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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 extrauterine life. Conjugated bilirubin exceeds 1.5 to 2.0 mg/dl. Conjugated bilirubin generally exceeds 20% of the total bilirubin. Bilirubin Production erythrocyte hemoglobin muscle myoglobin cytochromes catalases Heme reticuloendothelial cell heme oxygenase CO + Fe Biliverdin biliverdin reductase Bilirubin Albumin Bilirubin liver Bilirubin Uptake, Conjugation, Excretion SINUSOID HEPATOCYTE DISSE 2. UPTAKE Alb B B R UDPG GLUCURONYL TRANSFERASE UDP G GST B 3. CONJUGATION E.R. G B G 4. EXCRETION BILE CANALICULUS Conjugated Hyperbilirubinemia B-G B-G B- B-G B-G uBg B-G dark urine sB uBg acholic stools B B-G Neonatal Cholestasis Conjugated hyperbilirubinemia extrahepatic intrahepatic 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 Genetic/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) TORCHES 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 Metabolic (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 Zellweger 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 ETIOLOGIES Miscellaneous Arteriohepatic dysplasia (Alagille syndrome) Nonsyndromic paucity of intrahepatic bile ducts Caroli’s disease Byler’s disease, PFIC Congenital hepatic fibrosis COMMON ETIOLOGIES Premature infants Sepsis/Acidosis TPN-associated Drug-induced Idiopathic neonatal hepatitis Extrahepatic 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 lifethreatening conditions. Identify disorders amenable to surgical therapy within an appropriate time-frame. Avoid surgical intervention in intrahepatic diseases. Bu Bc ± Bu Bu • Physiological • Breast Milk • Hemolysis - Rh - ABO • Hypothyroidism Bc ± Bu dark urine acholic stools Bc ± Bu dark urine acholic stools BEWARE!!! • 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 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 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 with 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) Exploratory laparotomy with intraoperative cholangiogram ESTIMATED FREQUENCY OF VARIOUS CLINICAL FORMS OF NEONATAL CHOLESTASIS PROPOSED SUBTYPES OF INTRAHEPATIC CHOLESTASIS Investigation of Cholestasis Objectives intrahepatic or extrahepatic ? treatable disorder ? liver damage ? complications of cholestasis ? Investigation of Cholestasis Special Tests 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 Pick disease type C) bile acids Investigation of Cholestasis Special Tests (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 Investigation of Cholestasis Special Tests (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) Endoscopic 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 ducts 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 is 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 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. 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 < 60 days 80% 60 - 90 days 50% > 90 days 10-20% Long-term - 10 yr. survival (no transplant) 20 - 40% US,France 50% Japan Liver transplantation - required for ~80% Extrahepatic Neonatal Cholestasis extrahepatic biliary atresia choledochal cyst inspissated bile syndrome bile duct stenosis spontaneous perforation of bile duct cholelithiasis tumors, masses Persistent Familial Intrahepatic Cholestasis normal gGT PFIC 1 high gGT PFIC 2 Byler Disease Amish Byler Syndrome Middle Eastern 18q21-22 2q24 Benign Recurrent Intrahepatic Cholestasis PFIC 3 7q21 Intrahepatic Cholestasis Pregnancy junctional complex basolateral membrane apical membrane sinusoid canaliculus hepatocyte sinusoid hepatocyte basolateral membrane apical membrane rate-limiting against concentration gradient (x1000 for bile salts) energy requiring H2O [BS] [BS] bile saltdependent bile flow bile saltindependent bile flow + Na -dependent + K + + Na /K ATPase + Na + Na NTCP BS + Na Taurocholate Cotransporting Polypeptide Bile Salt Uptake + Na -independent + Na -dependent Bile Salt Uptake + Na -independent + K + + Na /K ATPase + Na + - Na NTCP BS A OATPs BS ,OA drugs + Na Taurocholate Cotransporting Polypeptide Organic Anion Transporting Polypeptides Organic Cation Transporter + OC OCT1 - A OATPs BS ,OA drugs Organic Cation Transporter + K + + Na /K ATPase + Na + + OC OCT1 - Na NTCP BS A OATPs BS ,OA drugs + Na Taurocholate Cotransporting Polypeptide Organic Anion Transporting Polypeptides Multi-drug Resistance Protein MRP 1 3 6 + K + + Na /K ATPase + Na + + OC OCT1 - Na NTCP BS A OATPs BS ,OA drugs + Na Taurocholate Cotransporting Polypeptide Organic Anion Transporting Polypeptides ABC TRANSPORTERS ATP Binding Cassette BSEP Bile Salt Export Pump (SGPC) (cBAT) - BS Multi-drug Resistance Protein 2 BSEP - BS MRP2 Anionic Conjugates •leukotriene C4 •bilirubin-G •BA-G, BA-S •drugs •glutathione-S •17b-estradiol-G canalicular Multi-specific Organic Acid Transporter Multi Drug Resistance gene product Phospholipids MDR3 BSEP - BS MRP2 Anionic Conjugates hydrophobic cations physiological?? anti-cancer drugs Phospholipids MDR1 MDR3 BSEP MRP2 - BS Anionic Conjugates + + Na /K ATPase MDR1 OCT1 - Cl channel NTCP MDR3 BSEP AE2 MRP2 GSH transporter OATPs 11b canaliculus - Cl cholangiocyte CFTR Cystic Fibrosis Transmembrane Regulator AE2 HC0 - Cl P-type ATPase Aminophospholipids FIC1 Persistent Familial Intrahepatic Cholestasis normal gGT PFIC 1 high gGT PFIC 2 Byler Disease Amish Byler Syndrome Middle Eastern 18q21-22 2q24 Benign Recurrent Intrahepatic Cholestasis PFIC 3 7q21 Intrahepatic Cholestasis Pregnancy PFIC 2 Byler Syndrome Middle Eastern + neonatal hepatitis jaundice pruritus BSEP Bile Salt Export Pump (SGPC) (cBAT) normal bile BS gGT salts in bile in plasma persistent, liver progressive failure 2-10 yr pruritus normal gGT gGT BS hepatitis BSEP BS BS MRP2 BA-G BA-S B-G bile salts in bile in plasma jaundice • 2q24 • ABC B11 • liver-specific Bile Salts Persistent Familial Intrahepatic Cholestasis normal gGT PFIC 1 high gGT PFIC 2 Byler Disease Amish Byler Syndrome Middle Eastern 18q21-22 2q24 Benign Recurrent Intrahepatic Cholestasis PFIC 3 7q21 Intrahepatic Cholestasis Pregnancy PFIC 3 elevated gGT neonatal hepatitis jaundice milder pruritus PL liver Phospholipids MDR3 : BA ratio in bile persistent, Multi Drug Resistance gene product progressive failure 2-10 yr • 7q 21 • ABC B4 • phospholipid flippase/translocase • liver-specific PHOSPHATIDYL CHOLINE flippase Phospholipids MDR3 PL mixed micelles chol BS BSEP Phospholipids MDR3 PL PL mixed micelles chol BS BSEP Phospholipids MDR3 PL mixed micelles chol BS BSEP cholangiopathy bile duct proliferation portal inflammation fibrosis Phospholipids MDR3 PL MDR3 chol BS BSEP cholangiopathy bile duct proliferation portal inflammation fibrosis Phospholipids MDR3 PL MDR3 gGT gGT BS BSEP high gGT Conjugated Hyperbilirubinemia G - B G B EXCRETION B CONJUGATION UPTAKE PRODUCTION Bu Bc Dubin-Johnson Rotor Dubin Johnson conjugated hyperbilirubinemia no liver disease normal liver enzymes brown-black pigment in hepatocytes Multi-drug Resistance Protein 2 MRP2 Anionic Conjugates •bilirubin-G •BA-G, BA-S •glutathione-S canalicular Multi-specific Organic Acid Transporter conjugated B-G hyperbilirubinemia MRP3 MRP2 B-G MRP3 Bc B-G B- B-G B-G uBg uBg B-G dark urine sB acholic stools uBg B B-G conjugated B-G hyperbilirubinemia MRP3 pigment BSEP BS no cholestasis MRP2 B-G • multi-specific organic anion conjugate transporter • ABC C2 • liver, kidney, intestine Organic Anion Conjugates Persistent Familial Intrahepatic Cholestasis normal gGT PFIC 1 high gGT PFIC 2 Byler Disease Amish Byler Syndrome Middle Eastern 18q21-22 2q24 Benign Recurrent Intrahepatic Cholestasis PFIC 3 7q21 Intrahepatic Cholestasis Pregnancy PFIC 1 Byler Disease Amish intermittent persistent progressive liver disease ± diarrhea, pancreatitis, hearing loss P-type ATPase Aminophospholipids FIC1 PFIC1 • P-type ATPase family (ion transport pumps) • 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 pancreatitis FIC1 diarrhea ALPHA-1-ANTITRYPSIN DEFICIENCY Alpha-1-antitrypsin makes up 90% of alpha-1globulin 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 accumulation 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 ducts, giant cell transformation, and/or fibrosis. Intrahepatic Neonatal Cholestasis Paucity of intrahepatic bile ducts Alagille Syndrome Alagille Syndrome 1969-Alagille et al., first reported patients with idiopathic bile duct paucity and similar clinical features including congenital heart disease 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 patients Chronic liver disease Characteristic facies Systolic murmur Vertebral arch defects Mental retardation, hypgonadism, Family history Intrahepatic Neonatal Cholestasis Paucity of intrahepatic bile ducts Alagille syndrome non-syndromic Clinical Features: Hepatic Hepatomegaly Neonatal hepatitis Splenomegaly Portal hypertension Cirrhosis Synthetic liver failure Clinical Features: Hepatic Cholestasis Jaundice Conjugated hyperbilirubinem ia in neonatal period Pruritis Xanthomas Biochemical abnormalities Clinical Features: Cardiovascular Murmur Most common cardiac manifestation of AGS Due to stenosis 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 fractures Osteopenia Rickets Absent 12th rib Clinical Features: Skeletal Butterfly Vertebrate Clinical Features: Ocular Posterior embryotoxon An abnormal prominence of Schwalbe’s line Present in 56-95% of AGS patients Seen in 8-15% of general population Clinical Features: Ocular Posterior Embryotoxon Posterior Embryotoxon: prominent Schwalbe's 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 Bile Acid Synthesis 1. 7α-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 Therapy of Neonatal Cholestasis Specific Therapy Malabsorption MCT Vitamins A, D, E, K Cholestasis/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 TREATMENT Medical management Nutritional support Treatment of pruritus Choleretics and bile acid-binders Management of portal hypertension and its consequences TREATMENT Nutritional support Adequate calories and protein Supplement calories with medium chain triglycerides Maintain levels of essential long-chain fatty acids Treatment and/or prophylaxis for fat-soluble vitamin deficiencies (vitamins A, D, E, and K) TREATMENT Nutritional support (cont.) Supplemental calcium and phosphate when bone disease is present Prophylaxis for zinc deficiency Low-copper diet as poorly excreted Sodium restriction when ascites present TREATMENT Treatment of pruritus Bile acid-binders: cholestyramine, cholestipol Ursodeoxycholic acid Phenobarbital as a choleretic Naloxone Rifampin TREATMENT Management of portal hypertension and its consequences Variceal bleeding Fluid rescuscitation Blood products Sclerotherapy Balloon tamponade Portovenous shunting Propanolol TREATMENT Management of portal hypertension and its consequences (cont.) Ascites Sodium restriction Diuretics: spironolactone, furosemide Albumin Paracentesis Thrombocytopoenia managed with platelet infusions when clinically indicated Neonatal Cholestasis Conjugated Hyperbilirubinemia REFER URGENTLY Thank you!
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