新生儿和婴儿胆汁淤积（英文版）

Neonatal and Infantile Cholestasis Ying-kit Leung, MD, FAAP President, Hong Kong Society of Paediatric Gastroenterology, Hepatology and Nutrition, Yantai, Shandong, July 2006 DEFINITION nNeonatal cholestasis is defined as conjugated hyperbilirubinemia developing within the first 90 days of extrauterine life. nConjugated bilirubin exceeds 1.5 to 2.0 mg/dl. nConjugated bilirubin generally exceeds 20% of the total bilirubin. Bilirubin Production Biliverdin Bilirubin erythrocyte hemoglobin muscle myoglobincytochromes catalases heme oxygenase biliverdin reductase reticulo- endothelial cell BilirubinAlbuminliver CO + Fe Heme GST Bilirubin Uptake, Conjugation, Excretion BBAlb G B G G B R GUDP UDP GLUCURONYL TRANSFERASE HEPATOCYTE SINUSOIDDISSE BILE CANALICULUS 2. UPTAKE 3. CONJUGATION 4. EXCRETION E.R. B-G B-G B- B-G B-G B-G BuBgsB uBg B-G dark urine acholic stools Conjugated Hyperbilirubinemia Conjugated hyperbilirubinemia extrahepaticintrahepatic Neonatal Cholestasis EXTRAHEPATIC ETIOLOGIES nExtrahepatic biliary atresia nCholedochal cyst nBile duct stenosis nSpontaneous perforation of the bile duct nCholelithiasis nInspissated bile/mucus plug nExtrinsic compression of the bile duct INTRAHEPATIC ETIOLOGIES nIdiopathic nToxic nGenetic/Chromosomal nInfectious nMetabolic nMiscellaneous INTRAHEPATIC ETIOLOGIES nIdiopathic Neonatal Hepatitis nToxic nTPN-associated cholestasis nDrug-induced cholestasis nGenetic/Chromosomal nTrisomy 18 nTrisomy 21 INTRAHEPATIC ETIOLOGIES nInfectious nBacterial sepsis (E. coli, Listeriosis, Staph. aureus) nTORCHES nHepatitis B and C nVaricella nCoxsackie virus nEcho virus nTuberculosis INTRAHEPATIC ETIOLOGIES nMetabolic nDisorders of Carbohydrate Metabolism nGalactosemia nFructosemia nGlycogen Storage Disease Type IV nDisorders of Amino Acid Metabolism nTyrosinemia nHypermethioninemia INTRAHEPATIC ETIOLOGIES nMetabolic (cont.) nDisorders of Lipid Metabolism nNiemann-Pick disease nWolman disease nGaucher disease nCholesterol ester storage disease nDisorders of Bile Acid Metabolism n3B-hydroxysteroid dehydrogenase/isomerase nTrihydroxycoprostanic acidemia INTRAHEPATIC ETIOLOGIES nMetabolic (cont.) nPeroxisomal Disorders nZellweger syndrome nAdrenoleukodystrophy nEndocrine Disorders nHypothyroidism nIdiopathic hypopituitarism INTRAHEPATIC ETIOLOGIES nMetabolic (cont.) nMiscellaneous Metabolic Disorders nAlpha-1-antitrypsin deficiency nCystic fibrosis nNeonatal iron storage disease nNorth American Indian cholestasis INTRAHEPATIC ETIOLOGIES nMiscellaneous nArteriohepatic dysplasia (Alagille syndrome) nNonsyndromic paucity of intrahepatic bile ducts nCarolis disease nBylers disease, PFIC nCongenital hepatic fibrosis COMMON ETIOLOGIES nPremature infants nSepsis/Acidosis nTPN-associated nDrug-induced nIdiopathic neonatal hepatitis nExtrahepatic biliary atresia nAlpha-1-antitrypsin deficiency nIntrahepatic cholestasis syndromes CLINICAL PRESENTATION nJaundice nScleral icterus nHepatomegaly nAcholic stools nDark urine nOther signs and symptoms depend on specific disease process GOALS OF TIMELY EVALUATION nDiagnose and treat known medical and/or life- threatening conditions. nIdentify disorders amenable to surgical therapy within an appropriate time-frame. nAvoid surgical intervention in intrahepatic diseases. BuBc Bu Bu Hemolysis Rh ABO Breast Milk Physiological Hypothyroidism Bc Bu dark urine acholic stools Bc Bu BEWARE! dark urine acholic stools hepatosplenomegaly bilirubinuria conjugated bilirubin abnormal LFTs EVALUATION nBasic evaluation nHistory and physical examination (includes exam of stool color) nCBC and reticulocyte count nElectrolytes, BUN, creatinine, calcium, phosphate nSGOT, SGPT, GGT, alkaline phosphatase nTotal and direct bilirubin nTotal protein, albumin, cholesterol, PT/PTT EVALUATION nTests for infectious causes nIndicated cultures of blood, urine, CSF nTORCH titers, VDRL nUrine for CMV nHepatitis B and C serology nOphthalmologic examination EVALUATION nMetabolic work-up nProtein electrophoresis, alpha-1-antitrypsin level and phenotype nThyroid function tests nSweat chloride nUrine/serum amino acids nReview results of newborn metabolic screen nUrine reducing substances nUrine bile acids EVALUATION nRadiological evaluation nUltrasonography nPatient should be NPO to increase likelihood of visualizing the gallbladder nFeeding with exam may demonstrate a functioning gallbladder nHepatobiliary scintigraphy nPremedicate with phenobarbital 5mg/kg/d for 3-5 days EVALUATION nInvasive studies nDuodenal intubation nPercutaneous liver biopsy nPercutaneous transhepatic cholangiography nEndoscopic retrograde cholangiopancreatography (ERCP) nExploratory laparotomy with intraoperative cholangiogram ESTIMATED FREQUENCY OF VARIOUS CLINICAL FORMS OF NEONATAL CHOLESTASIS PROPOSED SUBTYPES OF INTRAHEPATIC CHOLESTASIS nintrahepatic or extrahepatic ? ntreatable disorder ? nliver damage ? ncomplications of cholestasis ? Investigation of Cholestasis Objectives nXray nspine: butterfly vertebrae (Alagille) nskull, long bones (intrauterine infection) nsweat test (cystic fibrosis) nophthalmological examination ncataract (galactosemia, intrauterine infection) nretinopathy (intrauterine infection) nposterior embryotoxon (Alagille) nothers nbone marrow (Niemann Pick disease type C) nbile acids Investigation of Cholestasis Special Tests nultrasound choledochal cyst etc. postprandial contraction of gall bladder nhepatobiliary scan (99mTc H / B / DIS / PIP / IDA) after pretreatment with phenobarb or cholestyramine Investigation of Cholestasis Special Tests (cont) nultrasound choledochal cyst etc. postprandial contraction of gall bladder nhepatobiliary scan (99mTc H / B / DIS / PIP / IDA) after pretreatment with phenobarb or cholestyramine nERCP (endoscopic retrograde cholangiopancreatography) Investigation of Cholestasis Special Tests (cont) ancreatographyPholangioCetrograde R ndoscopicE Investigation of Cholestasis Special Tests (cont) nliver histology (needle biopsy) biliary atresia: portal ductal proliferation neonatal hepatitis: giant cells specific disorder e.g a1antitrypsin Biliary Atresia n Definition - Progressive scarring of bile ducts outside and inside of the liver that leads to complete blockage of bile flow in the first three months of life. n Bile is the yellow fluid made in the liver that helps digest food (fat) in the intestine Anatomy in Biliary Atresia Kasai Procedure KASAI PROCEDURE nPerformed for biliary atresia that is not surgically correctable with excision of a distal atretic segment. nRoux-en-Y portoenterostomy nBile flow re-established in 80-90% if performed prior to 8 weeks-old. nBile flow re-established in less than 20% if performed after 12 weeks-old KASAI PROCEDURE nSuccess of the operation is dependent on the presence and size of ductal remnants, the extent of the intrahepatic disease, and the experience of the surgeon. nComplications are ascending cholangitis and reobstruction as well as failure to re-establish bile flow. LIVER TRANSPLANTATION nSurvival rates approach 80% at 1 year and 70% at 5 years. nBiliary atresia is the most common indication for transplant and may be the initial treatment when detected late or may be used as a salvage procedure for a failed Kasai. nUsed early in cases of tyrosinemia. Outcome after Kasai procedure nShort-term - bile flow dependent on age at Kasai 90 days 10-20% nLong-term - 10 yr. survival (no transplant) 20 - 40% US,France 50% Japan nLiver transplantation - required for 80% nextrahepatic biliary atresia Extrahepatic Neonatal Cholestasis ncholedochal cyst ninspissated bile syndrome nbile duct stenosis nspontaneous perforation of bile duct ncholelithiasis ntumors, masses Persistent Familial Intrahepatic Cholestasis normal gGThigh gGT PFIC 1 Byler Disease Amish PFIC 2 Byler Syndrome Middle Eastern PFIC 3 18q21222q24 Benign Recurrent Intrahepatic Cholestasis Intrahepatic Cholestasis Pregnancy 7q21 basolateral membrane junctional complex apical membrane hepatocytehepatocyte canaliculussinusoidsinusoid ratelimiting against concentration gradient (x1000 for bile salts) energy requiring basolateral membrane apical membrane BS BS H2O bile salt dependent bile flow bile salt independent bile flow NTCP Na+ BS Na+/K+ ATPase K+ Na+ Na+ Taurocholate Cotransporting Polypeptide Bile Salt Uptake Na+dependentNa+independent OATPs A BS,OA drugs Organic Anion Transporting Polypeptides NTCP Na+ BS Na+/K+ ATPase K+ Na+ Na+ Taurocholate Cotransporting Polypeptide Bile Salt Uptake Na+independentNa+dependent OATPs A BS,OA drugs OCT1 Organic Cation Transporter OC+ NTCP Na+ BS Na+/K+ ATPase K+ Na+ OATPs A BS,OA drugs OCT1 Organic Anion Transporting Polypeptides Na+ Taurocholate Cotransporting Polypeptide Organic Cation Transporter OC+ NTCP Na+ BS Na+/K+ ATPase K+ Na+ OATPs A BS,OA drugs OCT1 Organic Anion Transporting Polypeptides Na+ Taurocholate Cotransporting Polypeptide OC+ MRP Multidrug Resistance Protein 136 ABC TRANSPORTERS ATP Binding Cassette BSEP BS Bile Salt Export Pump (SGPC) (cBAT) BSEP BS MRP2 Anionic Conjugates canalicular Multispecific Organic Acid Transporter Multidrug Resistance Protein 2 bilirubinG BAG, BAS glutathioneS leukotriene C4 drugs 17bestradiolG BSEP BS Phospholipids MDR3 MRP2 Anionic Conjugates Multi Drug Resistance gene product BSEP BS Phospholipids MDR3 MRP2 Anionic Conjugates hydrophobic cations physiological? anticancer drugs MDR1 NTCP Na+/K+ ATPase OCT1 OATPs BSEP MDR3 MRP2 AE2 Cl- channel GSH transporter MDR1 canaliculus cholangiocyte ClCFTR AE2 Cl HC0 FIC1 P-type ATPase Aminophospholipids 11b Cystic Fibrosis Transmembrane Regulator Persistent Familial Intrahepatic Cholestasis normal gGT PFIC 2 Byler Syndrome Middle Eastern 2q24 high gGT PFIC 1 Byler Disease Amish PFIC 3 18q2122 Benign Recurrent Intrahepatic Cholestasis Intrahepatic Cholestasis Pregnancy 7q21 PFIC 2 Byler Syndrome Middle Eastern + neonatal hepatitis jaundice pruritus normal gGT bile salts in bile in plasma persistent, progressive liver failure 210 yr BSEP BS Bile Salt Export Pump (SGPC) (cBAT) BG BSBS BSEPMRP2 BAG BAS BS BS gGT bile salts in bile in plasma normal gGT pruritus jaundice hepatitis BG Bile Salts 2q24 ABC B11 liverspecific normal gGT PFIC 2 Byler Syndrome Middle Eastern 2q24 PFIC 1 Byler Disease Amish 18q2122 Benign Recurrent Intrahepatic Cholestasis Persistent Familial Intrahepatic Cholestasis high gGT PFIC 3 Intrahepatic Cholestasis Pregnancy 7q21 Phospholipids MDR3 Multi Drug Resistance gene product PFIC 3 elevated gGT neonatal hepatitis jaundice milder pruritus PL : BA ratio in bile persistent, progressive liver failure 210 yr 7q 21 ABC B4 phospholipid flippase/translocase liverspecific PHOSPHATIDYL CHOLINE flippase Phospholipids BS PL mixed micelles MDR3 chol BSEP Phospholipids BS PL mixed micelles MDR3 chol BSEP PL Phospholipids BS PL mixed micelles MDR3 chol BSEP Phospholipids MDR3 BS PL MDR3 chol BSEP cholangiopathy bile duct proliferation portal inflammation fibrosis Phospholipids MDR3 PL MDR3 BSEP cholangiopathy bile duct proliferation portal inflammation fibrosis gGT BS gGTgGT high gGT UPTAKE CONJUGATION EXCRETION PRODUCTION G B B-G B BuBc Bc Dubin-Johnson Rotor Conjugated Hyperbilirubinemia MRP2 Anionic Conjugates canalicular Multispecific Organic Acid Transporter bilirubinG BAG, BAS glutathioneS Multidrug Resistance Protein 2 Dubin Johnson conjugated hyperbilirubinemia no liver disease normal liver enzymes brownblack pigment in hepatocytes MRP2 BG BG MRP3 conjugated hyperbilirubinemia B-G B-G B- B-G Bc B-G BuBgsB uBg uBg B-G dark urine acholic stools MRP3 BSEP BS MRP2 BG BG MRP3 conjugated hyperbilirubinemia no cholestasis pigment multispecific organic anion conjugate transporter ABC C2 liver, kidney, intestine Organic Anion Conjugates high gGT PFIC 2 Byler Syndrome Middle Eastern PFIC 3 2q24 Intrahepatic Cholestasis Pregnancy 7q21 Persistent Familial Intrahepatic Cholestasis normal gGT PFIC 1 Byler Disease Amish 18q2122 Benign Recurrent Intrahepatic Cholestasis FIC1 P-type ATPase Aminophospholipids PFIC 1 Byler Disease Amish intermittent persistent progressive liver disease diarrhea, pancreatitis, hearing loss PFIC1 Ptype ATPase family (ion transport pumps) 18q2122 bovine homologue aminophospholipid transport function maintenance of membrane lipid composition? expressed in cholangiocyte, hepatocyte?, intestine, pancreas, PHOSPHATIDYL SERINE BRIC mutations P motif FIC1 FIC1 diarrhea pancreatitis ALPHA-1-ANTITRYPSIN DEFICIENCY nAlpha-1-antitrypsin makes up 90% of alpha-1- globulin fraction nAssociated with PiZZ (about 10-20% will have liver disease) and rarely with PiSZ and PiZ-null phenotypes nBiopsy shows hepatocellular edema, giant cell transformation, necrosis, and pseudoacinar transformation. ALPHA-1-ANTITRYPSIN DEFICIENCY nBiopsy also shows accumulation of PAS- positive, diastase-resistant globules in the cytoplasm of periportal hepatocytes. nVarying degrees of fibrosis correlate with disease prognosis. INTRAHEPATIC CHOLESTASIS SYNDROMES nIncludes several diagnostic entities. nBiopsies show cholestasis. May show paucity of intrahepatic bile ducts, giant cell transformation, and/or fibrosis. nPaucity of intrahepatic bile ducts Intrahepatic Neonatal Cholestasis Alagille Syndrome Alagille Syndrome n1969-Alagille et al., first reported patients with idiopathic bile duct paucity and similar clinical features including congenital heart disease n1973-Watson & Miller recognized a syndrome that included pulmonary artery abnormalities, neonatal liver disease, somatic anomalies and a familial tendency nCoined term arteriohepatic dysplasia Paucity of Bile Ducts Alagille Syndrome n1975-Alagille et al., published extended observations in 15 patients nChronic liver disease nCharacteristic facies nSystolic murmur nVertebral arch defects nMental retardation, hypgonadism, nFamily history nPaucity of intrahepatic bile ducts nAlagille syndrome nnonsyndromic Intrahepatic Neonatal Cholestasis Clinical Features: Hepatic nHepatomegaly nNeonatal hepatitis nSplenomegaly nPortal hypertension nCirrhosis nSynthetic liver failure Clinical Features: Hepatic nCholestasis nJaundice nConjugated hyperbilirubinem ia in neonatal period nPruritis nXanthomas nBiochemical abnormalities Clinical Features: Cardiovascular nMurmur nMost common cardiac manifestation of AGS nDue to stenosis at some level in the pulmonary tree with or without structural cardiac disease Clinical Features: Skeletal n“Butterfly vertebrae” nShortened interpedicular distance nShortened distal phalanges nShortened distal radius and ulna nSpina bifida occulta nFusion of adjacent vertebrae nClubbing nPathologic fractures nOsteopenia nRickets nAbsent 12th rib Clinical Features: Skeletal Butterfly Vertebrate Clinical Features: Ocular nPosterior embryotoxon nAn abnormal prominence of Schwalbes line nPresent in 56-95% of AGS patients nSeen in 8-15% of general population Clinical Features: Ocular Posterior Embryotoxon Posterior Embryotoxon: prominent Schwalbes line is visible just inside the temporal limbus. Alagille Syndrome: Genetics nJAG1: Structure nExtracellular domain n21 amino acid signal peptide n40 amino acide DSL region n16 EGF-like regions nCysteine rich region nTransmembrane domain nIntracellular domain Defects of Bile Acid Synthesis 1. 7-hydroxylation of ster