Neonatal cholestasis syndrome

specially for postt graduates in pediatrics..... based on nelson, iap and aap guidelines

1. Neonatal Cholestasis Syndrome Dr. Gaurav Mukhija ( JR II) Moderator: Dr. Preeti Lata Rai Department of Pediatrics

2. DEFINITION Neonatal cholestasis is defined biochemically as prolonged elevation of the serum levels of conjugated bilirubin beyond the 1st 14 days of life. Jaundice that appears after 2 wk of age or continues to progress or does not resolve at this time should be evaluated Nelson Textbook of Pediatrics. Edition 20

3. Neonatal cholestasis is defined as conjugated hyperbilirubinemia occurring in the newborn as a consequence of diminished bile flow. Conjugated Hyperbilirubinemia in a neonate is defined as a serum direct/conjugated bilirubin concentration >1.0 mg/ dL if the total serum bilirubin (TSB) is 5.0 mg/ dL or >20% of TSB if the TSB is >5.0 mg/ dL NASPGHAN Definition IAP Recommendations

4. Incidence Western epidemiology: Affects one in 2500 live births India: 19% to 33% of all chronic liver diseases Hepatocellular causes - 45% to 69% Obstructive causes - 19% to 55% Idiopathic - 20 to 30% IAP Recommendations NASPGHAN

5. ETIOLOGIC PROFILE OF NEONATAL CHOLESTASIS IN INDIA Etiologic Factor N-1008* (%) N-420#(%) Obstructive causes Biliary atresia 34 30 Choledochal cysts 4 5 Hepatocellular causes Infections 17 18 Metabolic causes 4 12 Miscellaneous 2 3 Unknown etiology 30 31 Ductal paucity 3 1 Undifferentiated 6 1.2 *Based on cumulative data from eight tertiary care centers #Data from the largest single series IAP Recommendations

6. 6 Nelson Textbook of Pediatrics. Edition 20

7. 7 Extra Hepatic Cholestasis Obstruction Biliary atresia Biliary cysts Inspissated bile/plug syndrome Gallstones or biliary sludge Tumors Neonatal sclerosing cholangitis Up to date. Causes of neonatal cholestasis

8. Intrahepatic Cholestasis A. Disorders of membrane transport and secretion 1. Disorders of canalicular secretion a. Bile acid transport: Persistent, progressive (PFIC type 2) Recurrent, benign (BRIC type 2) b. Phospholipid transport: MDR3 deficiency (PFIC type 3) c. Ion transport: cystic fibrosis (CFTR) 2. Complex or multiorgan disorders a. FIC1 deficiency Persistent, progressive (PFIC type 1, Byler disease) Recurrent, benign (BRIC type 1) b. Neonatal sclerosing cholangitis (CLDN1) 8 Nelson Textbook of Pediatrics. Edition 20

9. 9 Intrahepatic Cholestasis B. Disorders of bile acid biosynthesis and conjugation 1 . 3-oxo Δ-4- steroid 5 β- reductase deficiency 2. 3 β- hydroxy-5-C27-steroid dehydrogenase/ isomerase deficiency 3. Oxysterol 7 α- hydroxylase deficiency 4. Bile acid-coenzyme A (CoA) ligase deficiency 5 . BAAT deficiency (familial hypercholanemia ) C. Disorders of embryogenesis 1. Alagille syndrome (Jagged1 defect, syndromic bile duct paucity) 2 . Ductal plate malformation (ARPKD, ADPLD, Caroli disease) D. Unclassified (idiopathic “neonatal hepatitis”): mechanism unknown Nelson Textbook of Pediatrics. Edition 20

10. Intrahepatic Cholestasis E. Infection Bacterial Viral F. Metabolic Galactosemia Tyrosinemia Niemann Pick Disease (Type c) Progressive Familial Intrahepatic Cholestasis Alpha 1 antitrypsin deficiency G. Alloimmune Gestational alloimmune liver disease (Neonatal Haemochromatosis ) Up to date. Causes of neonatal cholestasis

11. Intrahepatic Cholestasis Idiopathic neonatal hepatitis: either a sporadic or a familial form with onset at 1 month Cause - Unknown Male predominance Sporadic form – presumably have a specific yet undefined metabolic or viral disease. Familial forms – (15-20%) presumably reflect a genetic or metabolic aberration 11 Nelson Textbook of Pediatrics. Edition 20 NASPGHAN

12. Aagenaes syndrome (idiopathic familial intrahepatic cholestasis associated with lymphedema of the lower extremities) Locus: Mapped on chromosome 15q Cause of relationship: D ecreased hepatic lymph flow or hepatic lymphatic hypoplasia Presentation: Episodic cholestasis with elevation of serum aminotransferase, alkaline phosphatase, and bile acids . Between episodes, the patients are usually asymptomatic and biochemical indices improve . Prognosis: >50 % can expect a normal life span. 12 Nelson Textbook of Pediatrics. Edition 20

13. Zellweger (cerebrohepatorenal) syndrome (rare autosomal recessive genetic disorder) Incidence: 1 in 100,000 births , usually fatal in 6-12 mo. Presentation: Severe , generalized hypotonia and markedly impaired neurologic function with psychomotor retardation. abnormal head shape and unusual facies marked by progressive degeneration of the liver and kidneys hepatomegaly , renal cortical cysts stippled calcifications of the patella and greater trochanter ocular abnormalities Ultra structural examination: Hepatic cells show an absence of peroxisomes MRI performed in the 3rd trimester: prenatal diagnosis 13

14. Neonatal iron storage disease ( neonatal hemochromatosis) : Rapidly progressive disease characterized by: increased iron deposition in the liver, heart, and endocrine organs reticuloendothelial system iron stores not increased Cause: Familial Alloimmune disorder Presentation: multiorgan failure and shortened survival Laboratory findings: Hypoglycemia , H yperbilirubinemia , Hypoalbuminemia Elevated ferritin and profound hypoprothrombinemia. Serum aminotransferase levels may be high initially but normalize with the progression of the disease . 14 Nelson Textbook of Pediatrics. Edition 20

15. Confirmation of Diagnosis : Buccal mucosal biopsy or MRI demonstrating extra hepatic siderosis. Prognosis: Poor, liver transplantation can be curative Prevention in at risk Pregnancies: (Maternal treatment ) Beginning gestational age 18 wk High-dose IVIG (1 g/kg) once weekly during gestation After birth, affected neonates: Exchange transfusions IVIG (1 g/kg) stat Improves survival and reduces the need for liver transplantation. 15 Nelson Textbook of Pediatrics. Edition 20

16. Progressive Familial Intrahepatic Cholestasis 16 Nelson Textbook of Pediatrics. Edition 20

17. Disorders of Embryogenesis Alagille syndrome (arteriohepatic dysplasia): Most common syndrome with intrahepatic bile duct paucity Clinical manifestations: unusual facial characteristics (broad forehead, deep-set, widely spaced eyes, long, straight nose, underdeveloped mandible) ocular abnormalities (post. embryotoxon, microcornea, optic disk drusen, shallow ant. chamber) cardiovascular abnormalities (peripheral pulmonic stenosis, TOF, pulmonary atresia, VSD, ASD, coA) vertebral defects (butterfly vertebrae, fused vertebrae, spina bifida occulta, rib anomalies) tubulointerstitial nephropathy Other findings: short stature, pancreatic insufficiency, and defective spermatogenesis 17 Nelson Textbook of Pediatrics. Edition 20

18. Biopsy : In early life: inflammatory process involving the bile ducts Subsequent biopsy: subsidence of the inflammation, residual reduction in the number and diameter of bile ducts Serial assessment of hepatic histology often suggests progressive destruction of bile ducts Prognosis: If treated: Survival is good If untreated: Pruritus , xanthomas Marked elevated serum cholesterol levels Neurologic complications of vitamin E deficiency Association: Mutations in human Jagged1 gene (JAG1), (encodes a ligand for the notch receptor) 18 Nelson Textbook of Pediatrics. Edition 20

19. Caroli’s Disease (Type V choledochal cyst): Congenital, non familial, multiple, irregular dilatations of intrahepatic ducts with stenotic segments in between Associated with congenital Hepatic Fibrosis and Medullary Sponge Kidney Complications: Recurrent cholangitis Stones in Biliary Tree Portal Hypertension 19 Bailey & Love. Short Practice of S urgery. Edition 26

20. Obstructive Causes 20

21. BILIARY ATRESIA (noncystic obliterative cholangiopathy) 21 Nelson Textbook of Pediatrics. Edition 20

22. PATHOGENESIS 22 Nelson Textbook of Pediatrics. Edition 20

23. Presentation: Generally acholic stools with onset at about 2 weeks old Average birth weight Hepatomegaly with firm to hard consistency Female predominance No well-documented familial cases Increased incidence of polysplenia syndrome and intra-abdominal vascular anomalies Diagnosis: Normal uptake on radionucleotide scan with absent excretion Biopsy shows bile duct proliferation, bile plugs, portal or perilobular fibrosis and edema, and intact lobular structure 23 Nelson Textbook of Pediatrics. Edition 20 NASPGHAN

24. 24 Ultrasonography : triangular cord sign, which represents a cone-shaped fibrotic mass cranial to the bifurcation of the portal vein Nelson Textbook of Pediatrics. Edition 20

25. Specific Tests in the Evaluation of Patients with Suspected Neonatal Cholestasis 25 Nelson Textbook of Pediatrics. Edition 20

26. Laboratory Urgent investigations: CBC LFT: Total and direct bilirubin, SGOT, SGPT, alkaline phosphatase, GGT, PT/ apTT Urine for reducing sugars Electrolytes Blood culture. Urine culture, routine microscopy RBS (pre-feed) 26

27. Diagnostic algorithm for management of neonatal cholestasis IAP Recommendations

28. Radiological Evaluation Ultrasonography Excludes choledochal cyst, dilated CBD. Findings s/o BA: GB length (<1.5cm long/small lumen) GB contraction [CI<86% ± 18% (mean ± SD) in 6-week-old infants and 67% ± 42% in 4-month-old infants] Triangular cord sign: 3 mm or more thick ( Kanegawa et al. AJR 2003;181:1387) 28

29. HIDA Hepatobiliary Scintigraphy : Tc labelled IDA dyes used. Depends on hepatocellular function & patency of biliary tract. Neonatal Hepatitis: delayed uptake, n. excretion. Biliary Atresia: normal uptake, absent excretion. Sensitive (97%) not specific (80%) for EHBA 29 Nelson Textbook of Pediatrics. Edition 20

30. 30 LIVER BIOPSY: Most imp. Inv in differentiating NH and BA Accuracy - 83% to 97%. Prerequisites: Normal PT & platelet count Complications: Bleeding Bile peritonitis Pneumothorax

31. 31 Biopsy in neonatal hepatitis: severe, diffuse hepatocellular disease distortion of lobular architecture marked infiltration with inflammatory cells focal hepatocellular necrosis Marked irregularities in size of hepatocytes Bile canaliculi reduced Kupffer cells swollen Relative absence of bile duct proliferation Nelson Textbook of Pediatrics. Edition 20

32. Biopsy in Biliary Atresia: Proliferation of proximal ductules Bile plugs Portal tract lymphatics and arterioles dilated with edema and fibrosis Secondary paucity of portal bile ducts Intracellular and canalicular cholestasis Basic hepatic lobular architecture intact 32 Nelson Textbook of Pediatrics. Edition 20

33. Indications for laparotomy Acholic stools & liver biopsy - BA Biopsy equivocal but acholic stools, intrahepatic causes r/o, non excreting HIDA Biopsy equivocal,acholic stools, baby 7 wks - lap and peroperative cholangiogram Biopsy equivocal, acholic stools, ERCP atresia IAP Recommendations NASPGHAN

34. Medical Management 34 Nelson Textbook of Pediatrics. Edition 20

35. Diagnostic algorithm to help in the management of neonatal cholestasis 35 IAP Recommendations

36. KASAI PROCEDURE Performed for biliary atresia that is not surgically correctable with excision of a distal atretic segment. Roux-en-Y portoenterostomy Transection of the porta hepatis with anastomosis of bowel to the proximal surface of the transection . Progressive obliteration and cirrhosis - if flow not rapidly established in the 1st mo of life Success Rate: Successful If microscopic channels of patency > 150 μm in diameter 90% if performed prior to 8 weeks-old <20% if performed after 12 weeks-old 36 Nelson Textbook of Pediatrics. Edition 20

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38. Liver Transplantation : standard therapy for decompensated cirrhosis due to any cause 3 mo Post Kasai’s PE if bilirubin remains >6 mg/ dL Babies with BA who present with decompensated cirrhosis low albumin, prolonged INR ascites Survival: 5 year survival rates of 98% 10year survival rates of 90% 38 IAP Recommendations

39. Thank You..!! 39