neonatal cholestasis by dinesh viruvanti

overview of neonatal cholestasis

1. NEONATAL CHOLESTASIS Dr. Viruvanti Dinesh

2. OBJECTIVES Definition Etiology Approach to a case of NC Specific conditions causing NC Management

3. DEFINITION Conjugated hyperbilirubinemia in a neonate : Direct bilirubin concentration > 1.0 mg/dl if TSB < 5.0 mg/dl. Direct bilirubin concentration > 20% of TSB if TSB > 5.0 mg/dl. Neonatal Cholestasis: Conjugated hyperbilirubinemia occurring in a newborn as a consequence of diminished bile flow.

4. INCIDENCE 1 in 2500 infants in the West In India NC constitutes 19% to 33% of all CLDs in children reporting to tertiary care hospitals.* *Neonatal cholestasis: Consensus statement of the pediatric gastroenterology chapter of Indian Academy of Pediatrics 2014.

5. ETIOLOGY

6. ETIOLOGY (n=1008)* DISEASE GROUP CAUSES IN EACH SUBGROUP A. Hepatocellular 53% (n=533) Neonatal hepatitis 43% (n=468) Giant cell hepatitis 64% TORCH infections 22% Sepsis 8% Malaria, UTI etc 6% Metabolic 4% (n=43) Galactosemia 35% A1AT deficiency 33% ?? TPN related 19% Tyrosinemia 7% Storage disorders 4% Hemochromatosis 2% Others 2% (n=22) Inspissated bile plug syndrome Recurrent intrahepatic cholestasis PFIC Hypothyroidism *Neonatal cholestasis: Consensus statement of the pediatric gastroenterology chapter of Indian Academy of Pediatrics, 2014.

7. ETIOLOGY (n=1008)* DISEASE GROUP CAUSES IN EACH SUBGROUP B. Obstructive 38% (n=383) Biliary atresia 34% Choledochal cyst 4% C. Ductal paucity 3% (n=29) Syndromic variety 17% Non- Syndromic variety 83% D. Unknown 6% (n=63) *Neonatal cholestasis: Consensus statement of the pediatric gastroenterology chapter of Indian Academy of Pediatrics, 2014.

8. APPROACH TO A CASE OF NEONATAL CHOLESTASIS

9. HISTORY Gestational age: Prematurity is a risk factor for neonatal hepatitis SGA: Congenital infections Lethargy, decreased oral acceptance: Sepsis and Metabolic. Worsening of general condition after initiation of feeds: Galactosemia Bleeding manifestation: Liver dysfunction Acholic stools: Biliary obstruction Peculiar odour of urine: Tyrosinemia type 1 (cabbage colored urine) Consanguinity: Metabolic disorders(AR disorders) Maternal history: TORCH infections

10. PHYSICAL FINDINGS Assessment of general health: Sick looking- Sepsis, Metabolic, congenital infections Dysmorphic features: Alagille syndrome Head circumference: Microcephaly- TORCH Eye: Chorioretinitis - TORCH, Posterior embryotoxon and drusen : Alagille syndrome Hearing loss: Congenital CMV infection Stool inspection: Acholic stools- Biliary obstruction

11. INVESTIGATIONS The principal diagnostic concern to differentiate hepatocellular diseases from anatomical disorders & diseases which are managed medically from those requiring surgical intervention .

12. INVESTIGATIONS LFT- Serum Bilirubin-Total & Direct To establish cholestasis Prothrombin time/ International normalized ratio ( INR)- Measure severity of liver dysfunction Serum Transaminases -sensitive indicators of hepatocellular injury. lack specificity . Alkaline phosphatase high in biliary obstruction, low specificity Gamma- glutamyl transpeptidase (GGTP) marker of biliary obstruction Elevated - cholestatic disorders Low or normal levels - progressive familial intrahepatic cholestasis (PFIC), disorders of bile acid synthesis

13. 2. ABDOMINAL ULTASONOGRAPHY- - Confirms existence of other surgically treatable conditions like choledochal cyst, inspissated bile plug syndrome & choledocholithiasis In BA, triangular cord sign, abnormal gallbladder morphology (not visualized or length <1.9 cm or lack of smooth/complete echogenic mucosal lining with an indistinct wall or irregular/lobular contour), no contraction of the gallbladder after oral feeding and non-visualized common bile duct (CBD). Screening for biliary atresia by infant stool color card in Taiwan. Pediatrics . 2006

14. 3. HIDA SCAN Radioactive tracer injected into vein in patent’s arm. Tracer travels through bloodstream to liver , where bile producing cells take it up Hepatic uptake of technetium-labeled iminodiacetic acid derivatives is normal in the patients of biliary atresia but excretion in intestine is absent But absence of flow into the intestine does not confirm atresia – can occur in severe hepatitis also. D elay in liver biopsy for it is not justified

15. 4. Exploratory Laparotomy and Direct Cholangiography - The gold standard to determine presence & site of obstruction 5. LIVER BIOPSY Early recognition of BA by liver biopsy avoids unnecessary laparotomy

16. 6. METABOLIC- Galactosemia Urine reducing substance positive, infant on lactose feeds Galactose-1 phosphate uridyl transferase (GALT) enzyme used for confirmation Tyrosinemia measurement of urinary succinylacetone, succinyl acetoacetate or assay of FAH gene is diagnostic Consensus statement of the Pediatric Gastroenterology Chapter, Indian Academy of Pediatrics . Indian Pediatr. 2013

17. 7. CONGENITAL INFECTIONS- In TORCH, CMV is most common -Assay of pp65 antigen and CMV polymerase chain reaction (PCR) are specific & reliable tests 8. Haemochromatosis Raised serum ferritin , uncorrected coagulopathy confirmed by buccal mucosal biopsy

18. Conjugated hyperbilirubinemia in a newborn is always pathological and requires evaluation. Any newborn with jaundice and dark urine staining the diaper with or without pale stools should be strongly suspected to have NC.

19. SPECIFIC CONDITIONS CAUSING NC

20. BILIARY ATRESIA Idiopathic progressive obstructive cholangiopathy of both the intra- and extra-hepatic biliary tree. Leads to chronic cholestasis, progressive fibrosis and eventually biliary cirrhosis. Usually manifests in the first few months of life with Jaundice, pale stools, high colored urine and hepatomegaly Fatal if left untreated in first 2 years of life Incidence: 1:15,000* * McKiernan PJ et al.The frequency and outcome of biliary atresia in the UK and Ireland.Lancet.2000

21. BILIARY ATRESIA

22. BILIARY ATRESIA Jaundice, high colored urine and pale stools Firm hepatomegaly Clinically not sick looking Raised AST and ALT Raised GGT Coagulopathy responsive to Vit -K

23. BILIARY ATRESIA Pale stools. (Sensitivity-89.7%, Specificity-99.9%) 1 Raised GGT (GGT > 300IU/L – specificity of 98.1%) 2 USG: GB: small or not visualized, Triangular cord sign Liver biopsy : Sensitivity 94-97% Triad of 1.Bile ductular proliferation, 2.Fibrosis, 3.Widening of portal tract Laparotomy and intra-operative cholangiography: Gold standard 1.Chen SM et al. Screening for biliary atresia by infant stool color card in Taiwan. Pediatrics. 2006. 2.Tang KS et al. Gamma- glutamyl transferase in the diagnosis of biliary atresia. Acta Paediatr Taiwan.2007.

24. BILIARY ATRESIA Triangular cord sign : It is a triangular or tubular echogenic cord of fibrous tissue seen in the porta hepatis at ultrasonography and is relatively specific in the diagnosis of   biliary atresia . This sign is useful in the evaluation of infants with cholestatic  jaundice, helping for the differential diagnosis of biliary atresia from neonatal hepatitis. It is defined as more than 4 mm thickness of the echogenic anterior wall of the right portal vein (EARPV) measured on a longitudinal ultrasound scan

25. KASAI PORTOENTEROSTOMY - Removal of the atretic extrahepatic tissue and a Roux-en-Y jejunal loop anastomosis to hepatic hilum . -Half of the patients normalize their bilirubin after Kasai’s PE performed within six months - 20% of patients undergoing Kasai’s during infancy survive into adulthood with their native liver Screening and outcomes in biliary atresia: summary of a National Institutes of Health workshop. Hepatology. 2007

26. Outcome of Kasai portoenterostomy (PE) is directly related to age of surgery & expertise of treating unit PE when performed earlier than 60 days of age established adequate bile flow in 64.7% of patients compared with 31.8% when performed later Impact of age at Kasai operation on its results in late childhood and adolescence: a rational basis for biliary atresia screening. Pediatrics. 2009

27. IDIOPATHIC NEONATAL HEPATITIS AKA Giant cell hepatitis No cause identified More common in Preterms . Characterized by lobular disarray, ballooning of hepatocytes, focal hepatic necrosis and Giant cell transformation. Sporadic and Familial types Sporadic: good prognosis, 90% resolution by 1yr of age Familial: relatively poor prognosis. Treatment: Supportive.

28. GALACTOSEMIA AR Deficiency of Galcatose-1-phosphate uridyl transferase (GALT) Accumulation of toxic metabolites in liver, kidney and brain Presentation at 1-2 wks of life, after ingestion of milk. Jaundice, Hepatosplenomegaly , liver dysfunction, hypoglycemia, Renal tubular dysfunction, hypotonia , Nuclear cataract, E.coli sepsis. If not treated, progressive liver damage leading to cirrhosis and death Screening test: Non glucose reducing substance in the urine Diagnostic test: Measurement of GALT activity in RBCs Treatment: Lifelong restriction of galactose or lactose containing foods

29. PFIC Progressive Familial Intrahepatic Cholestasis AR inheritence PFIC-1 : FIC-1 gene mutation, encodes p-type ATPase, involved in aminophospholipid transport, Chr18q PFIC-2: BSEP mutation (AKA SPGP), involved in ATP dependent canalicular bile acid transport, Chr2q PFIC-3: MDR3 mutation , encodes biliary phospholipid transporter

30. PFIC contd.. PFIC-1 : Systemic involvement- Liver, pancreas, diarrhoea . Normal or Low GGT Liver biopsy: Paucity of interlobular bile ducts Supportive care Cirrhosis in first decade of life Liver transplant in second decade decade

31. PFIC contd.. PFIC-2: Liver specific involvement Normal or Low GGT Liver biopsy: Giant cell hepatitis, canalicular and hepatocellular steatosis . Supportive care Worse prognosis Liver transplant in first decade of life

32. PFIC contd.. PFIC-3: Presentation in early adulthood H/O cholestasis of pregnancy in the mother Markedly elevated GGT Liver biopsy may mimic biliary atresia Supportive care, UDCA. Liver transplantation in UDCA unresponsive cases.

33. CONGENITAL CMV INFECTION Petechiae , Hepatosplenomegaly and jaundice are the most common presenting features (60-80% of the cases) Microcephaly with or without cerebral calcifications, IUGR and prematurirty (30-50% of the cases) Important cause of SNHL CMV causes intrahepatic bile duct destruction and paucity. Serum IgM level: unreliable for diagnosis and should not be used. PP65 antigen assay and Urinary CMV PCR are more reliable IV Gancyclovir @ 6mg/kg/day in 2 divided doses for 42days Or Oral Valgancyclovir @ 16mg/kg/dose BD

34. ALAGILLE SYNDROME AD Inheritence JAG-1 gene mutation on Chr12p This gene encodes a ligand for Notch signalling pathway Chronic cholestasis, Characteristic facies ( broad forehead, small pointed chin, saddle nose with bulbous tip, hypertelorism ), Cardiac abnormalities, Ocular abnormalities (posterior embryotoxon , drusen ), Skeletal abnormalities (butterfly vertebrae, curved phalanges, short ulna), Renal abnormalities. Usually present as Neonatal cholestasis. Characteristic facies may not be evident at the neonatal period Liver biopsy: bile duct paucity Supportive management 50% of the cases: Cirrhosis by the end of 1 st decade, Liver transplant.

35. HEREDITARY TYROSINEMIA-1 Mutation in the gene encoding FAA hydrolase

36. HEREDITARY TYROSINEMIA-1 Accumulation of FAA and MAA FAA and MAA get converted to Succinyl acetoacetate, which gets accumulated in liver and kidneys Neonatal cholestasis in 1/3 rd of the cases Vomiting, diarrhoea , cabbage like odour , hepatomegaly, coagulopathy, hypoglycemia Acute liver failure Cirrhosis 1/3 rd of the cases which survive beyond 10 years develop HCC

37. HEREDITARY TYROSINEMIA-1 Screening : high Alpha-fetoprotein Confirmation: Increased urinary succinylacetone Treatment: Dietary restriction of Phenylalanine and tyrosine Nitisinone (NTBT/ Orfadin ): inhibitor of PHPP Dioxygenase . Started at 1mg/kg/day PO in 2 divided doses may be increased to 1.5mg/kg/day Liver transplant: failure of pharmacotherapy or when HCC is suspected.

38. NEONATAL HEMOCHROMATOSIS Newly recognized and rare syndrome ?? Gestational alloimmune disease Iron deposition in liver, acinar cells of pancreas, minor salivary glands, proximal renal tubules, adrenal cortex, thyroid and myocardium ALF/ congenital cirrhosis Oligohydramnios , placental oedema , IUGR Hyperbilirubinemia , Coagulopathy, Hypoalbuminemia , Ascitis and Splenomegaly

39. NEONATAL HEMOCHROMATOSIS Low to normal transaminases Hypoalbuminemia , thrombocytopenia Screening: High ferritin, Low serum transferrin, high transferrin saturation Confirmation: Lip biopsy showing Iron deposition in minor salivary glands or MRI pancreas showing low signal intensity on T2W

40. NEONATAL HEMOCHROMATOSIS TREATMENT : IVIG DVET Antioxidant cocktail: N-acetyl cysteine: 140 mg/kg PO, then 70mg/kg 4 hrly for 19 doses Selenium: 2-3 mcg/kg/day IV over 24hrs Alpha tocopheryl PEG succinate: 20-30U/kg/day PO PGE1: 0.4-0.6 mcg/kg/ hr IV for 2-3 wks Desferrioxamine : 30mg/kg/day IV infused over 8hrs, until Ferritin levels < 500mcg/L At-risk pregnancies(previous child Neonatal hemochromatosis) : IVIG at 1g/kg IV given weekly to the pregnant woman starting from 18 th week of gestation. Liver transplant if no response

41. MANAGEMENT

42. GENERAL MANAGEMENT Nutritional support : NC children are underweight and will need nutritional support. Calorie requirement is 125% of the RDA Breast feeding should be encouraged and 1-2ml/kg/day MCT oil should be administered in 2-4 divided dosed in EBM

43. PRURITIS: UDCA – 20mg/kg/day Rifampicin - 5-10mg/kg/day Phenobarbitone - 5-10mg/kg/day

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