NEONATAL JAUNDICE(liver disorder IN NEONATES).pptx

Neonatal jaundice

1. NEONATAL JAUNDICE Priyanka Medhi

2. FRAMEWORK Billirubin Metabolism Special characteristic in neonates Indirect and direct hyperbilirubinemia Cholestatic jaundice

3. METABOLISM OF BILIRUBIN

4. IN A NEONATE Increased RBC’s Shortened RBC lifespan Immature hepatic uptake & conjugation Increased enterohepatic circulation

5. INDIRECT HYPERBILIRUBINEMIA

6. PHYSIOLOGIC HYPERBILIRUBINEMIA The serum UCB level of most newborn infants rises to >2 mgldL in the first week of life This level usually rises in full-term infants to a peak of 6 to 8 mg/ dL by 3 to 5 days of age and then falls. A rise to 12 mg/ dL is in the physiologic range In premature infants, the peak may be 10 to 12 mg/ dL on the fifth day of life, possibly rising > 15 mg/ dL without any specific abnormality of bilirubin metabolism

7. NONPHYSIOLOGIC HYPERBILIRUBINEMIA The following situations suggest non physiologic hyperbilirubinemia and require evaluation: Onset of jaundice before 24 hours of age Any elevation of serum bilirubin that requires phototherapy A rise in serum bilirubin levels of >0.2 mg/ dL /hour Signs of underlying illness in any infant Jaundice persisting after 8 days in a term infant or after 14 days in a premature infant

8. Important Risk Factors for Severe Hyperbilirubinemia Predischarge TSB or TcB measurement in high-risk or high-intermediate zone Lower gestational age Exclusive breastfeeding, especially if it is not going well and infant has excessive weight loss Jaundice in the first 24 hours of age lsoimmune or other hemolytic disease Previous sibling with jaundice Cephalohematoma or significant bruising East Asian race

9. BREASTFEEDING JAUNDICE Starvation jaundice- cycle of decreased demand and supply After day 3 of life compared to formula-fed infants The main factor is a decreased intake of milk that leads to slower bilirubin elimination and increased enterohepatic circulation

10. Breast milk jaundice Is of late onset By day 4 the bilirubin level continues to rise If breastfeeding is continued, the levels stay elevated and then fall by 4 to 12 weeks of age If breastfeeding is stopped, the bilirubin level will fall rapidly in 48 hours These infants show good weight gain, have normal liver function test (LFT) results, and show no evidence of hemolysis Recurrence rate of 70% in future pregnancies The mechanism: an unidentified factor interfering with bilirubin metabolism

11. BILIRUBIN TOXICITY Acute bilirubin encephalopathy is the clinical manifestation of bilirubin toxicity seen in the neonatal period Early phase: Hypotonia, lethargy, high-pitched cry, and poor suck Intermediate phase: Hypertonia of extensor muscles with iirritability , fever, and seizures. All infants who survive this phase develop chronic bilirubin encephalopathy Advanced phase: Pronounced opisthotonus , shrill cry, apnea, seizures, coma, and death Kernicterus: pathologic diagnosis. Chronic and permanent sequelae of bilirubin toxicity

12. MANAGEMENT Early identification Hydration Phototherapy Exchange transfusion

13. PHOTOTHERAPY When the level of bilirubin may be hazardous to the infant Prophylactic phototherapy is indicated in ELBW infants or severely bruised infants, when the TSB is anticipated to increase rapidly In hemolytic disease of the newborn, phototherapy is started immediately during the wait for exchange transfusion

14. EXCHANGE TRANSFUSION Removes partially hemolyzed and antibody- coated RBCs, as well as unattached antibodies, and replaces them with donor RBCs, lacking the sensitizing antigen As bilirubin is removed from the plasma, extravascular bilirubin will rapidly equilibrate and bind to the albumin in the exchanged blood Within half an hour after the exchange, bilirubin levels return to 60% of pre-exchange levels, representing the rapid influx of bilirubin in to the vascular space

15. NEONATAL CHOLESTASIS

16. Prolonged elevation of conjugated bilirubin beyond 1 st 14 days of life Serum direct bilirubin > 1mg/dl if TSB <5mg/dl or > 20% of TSB if TSB >5mg/dl Any newborn with jaundice and dark yellow urine with or without pale stools should be strongly suspected to have NC

17. INFECTIONS Generalized bacterial sepsis Viral hepatitis Hepatitides A, B, C, D, E Cytomegalovirus Rubella virus Herpesviruses: Herpes simplex, HHV 6/7 Varicella virus Coxsackie virus Echovirus Reovirus type 3 Parvovirus B19 HIV Adenovirus Others • Toxoplasmosis • Syphilis • Tuberculosis • Listeriosis • Urinary tract infection

18. METABOLIC Disorders of amino acid metabolism • Tyrosinemia Disorders of lipid metabolism • Wolman disease • Niemann -Pick disease (type C) • Gaucher disease Cholesterol ester storage disease Disorders of carbohydrate metabolism • Galactosemia • Fructosemia • Glycogenosis IV Disorders of bile acid biosynthesis Other metabolic defects • α1- Antitrypsin deficiency • Cystic fibrosis • Hypopituitarism • Hypothyroidism • Zellweger ( cerebrohepatorenal ) syndrome • Wilson disease • Neonatal iron storage disease • Indian childhood cirrhosis/infantile copper overload • Congenital disorders of glycosylation

19. INTRAHEPATIC CHOLESTASIS SYNDROMES “ Idiopathic” neonatal hepatitis Alagille syndrome Intrahepatic cholestasis (progressive familial intrahepatic cholestasis [PFIC]) • FIC-1 deficiency • BSEP (bile salt export pump) deficiency • MDR3 deficiency Familial benign recurrent cholestasis associated with lymphedema ( Aagenaes syndrome) ARC (arthrogryposis, renal dysfunction, and cholestasis) syndrome Caroli disease (cystic dilation of intrahepatic ducts)

20. CHROMOSOMAL CONDITION Trisomies 17, 18, 21 EXTRAHEPATIC DISEASES Biliary atresia Sclerosing cholangitis Bile duct stricture/stenosis Choledochal – pancreaticoductal junction anomaly Spontaneous perforation of the bile duct Choledochal cyst Mass (neoplasia, stone) Bile/mucous plug (“ inspissated bile”)

21. MISCELLANEOUS Associated with enteritis Associated with intestinal obstruction Neonatal lupus erythematosus Myeloproliferative disease ( trisomy 21) Hemophagocytic lymphohistiocytosis (HLH) COACH syndrome (coloboma, oligophrenia, ataxia, cerebellar vermis hypoplasia, hepatic fibrosis) Shock and hypoperfusion Cholangiocyte cilia defects

22. EXTRATRAHEPATIC CHOLESTASIS

23. BILIARY ATRESIA

24. Most common surgically treatable cause of cholestasis in newborns Destructive inflammatory obliterative cholangiopathy of neonates that affects varying lengths of both intrahepatic and extrahepatic bile ducts If not corrected leads to secondary biliary cirrhosis ISOLATED BILIARY ATRESIA ASSOCIATED WITH  OTHER CONGENITAL ANOMALIES Postnatal form Fetal /embryonic form Accounts for 65-90% of cases Accounts for 10-35% of cases

25. ULTRASONOGRAPHY In biliary atresia it may demonstrate absence of the gallbladder and no dilatation of the biliary tree gallbladder length less than 1.9 cm a thin or indistinct gallbladder wall an irregular and lobular contour HEPATOBILIARY SCINTISCANNING Intestinal excretion of radiolabel confirms patency of the extrahepatic biliary system If time allows, all jaundiced infants undergoing hepatobiliary scintigraphy should be pretreated with phenobarbital (5 mg/kg/day) for 5 days before the study Reliability of the scintiscan is diminished at very high conjugated bilirubin levels (>20 mg/ dL )

26. OTHERS MRCP incomplete visualization of the extrahepatic biliary system sensitivity and specificity of 90% and 77%, respectively ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY (ERCP) PERCUTANEOUS LIVER BIOPSY most accurate nonsurgical diagnostic test differentiate between obstructive and hepatocellular causes of cholestasis with 90% sensitivity and specificity for biliary atresia bile ductular proliferation in the liver biopsy is considered diagnostic for biliary atresia INTRAOPERATIVE CHOLANGIOGRAPHY demonstrates anatomy and patency of the extrahepatic biliary tract

27. MANAGEMENT Surgical intervention is the only mechanism for a definitive diagnosis (intraoperative cholangiogram ) therapy (Kasai portoenterostomy ) Preoperative oral supplementation with fat-soluble vitamins or an intramuscular injection of vitamin K (1 mg) During the operation, the fibrotic biliary tract remnant is identified, and the patency of the biliary system is assessed In most cases of atresia, dissection into the porta hepatis and creation of a Roux- en -Y anastomosis with a 35-cm to 40-cm retrocolic jejunal segment is the procedure of choice

28. POSTOPERATIVE MEDICAL REGIMEN AFTER HEPATIC PORTOENTEROSTOMY Ursodiol:10-15 mg/kg/dose BID day Trimethoprim-Sulfamethoxazole: 2.5 mg/kg/day based on Trimethoprim component dosing Vitamins Prednisone: 2 mg/kg/day and taper over 6 weeks

29. IMPAIRMENT MANAGEMENT (NASPGHAN) MANAGEMENT IAP Malabsorption Medium chain TGs given Medium chain TGs given,breast feeding cont, 200 Kcal/kg/d,1-2 gm protein/kg/d Fat soluble vit malabsorption Vit A deficiency 10,000-15,000 IU/d AQUASOL-A 50,000 IU i.m –at diagnosis 10,000 IU monthly Vit E deficiency 50-400 IU/d; oral alfa tocopherol 50-200 mg/d orally Vit D deficiency 5000 -8000IU/d of D2 3-5 mcg/kg/d of 25 HCC 30,000 IU i.m –at diagnosis & monthly Vit K deficiency 2.5 -5.0 mg alternate day as water soluble derivative of menadione . 5 mg/d im x3 days,5 mg wkly. Perform PT monthly. Microutrient deficiency Ca, P, Zn supplementation Ca, P, Zn supplementation Water soluble Vit def. 2 times RDA supplementation 2-5 times RDA supplementation

30. Complications Cholangitis 33 to 6 0% of patients following portoenterostomy Treat with I/V fluids, broad spectrum antibiotics, choleretic agents and steroids Anastomosis failure Portal hypertension occur in more than 34-76% of infants eventually requiring liver transplant Progressive fibrosis and biliary cirrhosis Hepatocellular carcinoma

31. CHOLEDOCHAL CYSTS Choledochal cysts are congenital dilatations of the common bile duct that can cause progressive biliary obstruction and biliary cirrhosis Pathogenesis : reflux of pancreatic enzymes into the common bile duct, causing inflammation, localized weakness, and dilation of the duct C/F - Cholestatic jaundice with abdominal mass; severe liver dysfunction including ascites and coagulopathy Treatment of choice is primary excision of the cyst and a Roux en - Y choledochojejunostomy

32. Type Configuration Biliary Tract Incidence Treatment Extrahepatic Intra-hepatic I A Saccular Most or all >50 % to 75 % Excision of involved portion of extrahepatic tract + Roux-en-Y Hepato-jejunostomy B Limited C Fusiform Most or all II Isolated Diverticulum Of CBD 5 % Excision with closure of defect over T-tube or same as above III Intraduodenal Part of CBD 5 % < 3 cm = endoscopic sphincterotomy > 3cm = excision via transduodenal approach CHOLEDOCHOCELE TODANI(1977) CLASSIFICATION

33. Type Configuration Biliary Tract Incidence Treatment Extrahepatic Intra-hepatic IV A Multiple Dilations 30 % Extrahepatic Excision of involved portion + Roux-en-Y Hepato-jejunostomy Intrahepatic Resection of segment or lobe Or transplantation B V 1 % VI Isolated Cyst of Cystic Duct Extremely Rare Cystic Duct ligation near CBD CAROLI DISEASE (1958) NOT part of Todani Classification

34. INTRAHEPATIC CHOLESTASIS

35. Subtypes oF Intrahepatic Cholestasis Disorders of bile acid biosynthesis and conjugation Disorders of membrane transport and secretion Disorders of embryogenesis Unclassified (idiopathic “neonatal hepatitis”)

36. BILE ACID BIOSYNTHESIS

37. Disorders of bile acid biosynthesis and conjugation 3β- hydroxy-5-C27-steroid dehydrogenase/isomerase deficiency (HSD3B7) 3-oxo Δ-4- steroid 5 β- reductase deficiency (AKR1D1) Oxysterol 7 α- hydroxylase deficiency Bile acid-coenzyme A (CoA) ligase deficiency BAAT deficiency (familial hypercholanemia )

38. Deficiency of 3 β- hydroxy - Δ5- C27-steroid oxidoreductase (3β-HSD) The 2nd step in bile acid biosynthesis Causes progressive familial intrahepatic cholestasis C/F - -jaundice with increased aminotransferase levels, hepatomegaly; GGT levels are normal Histology - ranging from giant cell hepatitis to chronic hepatitis Diagnosis- by mass spectrometry detection of C24 bile acids in urine, which retain the 3β-hydroxy-Δ5 structure Management - Primary bile acid therapy

39. Deficiency of Δ4-3-oxosteroid-5β reductase (AKR1D1) The 4th step in the pathway of cholesterol degradation to the primary bile acids C/F - cholestasis and liver failure developing shortly after birth, with coagulopathy and metabolic liver injury resembling tyrosinemia Hepatic histology- lobular disarray with giant cells, pseudoacinar transformation, and canalicular bile stasis. Diagnosis- Mass spectrometry is required to document increased urinary bile acid excretion and the predominance of oxo-hydroxy and oxo-dihydroxy cholenoic acids Treatment: cholic acid and ursodeoxycholic acid

40. Bile acid– CoA Ligase deficiency & Bile acid – CoA:aminoacid N-acetyl transferase deficiency (BAAT) Conjugation with the amino acids glycine and taurine is the final step in bile acid synthesis Two enzymes catalyze the amidation of bile acids first reaction, a CoA thioester is formed by the rate-limiting Bile acid-CoA Ligase Other reaction coupling of glycine or taurine and is catalyzed by a cytosolic Bile acid–CoA: amino acid N-acyltransferase C/F - conjugated hyperbilirubinemia, growth failure, or fat-soluble vitamin deficiency Diagnosis - identified with mutation of the bile acid–CoA ligase gene Management - Glycocholic acid

41. TRANSPORT & SECRETION OF BILE ACID

42. PHYSIOLOGY OF TRANSPORT Albumin-bound bile acids that reach the liver mainly via the portal blood are efficiently removed by transport proteins located at the sinusoidal membrane of hepatocytes In the overall process of bile acid transport from blood to bile, canalicular secretion is the limiting step

43. DISORDERS OF MEMBRANE TRANSPORT AND SECRETION Disorders of canalicular secretion a. Bile acid transport: BSEP deficiency Persistent, progressive (PFIC type 2) Recurrent, benign (BRIC type 2) b . Phospholipid transport:MDR3 deficiency (PFIC type 3) c. Ion transport: cystic fibrosis (CFTR) Complex or multiorgan disorders a. FIC1 deficiency Persistent, progressive (PFIC type 1, Byler disease ) Recurrent, benign (BRIC type 1) b. Neonatal sclerosing cholangitis (CLDN1) c. Arthrogryposis-renal dysfunction-cholestasis syndrome (VPS33B)

44. Progressive familial intrahepatic cholestasis type 1 (PFIC 1) (formerly known as Byler disease) Present with steatorrhea, pruritus, vitamin D–deficient rickets, gradually developing cirrhosis, and low/normal γ- glutamyl transpeptidase (GGT) levels Locus chromosome 18q12 defect in the gene for F1C1 F1C1 is P type ATPase that facilitating the transfer of phosphotydyl serine(role in intestinal bile absorption); defective F1C1 might a result intrahepatic cholestasis Nonsense, frame shift, and deletional mutations cause PFIC type 1 Missense and split-type mutations result in BRIC type I

45. PFIC type 2 (BSEP deficiency) Is mapped to chromosome 2q24 and the disease results from defects in the canalicular adenosine triphosphate–dependent bile acid transporter BSEP(ABCB11) The progressive liver disease results from accumulation of bile acids secondary to reduction in canalicular bile acid secretion Mutation in ABC11 is also described in another disorder, BRIC type2, characterized by recurrent bouts of cholestasis

46. PFIC type 3 (MDR3 disease) Results from defects in canalicular phospholipids flippase , MDR3 (ABCB4) , which results in deficient translocation of phosphatidylcholine across the canalicular membrane Mothers who are heterozygous for this gene can develop intrahepatic cholestasis during pregnancy GGT is high

47. DISORDERS OF EMBRYOGENESIS

48. Disorders of embryogenesis Alagille syndrome (Jagged1 defect causing syndromic bile duct paucity) Ductal plate malformation (ARPKD, ADPLD, Caroli disease)

49. Alagille syndrome ( arteriohepatic dysplasia) Facial characteristics: broad forehead; deep-set, widely spaced eyes; long, straight nose; and an underdeveloped mandible Ocular abnormalities: posterior embryotoxon, microcornea, optic disk drusen , shallow anterior chamber Cardiovascular abnormalities usually peripheral pulmonic stenosis, sometimes tetralogy of Fallot , pulmonary atresia, VSD, ASD, aortic coarctation Vertebral defects butterfly vertebrae, fused vertebrae, spina bifida occulta , rib anomalies Tubulointerstitial nephropathy Pancreatic insufficiency Defective spermatogenesis

50. IDIOPATHIC NEONATAL HEPATITIS Idiopathic neonatal hepatitis is a disease of unknown cause sporadic familial form Metabolic /viral disease Genetic /metabolic aberration

51. Aagenaes syndrome Idiopathic familial intrahepatic cholestasis associated with lymphedema of the lower extremities May be attributable to decreased hepatic lymph flow or hepatic lymphatic hypoplasia Present with episodic cholestasis with elevation of serum aminotransferases, alkaline phosphatase and bile acids The locus: chromosome 15q

52. Zellweger syndrome ( cerebrohepatorenal ) Is a rare autosomal recessive genetic disorder marked by progressive degeneration of the liver and kidneys usually fatal in 6-12 mo Presents with generalized hypotonia and markedly impaired neurologic function with psychomotor retardation Abnormal head shape and down’s like facies , hepatomegaly, renal cortical cysts, stippled calcifications of the patellas and greater trochanter with ocular abnormalities Hepatic cells has absence of peroxisomes

53. Neonatal iron storage disease (neonatal hemochromatosis) Increased iron deposition in the liver, heart, and endocrine organs with multiorgan failure Alloimmune disorder with maternal antibodies directed against the fetal liver C/F- hypoglycemia , hyperbilirubinemia, hypoalbuminemia, elevated ferritin and profound hypoprothrombinemia Diagnosis: MRI demonstrating extrahepatic siderosis Confirmed by buccal mucosal biopsy The prognosis is poor; liver transplantation can be curative

54. Management

55. Investigations CBC with PS LFT: Total and direct bilirubin, SGOT, SGPT, alkaline phosphatase, GGT, PT/PTT Electrolytes Blood culture Urine culture, urine reducing substances, urine routine microscopy RBS (pre-feed)

56. NEXT LEVEL INVESTIGATIONS Ophthalmologic examination Serum/ urine bile acid levels DCT and coomb’s test Cholesterol, triglycerides, S. iron and ferritin levels TORCH screen Sweat chloride HBsAG , HIV in mother and infant T4, TSH Enzyme essays

57. Ultrasonography HIDA scan MRCP ERCP Duodenal intubation Percutaneous transhepatic cholangiography Percutaneous liver biopsy Exploratory laparotomy with intraoperative cholangiogram

58. Sonogram illustrates method of measuring gallbladder length ( long arrow ) and width ( short arrow ). These measurements were obtained using maximal longitudinal image

59. ERCP image

60. intra- and extrahepatic (c) biliary dilatation, as well as focal intrahepatic biliary cystic dilatations (arrows) g = gallbladder

61. Percutaneous Transhepatic Cholangiography

62. MANAGEMENT MEDICAL Nutrition UDCA Vitamin supplementation SURGICAL Kasai’s Resection of cysts Transplant

63. Reference 20 th Edition Nelson 7 th Edition Cloherty 9 th Edition Avery Articles

64. THANK YOU!