黄疸-北京协和医学院八年制及研究生教学课件

Jaundice,Yuan-Fang Chen,A Brief Review of Bilirubin Physiology,Production, transportation, conjugationRoles of liver in bilirubin metabolismEnterohepatic circulation of bilirubin,Spleen,Bone Marrow,Senescent Red Cells80%,Ineffective Erythropoiesis15%,Hemoglobin,Heme,Globin,Reticulo-endothelialsystem,Unconjugated Bilirubin,tightly bound to ALB,Plasma,UCB bound to GSTs,Hemoproteins: CytochromesMyoglobins,Conjugated Bilirubin canaliculi, bile ducts,Liver,UGT,Bilirubin:4mg/kg/d,Conjugation Uptake Intracellular binding Conjugation Excretion,Trans- portation,Production Breaking-down of RBC HGB degradation Transfoamation of Heme to UCB,Bilirubin Metabolism,UCB,Unconjugated Bilirubin, UCB,(250300mg),5%,Biliverdin,Heme oxygenase,Biliverdin reductase,Hepatocellular bilirubin transport,ALB: albumin, UCB: unconjugated bilirubin, BT: bilirubin transporter,GST: glutathione-S-transferase (ligandin), UGT1A1: uridine diphosphateglucuronyltransferase A1, BMG &BDG: bilirubin mono- & diglucuronide, MRP2: Multidrug resistance-associated protein 2.,Hepatocyte,Canaliculus,(ligandin),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.,Kidney,Urine,Small intestine,Bile Duct,CB,Stool80% excretedas Urobilinogen,Urobilin/stercobilin,Portal vein,20% UBGReabsorbed,UrineUrobilinogen 2% bilirubin product,Unconjugated bilirubinConjugated bilirubinUrobilin,stercobilin,Colon,BacterialGlucu-ronidase,UCB,10% UBG,Liver,Systemiccirculation,UBG90%,sinusoid,CB,UBGproduced,Enterohepatic Circulation of Bilirubin,CB,A Brief Review of Bilirubin Pathophysiology,Definition of jaundiceUCB versus CB Clinical classification of hyperbilirubinemiaPredominant hyper-UCBPredominant hyper-CBImplications of urinary bilirubinsConsequences of sustained hyperbilirubin,Jaundice, or icterus, is the yellowish pigmen-tation 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.,Definition of Jaundice,UCB versus CB:Clinical Relevance,Unconjugated bilirubin (UCB): Apolar and insoluble in water. Lipid-soluble, readily traversing the blood-brain-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).,Clinical Classification of Hyperbilirubinemia,Predominantly UCB HyperbilirubinemiaOverproductionDecreased uptakeDecreased conjugationPredominantly CB HyperbilirubinemiaHepatic cellular disease or damage Cholestasis: Intrahepatic cholestasis Extrahepatic cholestasis,Predominant UCB Hyperbilirubinemia,Overproduction of UCB Hemolysis: Inherited: spherocytosis, sickel cell anemia, G-6-P or PK deficiency Acquired: immune hemolysis, PNH, pulmonary infarction, microangio- pathic hemolytic anemia, hematoma. Ineffective erythropoiesis: Vit B12, folate, or iron deficiency Thalassemia,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(cntd),Decreased conjugation: Neonatal jaundice: Immature development of UGT1A1. Inherited diseases: Crigler-Najjar syndrome type I & II, Gilbert syndrome, due to abnor- mal UGT genes. Drug-induced: chloramphenicol, gentamycin, novobiocin, pregnanediol, etc. Post-hepatitis hyperbilirubinemia: a mild to modest reduction of bilirubin-conjugation capacity may be observed.,UCB Hyperbilirubinemia(cntd),Intra-hepatic cholestasis: Defects in hepatic excretory function: Cholestatic hepatitis: viral, alcoholic, auto- immune hepatitis Drug-induced cholestasis: androgens, estro- gens, cyclosporins, thiouracils, phenothia- ines, captopril, chlorpromazine, erythromycin Sepsis induced by Gram-negative bacteria Cholestasis in pregnancy Inherited disease: Dubin-Johnson syndrome Rotor syndrome,Predominant CB Hyperbilirubinemia,(Intra-hepatic cholestasis, cntd) 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,CB Hyperbilirubinemia(cntd),Extrahepatic biliary obstruction:Malignant: Pancreatic/Ampullary carcinoma Carcinoma of CBD or gallbladder Extramural bile duct compression due to malignant lesionsBenign: Gallstones Bile duct compression: chronic pancreatitis Bile duct stricture post-operative, PSC AIDS cholangiopathy,CB Hyperbilirubinemia(cntd),Kidney,Urine,CB,Stool80% excretedas UBG, UB, SB,Portal vein,20% UBGReabsorbed,Urine UBG 2% bilirubin productOverflown CB,Unconjugated bilirubinConjugated bilirubinUrobilin,stercobilin,BacterialGlucu-ronidase,UCB,10% UBG,Liver,Systemiccirculation,UBG90%,CB overflow,UBGproduced,Urinary Excretion of Bilirubin,Small intestine,Colon,CB,Bile Duct,Implications of Urinary Bilirubins,Urine UBG (urobilinogen)PhysiologicalPathological: Overproduction of UCB or CBUrine CB (conjugated bilirunin)Always pathological, caused by: overflow or regurgitation of CB due to obstruction of intra- or extra- bile duct system,Conjugated Hyperbilirubinemia:Associated bile acid excretion Absorption of fat and fat-soluble Vit K & D coagulopathy and osteoporosisHypercholesterolemiaRenal failurePigment gallstonesUnconjugated Hyperbilirubinemia:Kernicterus in neonates Pigment gallstones,Consequences of Sustained Hyperbilirubinemia,History-takingin Jaundice,History-taking,Onset and progression: Acute or insidious onset Any prodromal symptoms: fever and flu- like symptoms, nausea and anorexia Duration of jaundice Persistent, progressive, recurring, or fluctuating,Associated Symptoms: Weight loss, anorexia, fatigue Abdominal pain, GI bleeding Fever and shaking chills Pruritus and change in stool color,History that may assess the cause of jaundice: Epidemiology: isolated, epidemic, or endemic; travel; exposure to hepatitis, parasites; blood transfusion, etc. Hx of medications, alcohol, drug abuse; exposure to chemicals Hx of gallstones, prior GI/biliary surgery Accompanying systemic diseases: liver, hematological, immunological diseases, severe systemic infection or organ failure Hereditary diseases that may lead to jaundice,PhysicalExaminationin Jaundice,Physical Examination,General condition: acutely or chronically ill? nutritional status, mental statusFeatures of Jaundice: Light, lemon-yellow: hemolytic jaundice Dark and dirty: long-standing cholestasis Bronze: hemochromatosisThe Abdomen: Hepatomagaly and/or spleenomagaly Palpable gallbladder or Murphys sign Distention and shifting dullness Abdominal mass,Look for physical signs possibly asso-ciated with jaundice-related diseases: Virchows node, periumbilical lymph node, and rectal mass in tumors Dilated veins in abdominal wall, spider angioma, palmar erythema, gynecomastia, edema in cirrhosis of liver Disorientation/confusion/coma, asterixis, ankle clonus, incoordiation in hepatic encephalopathy,Laboratory Testsin Jaundice,Initial laboratory tests for jaundice:,CBCSerum UCB and CBUrine bilirubin and urobilinogenALT/ASTALP/GGTSerum ALBProthrombin time,Five steps for clinical reasoning in jaundice:Is it predominant UCB or CB hyperbilirubin-emia? Is it isolated hyperbilirubinemia or associated with other liver function damage?If isolated and unconjugated, how to define the cause?If predominant CB hyperbilirubinemia, is it due to cholestasis or hepatocellular diseases?If it is cholestasis, is it intra- or extrahepatic?,Is it predominant UCB-HB or CB-HB? How to differentiate?,UCB-HB * CB-HB *Serum CB/TB * Bilirubin level Urine Bilirubin Urine UBG AST & ALT * UCB-HB: Predominant UCB hyperbilirubinemiaCB-HB: Predominant CB hyperbilirubinemiaTB: Total bilirubin,Is it predominant UCB-HB or CB-HB? How to differentiate?,UCB-HB * CB-HB *Serum CB/TB * 0.2Bilirubin level 5mg/dlmay be ( 0.5 ALT,AST ALP,GGT ALB N or LowNormalPT N or prolonged, Prolonged, incorrectable correctable Stool Normal color Pale lookingUrine UBG ,If it is cholestasis, is it intra- or extrahepatic? How to differentiate?,Intrahepatic ExtrahepaticSite of lesions US,CT, MRCP, ERCP ALP,GGT,If it is cholestasis, is it intra- or extrahepatic? How to differentiate?,Intrahepatic ExtrahepaticSite of Canaliculi/ductules, Extrahepatic lesions hepatocytes bile ductsUS,CT, Bile ducts normal Bile ducts dilated,MRCP, Normal obstructed by ERCP stones, tumors, stricturesALP,GGT ,Five steps for clinical reasoning in jaundice:Is it predominant UCB or CB hyperbilirubin-emia? Is it isolated hyperbilirubinemia or associated with other liver function damage?If isolated and unconjugated, how to define the cause?If predominant CB hyperbilirubinemia, is it due to cholestasis or hepatocellular diseases?If it is cholestasis, is it intra- or extrahepatic?,Simple Review Questions:Can CB appear in the normal urine?Where is urinary urobilinogen (UBG) produced?If the bile system is completely obstructed, what will happen to urinary UBG? What does it imply if urinary UBG is (+) but bilirubin is negative?,Initial lab tests: CBC, urine, ALT/AST, bilirubin, ALP, GGT, ALB, PT,Isolated UCB,History, PE,Predominant CB,Viral markers Auto-antibodies Toxicology screen,Ultrasound,Bile ductsnot dilated,Bile ducts dilated,Hemolytic testsRBC life spanAbnormal HBGsAuto-antibodiesReview drugsFamily pedigree,Liver functionimpaired,Intrahepatic cholestasisViral markersReview drugsAutoantibodiesTreat sepsis Pregnancy,Extrahepatic cholestasisCT, ERCPMRCP for: Tumors Galstones Stricture,Flow Chart,Hereditary/acquired hemolytic disordersAutoimmune diseaseDrug-inducedHereditary dusease,Liver Biopsy,LFT moderatelydamaged or N,Key Points,Definition of jaundiceReview of bilirubin metabolismCharacters of unconjugated and conjugated bilirubinsClinical classification of jaundiceCommon causes of jaundice,Key Points (cntd),Major points in history-taking and physical examination in patients with jaundice.Lab tests for differentiation of jaundice: Unconj. vs conj. hyperbilirubinemia Hepatocellular vs cholestasis Intrahepatic vs extrahepatic cholestasis,A 5-yr old boy was found “looks yellow” for five days without apparent discomfort. P.E. revealed lemon-yellow skin and yellowish sclera, the spleen was palpable 5 cm below the left costal margin. Laboratory results: TBil 4mg/dl(68.4mol/l); CB/TB=0.15; ALT and other hepatic enzymes normal; Urine urobilinogen (+) and bilirubin () Q: What type of jaundice is it? What is the most likely diagnosis?,Case 1,Case 2,A 30-yr old female patient was admitted because of anorexia, fatigue, and pain over right costal area for 2 weeks. Her mother was diagnosed as acute hepatitis B six weeks ago. PE revealed jaundice over sclerae and a tender liver 2 cm below the right costal margin.Q1: What is the most likely diagnosis?,Q2: What laboratory abnormalities do you expect? (Elevated or lowered? Slightly, moderately, or significantly?)ALT & ASTALP & GGTSerum bilirubinCB/TB Urine urobilinogen,Case 2 (cntd),Q2: What laboratory abnormalities do you expect? (Elevated or lowered? Slightly, moderately, or significantly?)ALT & ASTALP & GGTSerum bilirubinCB/TB Urine urobilinogen,Case 2 (cntd), 0.5 +,Case 3,A 40-yr old female patient