (step 1 ), which is immediatelyreduced to bilirubin by biliverdin reductase.
  9. 9. • Bilirubin thus formed outside the liver isreleased and bound to serum albumin (step2).
  10. 10. • Albumin binding is necessary to transportbilirubin because bilirubin is virtuallyinsoluble in aqueous solutions at physiologicpH.
  11. 11. • Hepatic processing of bilirubin involvescarrier-mediateduptake at thesinusoidal membrane (step 3),
  12. 12. •conjugationwith one or two molecules of glucuronic acid bybilirubin uridine diphosphate (UDP)–glucuronyltransferase (UGT1A1, step 4) in theendoplasmic reticulum, andexcretionof the water-soluble, nontoxic bilirubin
  13. 13. • Most bilirubin glucuronides aredeconjugated in the gutlumen by bacterial β-glucuronidases anddegraded to colorlessurobilinogens (step 5).
  14. 14. • The urobilinogens and the residue of intactpigment are largely excreted in feces.
  15. 15. • Approximately 20% of the urobilinogensformed are reabsorbed in the ileum andcolon, returned to the liver, and re-excretedinto bile.
  16. 16. • A small amount of reabsorbed urobilinogenis excreted in the urine.
  17. 17. Bilirubin metabolism and elimination.(1) Normal bilirubin production from heme (0.2–0.3gm/day) is derived primarily from the breakdown ofsenescent circulating erythrocytes.(2) Extrahepatic bilirubin is bound to serum albumin anddelivered to the liver.(3) Hepatocellular uptake and(4) glucuronidation in the endoplasmic reticulumgenerate bilirubin monoglucuronides anddiglucuronides, which are water soluble and readilyexcreted into bile.(5) Gut bacteria deconjugate the bilirubin and degradeit to colorless urobilinogens. The urobilinogens andthe residue of intact pigments are excreted in thefeces, with some reabsorption and excretion intourine.
  18. 18. Pathophysiology of Jaundice• Both unconjugated bilirubin and conjugatedbilirubin (bilirubin glucuronides) mayaccumulate systemically. There are twoimportant pathophysiologic differencesbetween the two forms of bilirubin.
  19. 19. • Unconjugated bilirubin is virtuallyinsoluble in water at physiologic pH andexists in tight complexes with serum albumin.This form cannot be excreted in the urineeven when blood levels are high.
  20. 20. • Normally, a very small amount ofunconjugated bilirubin is present as analbumin-free anion in plasma. This fraction ofunbound bilirubin may diffuse into tissues,particularly the brain in infants, and producetoxic injury.
  21. 21. • The unbound plasma fraction may increase insevere hemolytic disease or when protein-binding drugs displace bilirubin fromalbumin. Hence, hemolytic disease of thenewborn (erythroblastosis fetalis) may leadto accumulation of unconjugated bilirubin inthe brain, which can cause severe neurologicdamage, referred to as kernicterus.
  22. 22. • In contrast, conjugated bilirubin is water-soluble, nontoxic, and only loosely bound toalbumin. Because of its solubility and weakassociation with albumin, excess conjugatedbilirubin in plasma can be excreted in urine.
  23. 23. • With prolonged conjugatedhyperbilirubinemia, a portion of circulatingpigment may become covalently bound toalbumin; this is termed the bilirubin deltafraction.
  24. 24. • Serum bilirubin levels in the normal adultvary between 0.3 and 1.2 mg/dL, and• the rate of systemic bilirubin production isequal to the rates of hepatic uptake,conjugation, and biliary excretion.
  25. 25. • Jaundice becomes evident when the serumbilirubin levels rise above 2.0 to 2.5 mg/dL;levels as high as 30 to 40 mg/dL can occurwith severe disease.
  26. 26. Jaundice occurs when the equilibrium betweenbilirubin production and clearance is disturbed byone or more of the following mechanisms :(1) excessive extrahepatic production of bilirubin;(2) reduced hepatocyte uptake;(3) impaired conjugation;(4) decreased hepatocellular excretion; and(5) impaired bile flow.
  27. 27. • The first three mechanisms produceunconjugated hyperbilirubinemia, and thelatter two produce predominantlyconjugated hyperbilirubinemia.
  28. 28. Neonatal JaundiceBecause the hepatic machinery for conjugating andexcreting bilirubin does not fully mature untilabout 2 weeks of age, almost every newborndevelops transient and mild unconjugatedhyperbilirubinemia, termed neonatal jaundice orphysiologic jaundice of the newborn.
  29. 29. • This may be exacerbated by breastfeeding, asa result of the presence of bilirubin-deconjugating enzymes in breast milk.Nevertheless, sustained jaundice in thenewborn is abnormal.
  30. 30. CholestasisCholestasis denotes a pathologic condition ofimpaired bile formation and bile flow,leading to accumulation of bile pigment inthe hepatic parenchyma.
  31. 31. It can be caused by extrahepatic orintrahepatic obstruction of bile channels, orby defects in hepatocyte bile secretion.
  32. 32. • Patients may have jaundice, pruritus, skinxanthomas (focal accumulation ofcholesterol), or symptoms related tointestinal malabsorption, includingnutritional deficiencies of the fat-solublevitamins A, D, or K.
  33. 33. • A characteristic laboratory finding is elevatedserum alkaline phosphatase and γ-glutamyltranspeptidase (GGT), enzymes present onthe apical membranes of hepatocytes andbile duct epithelial cells.
  34. 34. HCC

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