1、Neonatal and Infantile Cholestasis,Ying-kit Leung, MD, FAAP President, Hong Kong Society of Paediatric Gastroenterology, Hepatology and Nutrition, Yantai, Shandong, July 2006,DEFINITION,Neonatal cholestasis is defined as conjugated hyperbilirubinemia developing within the first 90 days of extrauteri
2、ne life. Conjugated bilirubin exceeds 1.5 to 2.0 mg/dl. Conjugated bilirubin generally exceeds 20% of the total bilirubin.,Bilirubin Production,Biliverdin,Bilirubin,erythrocyte hemoglobin,muscle myoglobin,cytochromes catalases,heme oxygenase,biliverdin reductase,reticulo-endothelialcell,Bilirubin,Al
3、bumin,liver,CO + Fe,Heme,GST,Bilirubin Uptake, Conjugation, Excretion,B,B,Alb,G,B,G,G,B,R,GLUCURONYL TRANSFERASE,BILE CANALICULUS,2. UPTAKE,3. CONJUGATION,4. EXCRETION,E.R.,B-G,B-G,B-,B-G,B-G,B-G,B,uBg,sB,uBg,B-G,dark urine,acholic stools,Conjugated Hyperbilirubinemia,Conjugated hyperbilirubinemia,e
4、xtrahepatic,intrahepatic,Neonatal Cholestasis,EXTRAHEPATIC ETIOLOGIES,Extrahepatic biliary atresia Choledochal cyst Bile duct stenosis Spontaneous perforation of the bile duct Cholelithiasis Inspissated bile/mucus plug Extrinsic compression of the bile duct,INTRAHEPATIC ETIOLOGIES,Idiopathic Toxic G
5、enetic/Chromosomal Infectious Metabolic Miscellaneous,INTRAHEPATIC ETIOLOGIES,Idiopathic Neonatal Hepatitis Toxic TPN-associated cholestasis Drug-induced cholestasis Genetic/Chromosomal Trisomy 18 Trisomy 21,INTRAHEPATIC ETIOLOGIES,Infectious Bacterial sepsis (E. coli, Listeriosis, Staph. aureus) TO
6、RCHES Hepatitis B and C Varicella Coxsackie virus Echo virus Tuberculosis,INTRAHEPATIC ETIOLOGIES,Metabolic Disorders of Carbohydrate Metabolism Galactosemia Fructosemia Glycogen Storage Disease Type IV Disorders of Amino Acid Metabolism Tyrosinemia Hypermethioninemia,INTRAHEPATIC ETIOLOGIES,Metabol
7、ic (cont.) Disorders of Lipid Metabolism Niemann-Pick disease Wolman disease Gaucher disease Cholesterol ester storage disease Disorders of Bile Acid Metabolism 3B-hydroxysteroid dehydrogenase/isomerase Trihydroxycoprostanic acidemia,INTRAHEPATIC ETIOLOGIES,Metabolic (cont.) Peroxisomal Disorders Ze
8、llweger syndrome Adrenoleukodystrophy Endocrine Disorders Hypothyroidism Idiopathic hypopituitarism,INTRAHEPATIC ETIOLOGIES,Metabolic (cont.) Miscellaneous Metabolic Disorders Alpha-1-antitrypsin deficiency Cystic fibrosis Neonatal iron storage disease North American Indian cholestasis,INTRAHEPATIC
9、ETIOLOGIES,Miscellaneous Arteriohepatic dysplasia (Alagille syndrome) Nonsyndromic paucity of intrahepatic bile ducts Carolis disease Bylers disease, PFIC Congenital hepatic fibrosis,COMMON ETIOLOGIES,Premature infants Sepsis/Acidosis TPN-associated Drug-induced Idiopathic neonatal hepatitis Extrahe
10、patic biliary atresia Alpha-1-antitrypsin deficiency Intrahepatic cholestasis syndromes,CLINICAL PRESENTATION,Jaundice Scleral icterus Hepatomegaly Acholic stools Dark urine Other signs and symptoms depend on specific disease process,GOALS OF TIMELY EVALUATION,Diagnose and treat known medical and/or
11、 life-threatening conditions. Identify disorders amenable to surgical therapy within an appropriate time-frame. Avoid surgical intervention in intrahepatic diseases.,Bu,Bc Bu,Bu,Hemolysis Rh ABO,Breast Milk,Physiological,Hypothyroidism,Bc Bu,dark urine,acholic stools,Bc Bu,BEWARE!,dark urine,acholic
12、 stools,hepatosplenomegaly bilirubinuria conjugated bilirubin abnormal LFTs,EVALUATION,Basic evaluation History and physical examination (includes exam of stool color) CBC and reticulocyte count Electrolytes, BUN, creatinine, calcium, phosphate SGOT, SGPT, GGT, alkaline phosphatase Total and direct
13、bilirubin Total protein, albumin, cholesterol, PT/PTT,EVALUATION,Tests for infectious causes Indicated cultures of blood, urine, CSF TORCH titers, VDRL Urine for CMV Hepatitis B and C serology Ophthalmologic examination,EVALUATION,Metabolic work-up Protein electrophoresis, alpha-1-antitrypsin level
14、and phenotype Thyroid function tests Sweat chloride Urine/serum amino acids Review results of newborn metabolic screen Urine reducing substances Urine bile acids,EVALUATION,Radiological evaluation Ultrasonography Patient should be NPO to increase likelihood of visualizing the gallbladder Feeding wit
15、h exam may demonstrate a functioning gallbladder Hepatobiliary scintigraphy Premedicate with phenobarbital 5mg/kg/d for 3-5 days,EVALUATION,Invasive studies Duodenal intubation Percutaneous liver biopsy Percutaneous transhepatic cholangiography Endoscopic retrograde cholangiopancreatography (ERCP) E
16、xploratory laparotomy with intraoperative cholangiogram,ESTIMATED FREQUENCY OF VARIOUS CLINICAL FORMS OF NEONATAL CHOLESTASIS,PROPOSED SUBTYPES OF INTRAHEPATIC CHOLESTASIS,intrahepatic or extrahepatic ? treatable disorder ? liver damage ? complications of cholestasis ?,Investigation of Cholestasis,O
17、bjectives,X-ray spine: butterfly vertebrae (Alagille) skull, long bones (intrauterine infection) sweat test (cystic fibrosis) ophthalmological examination cataract (galactosemia, intrauterine infection) retinopathy (intrauterine infection) posterior embryotoxon (Alagille) others bone marrow (Niemann
18、 Pick disease type C) bile acids,Investigation of Cholestasis,Special Tests,ultrasound choledochal cyst etc. post-prandial contraction of gall bladder hepatobiliary scan (99mTc - H / B / DIS / PIP / - IDA) after pre-treatment with phenobarb or cholestyramine,Investigation of Cholestasis,Special Test
19、s (cont),ultrasound choledochal cyst etc. post-prandial contraction of gall bladder hepatobiliary scan (99mTc - H / B / DIS / PIP / - IDA) after pre-treatment with phenobarb or cholestyramine ERCP (endoscopic retrograde cholangiopancreatography),Investigation of Cholestasis,Special Tests (cont),Endo
20、scopic Retrograde Cholangio-Pancreatography,Investigation of Cholestasis,Special Tests (cont),liver histology (needle biopsy) biliary atresia: portal ductal proliferation neonatal hepatitis: giant cells specific disorder e.g a1-antitrypsin,Biliary Atresia,Definition - Progressive scarring of bile du
21、cts outside and inside of the liver that leads to complete blockage of bile flow in the first three months of life. 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,Performed for biliary atresia that i
22、s not surgically correctable with excision of a distal atretic segment. Roux-en-Y portoenterostomy Bile flow re-established in 80-90% if performed prior to 8 weeks-old. Bile flow re-established in less than 20% if performed after 12 weeks-old,KASAI PROCEDURE,Success of the operation is dependent on
23、the presence and size of ductal remnants, the extent of the intrahepatic disease, and the experience of the surgeon. Complications are ascending cholangitis and reobstruction as well as failure to re-establish bile flow.,LIVER TRANSPLANTATION,Survival rates approach 80% at 1 year and 70% at 5 years.
24、 Biliary 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. Used early in cases of tyrosinemia.,Outcome after Kasai procedure,Short-term - bile flow dependent on age at Kasai 90 days 10-20
25、% Long-term - 10 yr. survival (no transplant) 20 - 40% US,France 50% Japan Liver transplantation - required for 80%,extrahepatic biliary atresia,Extrahepatic Neonatal Cholestasis,choledochal cyst inspissated bile syndrome bile duct stenosis spontaneous perforation of bile duct cholelithiasis tumors,
26、 masses,Persistent Familial Intrahepatic Cholestasis,normal gGT,high gGT,PFIC 1 Byler Disease Amish,PFIC 2 Byler Syndrome Middle Eastern,PFIC 3,18q21-22,2q24,Benign Recurrent Intrahepatic Cholestasis,Intrahepatic Cholestasis Pregnancy,7q21,basolateral membrane,junctional complex,apical membrane,hepa
27、tocyte,hepatocyte,canaliculus,sinusoid,sinusoid,rate-limiting 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 Cotrans
28、porting Polypeptide,Bile Salt Uptake,Na+-dependent,Na+-independent,OATPs,A-,BS-,OA- drugs,Organic Anion Transporting Polypeptides,Bile Salt Uptake,Na+-independent,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 Tr
29、ansporting 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,Multi-drug Resistance Protein,1,3,6,ABC TRANSPO
30、RTERS,ATP Binding Cassette,BSEP,BS-,Bile Salt Export Pump (SGPC) (cBAT),BSEP,BS-,MRP2,Anionic Conjugates,canalicular Multi-specific Organic Acid Transporter,Multi-drug Resistance Protein 2,bilirubin-G BA-G, BA-S glutathione-S,leukotriene C4 drugs 17b-estradiol-G,BSEP,BS-,Phospholipids,MDR3,MRP2,Anio
31、nic Conjugates,Multi Drug Resistance gene product,BSEP,BS-,Phospholipids,MDR3,MRP2,Anionic Conjugates,hydrophobic cations physiological? anti-cancer drugs,MDR1,NTCP,Na+/K+ ATPase,OCT1,OATPs,BSEP,MDR3,MRP2,AE2,Cl- channel,GSH transporter,MDR1,canaliculus,cholangiocyte,Cl-,CFTR,AE2,Cl-,HC0-,Aminophosp
32、holipids,11b,Cystic Fibrosis Transmembrane Regulator,PFIC 2 Byler Syndrome Middle Eastern + neonatal hepatitis jaundice pruritus normal gGT bile salts in bile in plasma persistent, progressive liver failure 2-10 yr,BSEP,BS,Bile Salt Export Pump (SGPC) (cBAT),B-G,BS,BS,BSEP,BA-G BA-S,BS,BS,bile salts
33、 in bile in plasma,normal gGT,pruritus,jaundice,hepatitis,B-G,Bile Salts,2q24 ABC B11 liver-specific,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 2-10 yr,7q 21 ABC B4
34、phospholipid flippase/translocase liver-specific,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 pro
35、liferation portal inflammation fibrosis,Phospholipids,MDR3,PL,MDR3,BSEP,cholangiopathy bile duct proliferation portal inflammation fibrosis,BS,gGT,gGT,high gGT,UPTAKE,CONJUGATION,EXCRETION,PRODUCTION,G,B,B-G,B,Bu,Bc,Bc,Dubin-Johnson,Rotor,Conjugated Hyperbilirubinemia,MRP2,Anionic Conjugates,canalic
36、ular Multi-specific Organic Acid Transporter,bilirubin-G BA-G, BA-S glutathione-S,Multi-drug Resistance Protein 2,Dubin Johnson conjugated hyperbilirubinemia no liver disease normal liver enzymes brown-black pigment in hepatocytes,MRP2,B-G,B-G,conjugated hyperbilirubinemia,no cholestasis,pigment,mul
37、ti-specific organic anion conjugate transporter ABC C2 liver, kidney, intestine,Organic Anion Conjugates,FIC1,P-type ATPase,Aminophospholipids,PFIC 1 Byler Disease Amish intermittent persistent progressive liver disease diarrhea, pancreatitis, hearing loss,PFIC1 P-type ATPase family (ion transport p
38、umps) 18q21-22 bovine homologue -aminophospholipid transport function - maintenance of membrane lipid composition? expressed in cholangiocyte, hepatocyte?, intestine, pancreas,PHOSPHATIDYL SERINE,BRIC mutations,P motif,FIC1,diarrhea,pancreatitis,ALPHA-1-ANTITRYPSIN DEFICIENCY,Alpha-1-antitrypsin mak
39、es up 90% of alpha-1-globulin fraction Associated with PiZZ (about 10-20% will have liver disease) and rarely with PiSZ and PiZ-null phenotypes Biopsy shows hepatocellular edema, giant cell transformation, necrosis, and pseudoacinar transformation.,ALPHA-1-ANTITRYPSIN DEFICIENCY,Biopsy also shows ac
40、cumulation of PAS-positive, diastase-resistant globules in the cytoplasm of periportal hepatocytes. Varying degrees of fibrosis correlate with disease prognosis.,INTRAHEPATIC CHOLESTASIS SYNDROMES,Includes several diagnostic entities. Biopsies show cholestasis. May show paucity of intrahepatic bile
41、ducts, giant cell transformation, and/or fibrosis.,Paucity of intrahepatic bile ducts,Intrahepatic Neonatal Cholestasis,Alagille Syndrome,Alagille Syndrome,1969-Alagille et al., first reported patients with idiopathic bile duct paucity and similar clinical features including congenital heart disease
42、 1973-Watson & Miller recognized a syndrome that included pulmonary artery abnormalities, neonatal liver disease, somatic anomalies and a familial tendency Coined term arteriohepatic dysplasia,Paucity of Bile Ducts,Alagille Syndrome,1975-Alagille et al., published extended observations in 15 patient
43、s Chronic liver disease Characteristic facies Systolic murmur Vertebral arch defects Mental retardation, hypgonadism, Family history,Paucity of intrahepatic bile ducts Alagille syndrome non-syndromic,Intrahepatic Neonatal Cholestasis,Clinical Features: Hepatic,Hepatomegaly Neonatal hepatitis Splenom
44、egaly Portal hypertension Cirrhosis Synthetic liver failure,Clinical Features: Hepatic,Cholestasis Jaundice Conjugated hyperbilirubinemia in neonatal period Pruritis Xanthomas Biochemical abnormalities,Clinical Features: Cardiovascular,Murmur Most common cardiac manifestation of AGS Due to stenosis
45、at some level in the pulmonary tree with or without structural cardiac disease,Clinical Features: Skeletal,“Butterfly vertebrae” Shortened interpedicular distance Shortened distal phalanges Shortened distal radius and ulna Spina bifida occulta,Fusion of adjacent vertebrae Clubbing Pathologic fractur
46、es Osteopenia Rickets Absent 12th rib,Clinical Features: Skeletal Butterfly Vertebrate,Clinical Features: Ocular,Posterior embryotoxon An abnormal prominence of Schwalbes line Present in 56-95% of AGS patients Seen in 8-15% of general population,Clinical Features: Ocular Posterior Embryotoxon,Poster
47、ior Embryotoxon: prominent Schwalbes line is visible just inside the temporal limbus.,Alagille Syndrome: Genetics,JAG1: Structure Extracellular domain 21 amino acid signal peptide 40 amino acide DSL region 16 EGF-like regions Cysteine rich region Transmembrane domain Intracellular domain,Defects of
48、Bile Acid Synthesis,1. 7-hydroxylation of sterol precursors,CTX,2. ring structure modification,3. side chain oxidation and shortening,4. conjugation of the bile acid with an amino acid,Specific TherapyMalabsorption MCT Vitamins A, D, E, KCholestasis/Pruritus/Hyperlipidemia cholestyramine 250-500 mg/kg/day phenobarbitone 3-10 mg/kg/day ursodeoxycholic acid 10-20 mg/kg/day rifampicin 10 mg/kg/day,Therapy of Neonatal Cholestasis,TREATMENT,Medical management Nutritional support Treatment of pruritus Choleretics and bile acid-binders Management of portal hypertension and its consequences,
