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Jaundice

Jaundice. Definition Accumulation of yellow pigment in the skin and other tissues (Bilirubin). Bilirubin Metabolism Bilirubin formation Transport of bilirubin in plasma Hepatic bilirubin transport Hepatic uptake Conjugation Biliary excretion Enterohepatic circulation. Iron hemoglobin

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Jaundice

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  1. Jaundice Definition Accumulation of yellow pigment in the skin and other tissues (Bilirubin)

  2. Bilirubin Metabolism • Bilirubin formation • Transport of bilirubin in plasma • Hepatic bilirubin transport • Hepatic uptake • Conjugation • Biliary excretion • Enterohepatic circulation

  3. Iron hemoglobin Globin RBCs Senecent RBCs Chiefly 70+% R CBR C MHO Bilirubin Biliverdin heme 20% Bilirubin nonhemoglobin heme nonhemoglobin hemoprotein Hepatic Hemoproteins 1-5% Premature destruction of newly formed RBCs Bilirubin formation 120ds

  4. Transport of Bilirubin in Plasma Albumin + UB UB ~ Albumin Complex H affinity binding sites 2:1 Bilirubin Plasma protein Albumin Molar Ratio L affinity binding sites >2:1 Bilirubin Other organic anions PH can be replaced by UB

  5. 1. Hepatic uptake of Bilirubin UCB~Albumin Complex Separated Bilirubin (be) taken up MTA (receptor ?) Plasma membrane of the liver 2.Conjugation of Bilirubin ligation (Y protein) transfer (be) bound to carrier protein UCB ER Conjugation (catalized by UDPGT) Z protein CB CBGA Hepatic Bilirubin Transport (lipid soluble) 3.Biliary Excretion of Bilirubin (water soluble) Transfer across Microvillar membrane CB Bile canaliculus

  6. UDPGT: Uridine Diphosphate Glucuronyl Transferase • UCB: because of its tight albumin binding and lipid solubility, it is not excreted in urine. • CB: is less tightly bound to albumin and is water soluble, so it is filtered at the glomerulus and appears in the urine.

  7. re-excreted excreted liver Bile feces 90% Entero-hepatic circulation T be degraded Bacterial Enzymes CB B and I Urobilinogens (coloress) feces (feceal urobilinogens) 50-200 mg/d mostly 20% Reabsorbed plasma trace circulation kidneys 4 mg/d urine urobilinogen • The serum of normal adults contains 1 mg of bilirubin per 100 ml. • In healthy adults The direct fraction is usually <0.2 mg/100 ml The indirect fraction is usually <0.8 mg/100 ml

  8. Pathophysiologic classification of Jaundice • Hemolytic Jaundice • Hepatic Jaundice • Obstructive Jaundice(Cholestasis) • Congenital Jaundice

  9. Jaundice classification • predominantly unconjugated hyperbilirubinaemia • predominantly conjugated hyperbilirubinaemia

  10. Hemolytic Jaundice Pathogenesis Overproduction Hemolysis (intra and extra vascular) • inherited or genetic disorders • acquired immune hemolytic anemia (Autoimmune hemolytic anemia) • nonimmune hemolytic anemia (paroxysmal nocturna Hemoglobinruia) • Ineffective erythropoiesis Overproduction may overload the liver with UB

  11. Hemolytic Jaundice Symptoms weakness, Dark urine, anemia, Icterus, splenomegaly Lab • UB without bilirubinuria • fecal and urine urobilinogen • hemolytic anemia • hemoglobinuria (in acute intravascular hemolysis) • Reticulocyte counts

  12. Hemolytic Jaundice(pre-hepatic) • Serum / blood: • bilirubin (micormoles/l) 50-150; normal range 3-17 • AST I.U. < 35; normal range <35 • ALP I.U. <250; normal range <250 • gamma GT I.U. 15-40; normal range 15-40 • albumin g/l 40-50; normal range 40-50 • reticulocytes(%) 10-30; normal range <1 • prothrombin time (seconds) 13-15; normal range 13-15

  13. Hemolytic Jaundice(pre-hepatic) • urinary changes: • bilirubin: absent • urobilinogen: increased or normal • faecal changes: stercobilinogen: normal

  14. Obstructive Jaundice Pathogenesis • it is due to intra- and extra hepatic obstruction of bile ducts • intrahepatic Jaundice: Hepatitis, PBC, Drugs • Extra Hepatic Biliary Obstruction: Stones, Stricture, Inflammation, Tumors, (Ampulla of Vater)

  15. Etiology ofObstructive Jaundice Intrahepatic-Liver cell Damage/Blockage of Bile Canaliculi • Drugs or chemical toxins • Dubin-Johnson syndrome • Estrogens or Pregnancy • Hepatitis-viral,chemical • Infiltrative tumors • Intrahepatic biliary hypoplasia or atresia • Primary biliary cirrhosis

  16. Etiology ofObstructive Jaundice Extrahepatic-Obstructive of bile Ducts • Compression obstruction from tumors • Congenital choledochal cyst • Extrahepatic biliary atresia • Intraluminal gallstones • Stenosis-postoperative or inflammary

  17. cholestasisclinical features • pain, due to gallbladder disease, malignancy, or stretching of the liver capsule • fever, due to ascending cholangitis • palpable and / or tender gallbladder • enlarged liver, usually smooth

  18. General signs of cholestasis • xanthomas: palmar creases, below the breast, on the neck. They indicate raised serum cholesterol of several months. Xanthomas on the tendon sheaths are uncommonly associated with cholestasis. • xanthelasma on the eyelids • scratch marks: excoriation • finger clubbing • loose, pale, bulky, offensive stools • dark orange urine

  19. Obstructive Jaundice Lab Findings • Serum Bilirubin • Feceal urobilinogen (incomplete obstruction) • Feceal urobilinogen absence (complete obstruction) • urobilinogenuria is absent in complete obstructive jaundice • bilirubinuria  • ALP  • cholesterol 

  20. Obstructive Jaundiceextrahepatic • serum / blood • bilirubin (micromoles/l) 100-500; normal range 3-17 • AST I.U. 35-400; normal range <35 • ALP I.U. >500; normal range <250 • gamma GT I.U. 30-50; normal range 15-40 • albumin g/l 30-50; normal range 40-50 • reticulocytes(%) <1; normal range <1 • prothrombin time (secs) 15-45; normal range 13-15 • ( " + parenteral vitamin K) falls

  21. Obstructive Jaundiceextrahepatic • urinary changes • bilirubin: increased • urobilinogen: reduced or absent • faecal changes stercobilinogen: reduced or absent

  22. Hepatic Jaundice Due to a disease affective hepatic tissue either congenital or acquired diffuse hepatocellular injury

  23. Hepatic Jaundice Pathogenesis • Impaired or absent hepatic conjugation of bilirubin • decreased GT activity (Gilbert‘s syndrome) • hereditary absence or deficiency of UDPGT (Grigler-Najjar Syndrome) • Familiar or hereditary disorders • Dubin-Johnson Syndrome • Rotor syndrome • Acquired disorders • hepatocellular necrosis • intrahepatic cholestasis (Hepatitis, Cirrhosis, Drug-related)

  24. Gross specimen of cirrhosis of the liver

  25. Hepatic Jaundice Symptoms weakness, loss appetite, hepatomegaly, palmar erythema, spider Lab Findings • liver function tests are abnormal • both CB and UCB • Bilirubinuria 

  26. HepaticJaundice • serum / blood • bilirubin (micromoles/l) 50-250; normal range 3-17 • AST I.U. 300-3000; normal range <35 • ALP I.U. <250-700; normal range <250 • gamma GT I.U. 15-200; normal range 15-40 • albumin g/l 20-50; normal range 40-50 • reticulocytes(%) <1; normal range <1 • prothrombin time (secs) 15-45; normal range 13-15 • ( " + parenteral vit. K) 15-45

  27. HepaticJaundice • urinary changes • bilirubin: normal or increased • urobilinogen: normal or reduced • faecal changes stercobilinogen: normal or reduced

  28. Jaundicediagnosis(1) • history and examination • urine, stools • serum biochemistry • bilirubin • transaminases - AST, ALT • albumin • alkaline phosphatase

  29. Jaundicediagnosis(2) • haematology • haemoglobin • WCC • platelets • prothrombin time +/- parenteral vitamin K • abdominal ultrasound and chest X-ray • further investigations - determined by the basis of the jaundice, e.g. pre-hepatic, hepatic, extra-hepatic

  30. conjugated hyperbilirubinaemia the liver is able to conjugate bilirubin, but the excretion is impaired. • failure of bilirubin excretion by hepatocytes: • Dubin-Johnson syndrome • Rotor's syndrome • obstruction to biliary flow i.e. cholestasis, both intra-hepatic and extra-hepatic

  31. The proportion of conjugated bilirubin to the total raised bilirubin • 20-40% of total: more suggestive of hepatic than posthepatic jaundice • 40-60% of total: occurs in either hepatic or posthepatic causes • > 50% of total: more suggestive of posthepatic than hepatic jaundice • less than 20% :secondary to haemolysis or constitutional e.g. Gilbert's disease, Crigler-Najjar syndrome

  32. unconjugated hyperbilirubinaemia • increased bilirubin formation • failure of bilirubin uptake(Gilbert's disease) • failure of bilirubin conjugation

  33. unconjugated hyperbilirubinaemiaincreased bilirubin formation • haemolysis • ineffective erythropoiesis: • megaloblastic anaemia • iron deficiency • haemoglobinopathies

  34. unconjugated hyperbilirubinaemiafailure of bilirubin conjugation • neonatal jaundice • Crigler Najjar syndrome • drug inhibition e.g. chloramphenicol • extensive hepatocellular disease e.g. hepatitis, cirrhosis

  35. Cholestasisdiagnosis • elevated serum bilirubin - in proportion to duration of cholestasis; returns to normal once cholestasis is relieved • raised serum alkaline phosphatase - to more than 3X upper limit of normal; • LFTs - aminotransferases mildly raised; raised gamma GT • increased urinary bilirubin • urinary urinobilinogen is excreted in proportion to amount of bile reaching the duodenum i.e. absence of urinobilinogen indicates complete biliary obstruction

  36. Identification of cause • dilated ducts on ultrasound - percutaneous transhepatic cholangiograpy • undilated ducts on ultrasound - endoscopic retrograde cholangio-pancreatography • needle biopsy of the liver

  37. Hepatocellular carcinoma

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