黄疸-北京协和医学院八年制及研究生教学课件

A Brief Review of Bilirubin Pathophysiology
• Definition of jaundice • UCB versus CB • Clinical classification of hyperbilirubinemia Predominant hyper-UCB Predominant hyper-CB • Implications of urinary bilirubins • Consequences of sustained hyperbilirubin
Definition of Jaundice
• Jaundice, or icterus, is the yellowish pigmentation of tissues (skin, sclera, mucosa, and body fluid) due to hyperbilirubinemia. • Jaundice hyperbilirubinemia. It becomes clinically evident only when serum bilirubin is 50 mol/L( 3mg/dl). If serum bilirubin is elevated yet still < 50 mol/L, jaundice is subclinical and not visible.
Reticuloendothelial system
Heme Biliverdin
Globin
Heme oxygenase Biliverdin reductase
Unconjugated Bilirubin, UCB Unconjugated Bilirubin
Plasma
Transportation Conjugation
Enterohepatic Circulation of Bilirubin
UCB
Systemic circulation
sinusoid
10% UBG
Liver
Portal vein
UBG 90%
CB Bile Duct CB
Kidney
20% UBG
Reabsorbed
CB
Urine Urine Urobilinogen
Predominant UCB Hyperbilirubinemia
• Overproduction of UCB
Hemolysis: Inherited: spherocytosis, sickel cell anemia, G-6-P or PK deficiency Acquired: immune hemolysis, PNH, pulmonary infarction, microangiopathic hemolytic anemia, hematoma. Ineffective erythropoiesis: Vit B12, folate, or iron deficiency Thalassemia
Predominant CB Hyperbilirubinemia
• Intra-hepatic cholestasis: Defects in hepatic excretory function:
Cholestatic hepatitis: viral, alcoholic, autoimmune hepatitis Drug-induced cholestasis: androgens, estrogens, cyclosporins, thiouracils, phenothiaines, captopril, chlorpromazine, erythromycin Sepsis induced by Gram-negative bacteria Cholestasis in pregnancy Inherited disease: Dubin-Johnson syndrome Rotor syndrome,
Jaundice
Yuan-Fang Chen
A Brief Review of Bilirubin Physiology
• Production, transportation, conjugation • Roles of liver in bilirubin metabolism • Enterohepatic circulation of bilirubin
CB Hyperbilirubinemia(cnt’d)
• Extrahepatic biliary obstruction: Malignant: Pancreatic/Ampullary carcinoma Carcinoma of CBD or gallbladder Extramural bile duct compression due to malignant lesions Benign: Gallstones Bile duct compression: chronic pancreatitis Bile duct stricture post-operative, PSC AIDS cholangiopathy
UCB Hyperbilirubinemia(cnt’d)
• Decreased hepatic uptake
Acquired: drugs (novobiocin), post-hepatitis hyperbilirubinemia Inherited: Gilbert, Crigler-Najjar, Rotor syndromes Physiological: neonatal jaundice, due to immature bilirubin uptake mechanism.
UCB Hyperbilirubinemia(cnt’d)
• Decreased conjugation:
Neonatal jaundice: Immature development of UGT1A1. Inherited diseases: Crigler-Najjar syndrome type I & II, Gilbert syndrome, due to abnormal UGT genes. Drug-induced: chloramphenicol, gentamycin, novobiocin, pregnanediol, etc. Post-hepatitis hyperbilirubinemia: a mild to modest reduction of bilirubin-conjugation capacity may be observed.
2% bilirubin product
UBG
produced
Stool Bacterial 80% excreted Glucuas Urobilinogen, Urobilin/stercobilin ronidase
Small intestine Colon
Unconjugated bilirubin Conjugated bilirubin Urobilin,stercobilin
Roles of the Liver in Bilirubin Metabolism
Uptake of UCB (unconjugated bilirubin). Intracellular binding of UCB to GSTs (ligandins) to form UCB:GST Conjugation of UCB with glucuronides via UGT1A1 to form BMG and BDG (CB). Active excretion (ATP-dependent) of CB into canaliculi and then ductules and bile ducts.
UCB
tightly bound to ALB
Hemoproteins: Cytochromes Myoglobins
Liver
Uptake Intracellular binding Conjugation Excretion
UCB bound to GSTs
UGT
Conjugated Bilirubin canaliculi, bile ducts
Clinical Classification of Hyperbilirubinemia
Predominantly UCB Hyperbilirubinemia Overproduction Decreased uptake Decreased conjugation Predominantly CB Hyperbilirubinemia Hepatic cellular disease or damage Cholestasis: Intrahepatic cholestasis Extrahepatic cholestasis
~5%
Hepatocellular bilirubin transport
Hepatocyte


(ligwenku.baidu.comndin)
Canaliculus
ALB: albumin, UCB: unconjugated bilirubin, BT: bilirubin transporter, GST: glutathione-S-transferase (ligandin), UGT1A1: uridine diphosphate glucuronyltransferase A1, BMG &BDG: bilirubin mono- & diglucuronide, MRP2: Multidrug resistance-associated protein 2.
Bilirubin Metabolism
Bilirubin: 4mg/kg/d
(250~300mg)
Spleen
Bone Marrow
Senescent Red Cells Ineffective Erythropoiesis 80% 15% Hemoglobin
Production
Breaking-down of RBC HGB degradation Transfoamation of Heme to UCB
UCB versus CB: Clinical Relevance
• Unconjugated bilirubin (UCB): Apolar and insoluble in water. Lipid-soluble, readily traversing the bloodbrain-barrier or placenta. Not excreted in bile or urine. Reversibly bound to serum ALB. • Conjugated bilirubin (CB): Polar, water-soluble and lipid-insoluble. Readily excreted in aqueous bile and urine. Does not traverse BBB or placenta. Also bound to serum ALB, T1/2 of CB is much longer (12-14 days vs 4 hrs for UCB).
CB Hyperbilirubinemia(cnt’d)
(Intra-hepatic cholestasis, cnt’d) Immune: Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), other autoimmune cholangiopathy Graft-versus-host disease Congestive heart failure, Budd-Chiari syndrome Environmental: chemical toxins, wild mushrooms