黄疸-北京协和医学院八年制及研究生教学课件

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.
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
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
~5%
Hepatocellular bilirubin transport
Hepatocyte


(ligandin)
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.
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).
Reticuloendothelial system
Heme Biliverdin
Globin
Heme oxygenase Biliverdin reductase
Unconjugated Bilirubin, UCB Unconjugated Bilirubin
Plasma
Transportation Conjugation
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,
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
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.
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
CB Hntra-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
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
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
tightly bound to ALB
Hemoproteins: Cytochromes Myoglobins
Liver
Uptake Intracellular binding Conjugation Excretion
UCB bound to GSTs
UGT
Conjugated Bilirubin canaliculi, bile ducts
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
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.
2% bilirubin product
UBG
produced
Stool Bacterial 80% excreted Glucuas Urobilinogen, Urobilin/stercobilin ronidase
Small intestine Colon
Unconjugated bilirubin Conjugated bilirubin Urobilin,stercobilin
Jaundice
Yuan-Fang Chen
A Brief Review of Bilirubin Physiology
• Production, transportation, conjugation • Roles of liver in bilirubin metabolism • Enterohepatic circulation of bilirubin