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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

Bilirubin formation
Chiefly 70+%

Senecent RBCs

Iron hemoglobin Globin

R C Bilirubin CBR Biliverdin MHO heme



nonhemoglobin heme Hepatic Hemoproteins nonhemoglobin hemoprotein


Premature destruction of newly formed RBCs

Transport of Bilirubin in Plasma

Albumin + UB UB ~ Albumin Complex

H affinity binding sites 2:1

L affinity binding sites

Molar Ratio

Plasma protein Albumin

Other organic anions can be replaced by PH


Hepatic Bilirubin Transport

1. Hepatic uptake of Bilirubin UCB~Albumin Complex Separated
(be) taken up Bilirubin MTA (receptor ?) Plasma membrane of the liver

2.Conjugation of Bilirubin
ligation (Y protein)
(be) bound to


(lipid soluble)

carrier protein


Conjugation (catalized by UDPGT)

3.Biliary Excretion of Bilirubin

Transfer across Microvillar membrane



(water soluble)

Bile canaliculus

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.

Entero-hepatic circulation
CB T B and I be degraded Bacterial Enzymes Urobilinogens (coloress)


feces (feceal urobilinogens)


50-200 mg/d liver re-excreted Bile excreted feces




kidneys urine urobilinogen

4 mg/d

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

Pathophysiologic classification of Jaundice

Hemolytic Jaundice

Hepatic Jaundice
Obstructive Jaundice(Cholestasis) Congenital Jaundice

Jaundice classification
predominantly unconjugated hyperbilirubinaemia predominantly conjugated hyperbilirubinaemia

Hemolytic Jaundice

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

Hemolytic Jaundice
weakness, Dark urine, anemia, Icterus, splenomegaly


UB without bilirubinuria fecal and urine urobilinogen hemolytic anemia hemoglobinuria (in acute intravascular hemolysis) Reticulocyte counts

Hemolytic Jaundice
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

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

Obstructive Jaundice
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)

Etiology of Obstructive 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

Etiology of Obstructive Jaundice

Extrahepatic-Obstructive of bile Ducts Compression obstruction from tumors Congenital choledochal cyst Extrahepatic biliary atresia Intraluminal gallstones Stenosis-postoperative or inflammary

cholestasis clinical 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

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

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

Obstructive Jaundice

urinary changes bilirubin: increased urobilinogen: reduced or absent faecal changes stercobilinogen: reduced or absent

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

Hepatic Jaundice

Impaired or absent hepatic conjugation of bilirubin

decreased GT activity (Gilberts syndrome) hereditary absence or deficiency of UDPGT (Grigler-Najjar Syndrome)
Dubin-Johnson Syndrome Rotor syndrome hepatocellular necrosis intrahepatic cholestasis
(Hepatitis, Cirrhosis, Drug-related)

Familiar or hereditary disorders

Acquired disorders

Hepatic Jaundice
weakness, loss appetite, hepatomegaly, palmar erythema, spider

Lab Findings
liver function tests are abnormal

both CB and UCB


Hepatic Jaundice
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

Hepatic Jaundice
urinary changes bilirubin: normal or increased urobilinogen: normal or reduced faecal changes stercobilinogen: normal or reduced

Jaundice diagnosis(1)
history and examination urine, stools serum biochemistry bilirubin transaminases - AST, ALT albumin alkaline phosphatase

Jaundice diagnosis(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. prehepatic, hepatic, extra-hepatic

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

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

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

increased bilirubin formation

haemolysis ineffective erythropoiesis: megaloblastic anaemia iron deficiency haemoglobinopathies

unconjugated hyperbilirubinaemia
failure of bilirubin conjugation

neonatal jaundice Crigler Najjar syndrome drug inhibition e.g. chloramphenicol extensive hepatocellular disease e.g. hepatitis, cirrhosis

Case Study1
History: 68-year-old,jaundice,stomach pain, dark urine,itching of the skin,rapid weight loss of 21lb Lab data CBC within narmal limits Total bilirubin:238mol/l GGT:300U/l ALP:360U/l AST:80u/l ALT:75u/l Urinalysis:positive bilirubin,normal urobilinogen Serum amylase:elevated

Case Study1
What is the most probable diagnosis for this patient? Which labtory tests provided the most information,and which provided the least?

Case Study2
History:38-year-old white female,jaundice,right upper quadrant abdominal pain,nausea,vomiting,itching skin.She has a history of intravenous drug use and alcohol abuse.

Case Study2
Lab data elevated total bilirubin(136 mol/l) elevated conjugated bilirubin(102mol/l) Urine:orange-brown,3+bilirubin,normal urobilinogen elevated ALP(1.5ULT),GGT(3ULT),ALT,AST(5ULT) Modest increase:Serum cholesterol and triglyceride

Case Study2
What is the probable diagnosis for this patient?Why? What other laboratory test would recommend to confirm this diagnosis? Which laboratory tests ordered provided the most information?Why?