Neonatal Cholestasis: Case Discussion and Review
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A case of a 3 month old boy with jaundice and pale stool is presented. On examination, he was icteric with hepatomegaly but no other abnormalities. Laboratory tests found direct hyperbilirubinemia. The objectives of the discussion are to understand neonatal cholestasis, evaluate cases, understand the differential diagnosis, and discuss treatment options. Neonatal cholestasis is prolonged conjugated hyperbilirubinemia beyond the first 14 days of life. Causes include extrahepatic conditions like biliary atresia or intrahepatic conditions like idiopathic neonatal hepatitis. Evaluation and management aim to identify treatable causes and prevent progression of liver disease.
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Neonatal Cholestasis: Case Discussion and Review
- 1. WELCOME Presenters: Dr. Maimuna Sayeed Dr. Zahid Hasan Dr. Raihanur Rahman
- 2. Case scenario Rizwan, a 3 month old boy presented with jaundice since 1st day of life & intermittent pale stool for same duration. He was delivered at term with average birth weight by LUCS. His perinatal period was uneventful and there was no H/O delayed passage of meconium, constipation, lethargy, vomiting, convulsion or any rash.
- 3. On examination, he was icteric & there was no facial dysmorphism. His weight & height were within normal range & hepatomegaly was present. Lab investigation showed direct hyperbilirubinemia.
- 5. Objectives • To know when cholestatic liver disease should be suspected in infant who has jaundice. • How to evaluate a neonate with conjugated hyperbilirubinemia. • To understand the differential diagnosis for neonatal cholestasis. • To know the therapeutic management of neonates with cholestasis.
- 6. Definition
- 7. Neonatal cholestasis is defined biochemically as prolonged elevation of the serum level of conjugated bilirubin beyond the 1st 14 days of life. (Nelson textbook of pediatrics, 20th ed.)
- 8. Cholestasis is defined as diminished bile formation or flow, and is manifested by abnormal conjugated hyperbilirubinemia: •a conjugated bilirubin ˃1 mg/dL, if the total bilirubin is ˂5 mg/dL •a conjugated bilirubin level ˃20% of the total bilirubin, if the total bilirubin is ˃5 mg/dl (Paediatric Practice Gastroenterology by Warren P. Bishop)
- 9. Pathogenesis
- 12. Etiologies
- 13. Neonatal cholestasis Extra hepatic disease Biliary atresia Choledochal cyst Spontaneous perforation of bile duct Inspissated bile syndrome Bile duct stenosis Extrinsic compression of the bile duct Intra hepatic disease Idiopathic Idiopathic Neonatal Hepatitis Infectious TORCH infection Bacterial sepsis Enterovirus Echovirus
- 14. Intra hepatic Metabolic Disorder of CHO metabolism Galactosemia Fructosemia Glycogen storage disease Disorder of amino acid metabolism Tyrosinemia Disorder of Lipid Metabolism Niemann-Pick disease Gaucher disease Peroxisomal disorders Zellweger syndrome Endocrine disorders Hypothyroidism Hypopituitarism Miscellaneous metabolic disorders Alpha-1-antitrypsin deficiency Cystic fibrosis Neonatal iron storage disease
- 15. Intra hepatic Toxic TPN–associated cholestasis Drug induced cholestasis Genetic/chromosomal Down’s Syndrome Intrahepatic bile duct paucity Syndromic Alagille syndrome Non-syndromic Cholestatic syndrome PFIC- type 1,2,3 Benign recurrent cholestasis Ischemic Perinatal asphyxia
- 16. Prevalence
- 17. •Neonatal cholestasis: 1 in 2500 live birth. •Biliary atresia: 1 in 10000 to 15000 infants. •Idiopathic neonatal hepatitis: 1 in 5000 to 10000 live birth. (McKiernan PJ et al. Lancet 2000)
- 18. Neonatal Hepatitis 35% Biliary Atresia 26% INH 24% Others 15% (Bazlul Karim AS, Kamal M, Cholestatic jaundice during infancy: experience at a tertiary-care center in Bangladesh, Indian J Gastroenterology, 2005 Mar-Apr;24(2):52-4.)
- 19. Biliary Atresia
- 21. •It is a progressive obliterative inflammatory process involving the bile ducts, resulting in obstruction of bile flow leading to cholestasis, hepatic fibrosis, and eventually cirrhosis. •Average birth weight •Hepatomegaly with firm to hard consistency •Female predominance •No well-documented familial cases
- 24. •Associated congenital anomalies: 1. Spleen- asplenia, polysplenia, double spleen 2. Portal vein- absent, cavernomatous transformation 3. Situs inversus 4. Malrotation of gut 5. Cardiac anomalies 6. Annular pancrease 7. Duodenal, esophageal, jejunal atresia 8. Polycystic kidney 9. Cleft palate
- 27. •It is an ever-shrinking percentage of cases of intrahepatic cholestasis (10-20%) in which the characteristic “giant cell hepatitis” lesion is present on liver biopsy & for which no infectious, genetic, metabolic or anatomic cause is identified. •Generally normal stools or acholic stools with onset at one month-old •Low birth weight •Normal liver on exam or hepatomegaly with normal to firm consistency •Male predominance •Familial cases (15-20%)
- 28. Difference Between BA & INH Characteristics Biliary Atresia Idiopathic Neonatal Hepatitis Sex Female Male Incidence Sporadic Familial (20%) Relation with gestational age Term, AGA Preterm, LBW, SGA Associated anomaly Present Absent Pale stool Persistently Intermittently Jaundice Mild to moderate Moderate to severe jaundice Hepatomegaly Abnormal size & consistency Common Thriving Thriving well Not thriving well
- 29. Biliary Atresia INH GGT Highly raised Mildly raised USG No contraction after meal Contraction of GB before and after meal Hepatobiliary Scintigraphy Dye uptake good but no excretion Less uptake but complete excretion Biopsy Architecture preserved Bile plug Bile ductular proliferation Periportal fibrosis Architecture lost Giant cell transformation
- 30. Choledochal Cyst
- 32. •Localized cystic dilatation of common bile duct is called choledocal cyst. •25% patient present in neonates with prolonged jaundice & cholestasis. •75% present later in childhood with the triad of •Intermittent jaundice •Recurrent abdominal pain •Abdominal mass
- 33. Galactosemia
- 35. •Manifested after ingestion of galactose containing milk. •Here galactose-1-phosphate accumulation occur due to galactose-1-phosphate Uridyl transferase enzyme deficiency. • Present with vomiting, loose motion, persistent jaundice, FTT, hepato-splenomegaly, septicemia, cataract, repeated hypoglycemia and convulsion.
- 37. •Conjugated hyperbilirubinemia resulting from severe jaundice associated hemolysis due to Rh or ABO incompatibility is termed as inspissated bile syndrome.
- 39. •Alpha-1-antitrypsin makes up 90% of alpha-1- globulin fraction •Biopsy also shows accumulation of PAS-positive, diastase-resistant eosinophilic granule. •Varying degrees of fibrosis correlate with disease prognosis.
- 41. •It develops in >50% of infants with birth weight <1000 gram & in <10% of term infants after giving prolonged parenteral feeding. •This may be due to lack of enteral feeding →reduction of gut hormone secretion → reduce bile flow → biliary stasis.
- 42. How to Evaluate a Neonate with Cholestatic Jaundice?
- 43. Cardinal Feature Appears within first 3 months of life •Jaundice •Dark urine •Pale stools •Hepatomegaly
- 44. Goals of Timely Evaluation •Diagnose and treat known medical and/or life- threatening conditions. •Identify disorders amenable to surgical therapy within an appropriate time-frame. •Avoid surgical intervention in intrahepatic diseases.
- 45. From History
- 46. History Taking Age at presentation Within first 3months of life Sex INH is common in male & BA is common in female Prolonged jaundice Persisting >2weeks after birth Pale stool • Persistent BA • Intermittent NHS Dark urine Cholestasis Abdominal distension Organomegaly Lethargy Galactosemia
- 47. Vomiting Galactosemia Pruritus Cholestasis Antenatal • Fever & Rash TORCH • Abortion • Miscarriage Metabolic Natal • Term BA • Pre-term INH Birth weight • SGA/LBW INH • AGA BA
- 48. Postnatal • Onset of jaundice • Poor feeding • Lethargy • Hoarse cry • Constipation • Delayed passage of meconium Hypothyroidism • Convulsion Congenital infection Developmental milestone • Normal BA • Delayed Congenital infection Hypothyroidism Metabolic diseases Family history • Consanguinity Metabolic disease • Sib affected INH
- 50. General Examination Appearance • Irritable, lethargic Congenital infection Metabolic diseases • Dysmorphic Alagille syndrome Down syndrome Hypothyroidism Head • Wide anterior fontanelle Hypothyroidism Down’s syndrome • Seborrheic Dermatitis Histiocytosis X Pallor Jaundice Vital signs • Heart rate • Respiratory rate Increase in infection
- 51. Alimentary System Oral cavity • Cleft lip • Cleft palate BA Abdomen • Pott belly • Umbilical hernia Hypothyroidism • Hepatomegaly (firm) • Splenomegaly BA Congenital infection • Right hypochondriac mass Choledochal cyst • Ascites Late stage (3-4 months later)
- 52. Cardio-pulmonary System Lungs • RTI Down’s syndrome Cystic fibrosis • Tachypnea Infection Heart • Murmur Congenital rubella syndrome Down’s syndrome Alagille syndrome • Endocardial cushion defect Down’s syndrome • TOF Alagille syndrome • Pulmonic stenosis/atresia Alagille syndrome
- 53. Upper limb • Simian crease • Clinodactyly Down’s syndrome Lower limb • Frog leg position • Saber shin • Osteochondritis Congenital syphilis • Sandal gap Down’s syndrome Anthropometry • OFC Microcephaly in congenital infection • Weight and height FTT in INH Congenital infection
- 54. Other Examination Skin survey • Rash Sepsis, TORCH • Dry skin • Dermatitis Hypothyroidism Eye examination • Cataract Galactosemia • Choreo-retinitis CMV Rubella Toxoplasma • Cherry red spots Niemen-Pick disease • Posterior embryotoxon Alagille syndrome • Optic nerve Hypoplasia Pan-hypopituitarism
- 56. Investigations
- 57. A. Initial investigations: To establish cholestasis and determine severity of liver disease 1. Fractionated S. Bilirubin 2. Liver function test •ALT •AST •PT •GGT •ALP •Serum albumin
- 58. B. To detect conditions that require immediate treatment- 1. CBC 2. Urine R/E 3. Cultures of blood & urine 4. Serum T4, TSH 5. To detect metabolic conditions- Urinalysis, urine for non glucose reducing substance 6. TORCHS IgM screening
- 59. C. To differentiate extrahepatic from intrahepatic causes of cholestasis 1. Imaging studies •Ultrasonography •Hepatobiliary scintigraphy 2. Percutaneous liver biopsy 3. Percutaneous trans-hepatic cholangiography
- 60. Ultrasonography USG of whole abdomen, with special attention to HBS, to see: •Absent/Small/non visualized gall bladder •Lack of post prandial contraction of GB. •Triangular cord sign •Choledochal cyst •Choledocholithiasis, biliary sludging •Perforation of bile duct Triangular Cord sign: a cone shaped fibrotic mass cranial to the bifurcation of portal vein.
- 62. Hepatobiliary Scintigraphy Premedication •Phenobarbitone: 5 mg/kg/day for 5 days. Dye used •HIDA: 99m Tc labelled imino-diacetic acid •DISIDA: 99m Tc di-isopropyl IDA •MBRIDA: Mebrophenine IDA
- 63. Normal
- 65. •Depends on hepatocellular function & patency of biliary tract •Sensitive (70%) but not so specific for EHBA •Neonatal Hepatitis: delayed uptake, normal excretion •Biliary Atresia: normal uptake, absent excretion
- 66. Percutaneous Liver Biopsy • Most important investigation in differentiating INH and BA. • Accuracy of 83% to 97%. • Prerequisites: Normal CBC, PT, APTT & USG • Complications: o Bleeding o Bile peritonitis o Pneumothorax
- 67. Findings: Biliary Atresia • Bile ductular proliferation • Bile plugs • Portal/peri-lobular edema and fibrosis • Intact basic lobular architecture
- 68. Findings: Idiopathic Neonatal Hepatitis •Distortion of lobular architecture •Giant cell transformation
- 70. To establish Other Diagnosis •Alpha Feto-protein level (Tyrosinaemia) •S. Alpha-1-antitrypsin level •Sweat chloride (Cystic fibrosis) •Urine/serum amino acids (Metabolic conditions) •X-ray chest (Congenital infection) •X-ray skull and long bones (Congenital infection) •Echo (Congenital infection, Alagille syndrome) •Bone marrow study (Storage disease)
- 72. A. Supportive Management •Parental counseling •Nutritional support •Treatment of pruritus •Choleretics and bile acid-binder
- 73. Nutritional Support •Adequate calories (125% of RDA) and protein •Supplement calories with medium chain triglycerides (Pregestimil, Portagen ) •Treatment and/or prophylaxis for fat-soluble vitamin deficiencies (vitamins A, D, E, and K) •Water soluble vitamins – Twice the RDA •Supplemental calcium and phosphate when bone disease is present
- 74. Dosage Schedule for Lipid Soluble Vitamins •Vitamin A: 25,000-50,000 IU I/M EAM •Vitamin D: 30,000-60,000 IU I/M EAM •Vitamin E: 25 IU/kg oral – Daily •Vitamin K: 1mg/kg I/M – 14 days
- 75. Treatment of Pruritus •As a choleretic •Ursodeoxycholic acid (20-25mg/kg/day) •Phenobarbital (5mg/kg/day) •Naltrexone •Diphenhydramine •Bile acid-binders •cholestyramine (4-8g/day) •Rifampicin (10mg/day) •Terfenadine (1-3mg/kg/day) •Photothearpy with UV/ Infrared rays x 3-10 min/day
- 76. B. Specific management •INH- no specific treatment •BA- Kasai procedure followed by Liver Transplantation •Hypothyroidism- life long thyroxine •Galactosemia- avoid galactose containing diet •Choledochal cyst- excision of the cyst •Congenital infection- according to causative organism •Liver transplantation
- 77. Kasai Procedure •Roux-en-Y porto-enterostomy •Bile flow re-established in 90% if performed prior to 8 weeks of life. •Bile flow re-established in less than 20% if performed after 12 weeks of life. •Complications are ascending cholangitis and re- obstruction as well as failure to re-establish bile flow.
- 79. Liver Transplantation Biliary atresia is the most common indication for transplant. Others are •When initial treatment was given lately/ Portoenterostomy not done •Failed portoenterostomy •Decompensated cirrhosis and end stage liver disease despite initial successful Kasai.
- 81. Prognosis and Outcome Biliary Atresia: • Age(< 8 wks): the single most important determinant in successful management of BA. • Patients undergoing Kasai’s procedure, 80% jaundice free if done before 60 days, as against 25-35% of infants operated later on. (Mieli –Vergani et al. LANCET 1989;1:421-423) • 50-80% will die without LT by 1 yr, if Kasai not done. • 90-100% will die by age 2 yrs • 70-80% require LT after Kasai during 1st 2 decade. • 80-90% long term survival after LT.
- 82. Neonatal Hepatitis: • No indicators to predict prognosis. • In sporadic case, 60-70% disease free survival, <5% severe liver disease or cirrhosis. • In familial case, 20-30% recover.