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Neonatal cholestasis
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Neonatal cholestasis

  2. 2. OBJECTIVESOBJECTIVES  To know when cholestatic liver disease should be excluded in the diagnosis of an infant who has jaundice.  How to evaluate a neonate with conjugated hyperbilirubinemia.  Know the therapeutic management of neonates with cholestasis.  Understand the differential diagnosis for neonatal cholestasis.
  3. 3. DEFINITIONSDEFINITIONS NASPGHAN Definition : Prolonged conjugated hyperbilirubinemia that occurs in the newborn period with conjugated bilirubin concentration >1 mg% if the total bilirubin <5.0mg% or >20% of the total bilirubin if the total bilirubin >5.0mg%. (Moyer et al J PEDIATR GASTROENTEROL NUTR 2004;39:115)
  4. 4. IAP Definition: Neonatal cholestasis is defined as conjugated hyperbilirubinemia > 1.5-2 mg% in a newborn/ infant with passage of high coloured urine with or without acholic stools. (Consensus report on neonatal cholestasis syndrome,INDIAN PEDIATRICS 2000;37:845-851)
  5. 5. Incidence:Incidence: Constitutes 30% of hepatobiliary disorders in india.( Consensus report on neonatal cholestasis syndrome,INDIAN PEDIATRICS 2000;37:845-851) Affects one in 2500 live births.
  6. 6. ETIOLOGIESETIOLOGIES Intrahepatic causes Extrahepatic causes
  7. 7. INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIES Hepatocellular causes Bile duct injury (Neonatal hepatitis) Idiopathic: INH Toxic Intrahepatic bile duct Genetic/Chromosomal hypoplasia or paucity Infectious Metabolic Miscellaneous
  8. 8. INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIES Idiopathic Neonatal Hepatitis Toxic ◦ TPN-associated cholestasis ◦ Drug-induced cholestasis Genetic/Chromosomal ◦ Trisomy 18 ◦ Trisomy 21
  9. 9. INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIES Infectious ◦ Bacterial sepsis (E. coli, Listeriosis, Staph. aureus) ◦ TORCHES ◦ Hepatitis B and C ◦ Echo virus
  10. 10. INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIES Metabolic ◦ Disorders of Carbohydrate Metabolism  Galactosemia  Fructosemia  Glycogen Storage Disease Type IV ◦ Disorders of Amino Acid Metabolism  Tyrosinemia  Hypermethioninemia
  11. 11. INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIES Metabolic (cont.) ◦ Disorders of Lipid Metabolism  Niemann-Pick disease  Gaucher disease ◦ Disorders of Bile Acid Metabolism  3B-hydroxysteroid dehydrogenase/isomerase  Trihydroxycoprostanic acidemia
  12. 12. INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIES Metabolic (cont.) ◦ Peroxisomal Disorders  Zellweger syndrome ◦ Endocrine Disorders  Hypothyroidism  Idiopathic hypopituitarism
  13. 13. INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIES Metabolic (cont.) ◦ Miscellaneous Metabolic Disorders  Alpha-1-antitrypsin deficiency  Cystic fibrosis  Neonatal iron storage disease
  14. 14. INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIES Miscellaneous ◦ Arteriohepatic dysplasia (Alagille syndrome) ◦ Nonsyndromic paucity of intrahepatic bile ducts ◦ Caroli’s disease ◦ Byler’s disease ◦ Congenital hepatic fibrosis
  15. 15. EXTRAHEPATIC ETIOLOGIESEXTRAHEPATIC 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
  16. 16. (Consensus report on neonatal cholestasis syndrome,INDIAN PEDIATRICS 2000;37:845-851)
  17. 17. CLINICAL PRESENTATIONCLINICAL PRESENTATION Jaundice Scleral icterus Hepatomegaly Acholic stools Dark urine Other signs and symptoms depend on specific disease process
  18. 18. GOALS OF TIMELY EVALUATIONGOALS 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.
  20. 20. Approach to diagnosis: NASPGHANApproach to diagnosis: NASPGHAN
  21. 21. History:History:
  22. 22. History (contd.)History (contd.)
  23. 23. Physical examination:Physical examination:
  24. 24. Physical exam (contd)Physical exam (contd)
  25. 25. Investigations:Investigations: Urgent investigations: ◦ CBC with PS, ◦ LFT: Total and direct bilirubin, SGOT, SGPT, alkaline phosphatase, GGT,PT/PTTK. ◦ Electrolytes. ◦ Blood culutre. ◦ Urine culture, routine microscopy. ◦ RBS (pre-feed). ◦ Ascitic tap (if ascitis).
  26. 26. Further tests:Further tests: Ophthalmologic examination. Serum/ urine bile acid levels. DCT and coomb’s test. Cord blood IGM. FTA-ABS, CFT for rubella, CMV, herpes. Sweat chloride. HBsAG in mother and infant. Liver biopsy: light microscopy. specific enzyme assay.
  27. 27. • TORCH,VDRL, Hepatitis B/C, HIV • T4,TSH • Serum cortisol • Alfa -1 AT levels and phenotype • Galactose -1 Phosphate Uridyl transferase (to r/o galactosemia) • Urinary succinyl acetone (to r/o tyrosinemia) • Cholesterol, triglycerides • S. iron and ferritin levels (to r/o neonatal hemachromatosis)
  28. 28. Radiological evaluationRadiological evaluation Ultrasonography  Excludes choledochal cyst, dilated CBD.  Findings s/o BA: 1. GB length (<1.5cm long/small lumen) 2. GB contraction [CI<86% ± 18% (mean ± SD) in 6-week- oldinfants and 67% ± 42% in 4-month-old infants] 3. Triangular cord sign: a triangular- or tubular-shaped echogenic densitythat was located immediately cranial to the portal vein bifurcation andwas 3 mm or more thick (Kanegawa et al. AJR 2003;181:1387)
  29. 29. Sonogram illustrates method of measuring gallbladder length (long arrow) and width (short arrow). These measurements were obtained using maximal longitudinal image.
  30. 30. 15-day-old female neonate with unknown cause of infantile cholestasis. Sonogram reveals tubular echogenic cord (arrows). "Triangular cord" was 0.3–0.4 cm wide and 1.3–1.6 cm long.
  31. 31. Hepatobiliary Scintigraphy: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. Phenobarbitol priming (5mg/kg x 5d)
  32. 32. Gayatri devi 2.5 m/F(2000) CHOLEDOCHAL CYST
  33. 33. Invasive studiesInvasive studies ◦ Duodenal intubation ◦ Percutaneous liver biopsy ◦ Percutaneous transhepatic cholangiography ◦ ERCP ◦ MRCP ◦ Exploratory laparotomy with intraoperative cholangiogram
  34. 34. ERCP imageERCP image
  35. 35. intra- and extrahepatic (c) biliary dilatation, as well as focal intrahepatic biliary cystic dilatations (arrows). g = gallbladder.
  36. 36. Percutaneous transhepaticPercutaneous transhepatic cholangiographycholangiography
  37. 37. LIVER BIOPSY:LIVER BIOPSY: Most imp. Inv in differentiating NH and BA. Accuracy of 83% to 97%. Prerequisites: Normal PT & platelet count. Complications: Bleeding Bile peritonitis Pneumothorax
  38. 38. F/o neonatal hepatitis:F/o neonatal hepatitis: Marked irregularities in size of hepatocytes. Bile canaliculi reduced. Kupffer cells swollen. Extramedullary hematopoiesis. Relative absence of bile duct proliferation.
  39. 39. f/o biliary atresia:f/o biliary atresia: Proliferation of proximal ductules. Bile plugs. Portal tract lymphatics and arterioles dilated. Secondary paucity of portal bile ducts. Intracellular and canalicular cholestasis.
  40. 40. Indications for laparotomy-IAPIndications for laparotomy-IAP 1) Acholic stools & liver bopsy-BA 2) Biopsy equivocal but acholic stools, intrahepatic causes r/o, non excreting HIDA. 3) Biopsy equivocal,acholic stools, baby 7 wks & lap and peroperative cholangiogram. 4) Biopsy equivocal, acholic stools, ERCP atresia.
  41. 41. EXTRAHEPATIC BILIARY ATRESIAEXTRAHEPATIC BILIARY ATRESIA 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
  42. 42. EXTRAHEPATIC BILIARY ATRESIAEXTRAHEPATIC BILIARY ATRESIA Increased incidence of polysplenia syndrome and intra-abdominal vascular anomalies 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
  43. 43. IDIOPATHIC NEONATAL HEPATITISIDIOPATHIC NEONATAL HEPATITIS 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%)
  44. 44. IDIOPATHIC NEONATAL HEPATITISIDIOPATHIC NEONATAL HEPATITIS Impaired uptake on radionucleotide scan with normal excretion Biopsy shows intralobular inflammation with focal hepatocellular necrosis and disruption of the hepatic architecture. No alteration of the bile ducts. Giant cell transformation occurs but is non-specific.
  45. 45. ALPHA-1-ANTITRYPSIN DEFICIENCYALPHA-1-ANTITRYPSIN DEFICIENCY Alpha-1-antitrypsin makes up 90% of alpha-1- globulin 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.
  46. 46. ALPHA-1-ANTITRYPSIN DEFICIENCYALPHA-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.
  47. 47. INTRAHEPATIC CHOLESTASISINTRAHEPATIC CHOLESTASIS SYNDROMESSYNDROMES Includes several diagnostic entities. Biopsies show cholestasis. May show paucity of intrahepatic bile ducts, giant cell transformation, and/or fibrosis.
  48. 48. TREATMENTTREATMENT Surgical ◦ Kasai procedure for biliary atresia ◦ Limited bile duct resection and re-anastomosis ◦ Choledochal cyst excision ◦ Cholecystectomy ◦ Liver transplantation
  49. 49. KASAI PROCEDUREKASAI 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
  50. 50. KASAI PROCEDUREKASAI 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.
  51. 51. TREATMENTTREATMENT Medical management ◦ Nutritional support ◦ Treatment of pruritus ◦ Choleretics and bile acid-binders ◦ Management of portal hypertension and its consequences
  52. 52. 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 –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 –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
  53. 53. TREATMENTTREATMENT Treatment of pruritus ◦ Bile acid-binders: cholestyramine (4-8 g/day) ◦ Ursodeoxycholic acid (15-20 mg/kg/day) ◦ Phenobarbital (5mg/kg/day) ◦ Rifampicin (10 mg/day) ◦ Terfenadine (1-3 mg/kg/day) ◦ Photothearpy with UV/ Infrared rays x 3-10 min/day
  54. 54. TREATMENTTREATMENT Management of portal hypertension and its consequences ◦ Variceal bleeding  Fluid rescuscitation  Blood products  Sclerotherapy  Balloon tamponade  Portovenous shunting  Propanolol
  55. 55. TREATMENTTREATMENT Management of portal hypertension and its consequences (cont.) ◦ Ascites  Sodium restriction  Diuretics: spironolactone, furosemide  Albumin  Paracentesis ◦ Thrombocytopenia managed with platelet infusions when clinically indicated
  56. 56. LIVER TRANSPLANTATIONLIVER TRANSPLANTATION 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. Cost: In excess of 100,000 $ Only few centres in india
  57. 57. Liver transplantationLiver transplantation Indications: 1)Decompensated liver disease(ascites and/or encephelopathy) . 2)Failed portoenterostomy. • 1-year survival rate- 85-90% • 5-8 year survival rate- 75-80% • 1/3 to 1/2patients are of Biliary Atresia.(Whitington et al SEMIN LIVER DIS1994;14:303-317)
  58. 58. PrognosisPrognosis Biliary Atresia: • Age(< 8 wks): the single most important determinant in successful management of BA. • Of pts. 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) Neonatal Hepatitis: • No indicators to predict prognosis.
  59. 59. Long term outcomeLong term outcome Biliary Atresia: Mean survival in untreated pts. :19 mths(Hays et al. SURGERY 1963;54:373-375) 3-year survival : <10% (Karrer et al J PEDIATR SURG 1990;25:1076-1080) Neonatal Hepatitis: Upto 60% of pts.with idiopathis NH recover completely without any specific therapy. Upto 10% die acutely of bleeding manifetstations or fulminant hepatic failure.  30 % progress to liver cirrhosis and death due to CLD.
  60. 60. Key messagesKey messages Refer early to specialised centres. Congenital infection is the commonest cause of cholestatic jaundice in infants. Percutaneous liver biopsy is safe and most useful for diagnosis. Surgery for BA and choledochal cyst should be done before 2 months of age.
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