August 5, 2005 Definition: Neonatal Cholestasis Prolonged conjugated hyperbilirubinemia in the newborn period Conjugated hyperbilirubinemia Conjugated bilirubin >1mg/dL if TB < 5mg/dL >20% Total Bilirubin if TB is >5 mg/dL Caused by a group of hepatobiliary diseases occuring within the first 3 months of life Occurs in 1:2500 live births Neonatal Cholestasis NASPGHAN Recommendations Evaluate infants with jaundice at the 2 week visit Up to 15% of infants are jaundiced at 2 weeks, the majority due to breast milk jaundice Timely and accurate diagnosis is crucial for successful treatment and favorable prognosis Breast-fed infants may have an evaluation delayed until 3 weeks if: Normal exam No h/o dark urine or light stools Reliably monitored Differential Diagnosis: Obstructive Cholestasis Biliary Atresia * accounts for 30% of all cases of neonatal cholestasis Choledochal cysts Gallstones Alagille syndrome Neonatal sclerosing cholangitis Cystic fibrosis Tumor Differential Diagnosis: Hepatocellular Cholestasis Idiopathic neonatal hepatitis Diagnosis based on liver biopsy findings: giant cell hepatitis Was thought to account for ~40% of neonatal cholestasis (with new diagnostic techniques, % is probably ~10-20%) 60-70% resolve without sequelae Infectious Viral: TORCH, CMV, HIV, viral hepatitis Bacterial: sepsis, syphilis, UTI Genetic/metabolic Alpha-1-antitrysin deficiency, galactosemia, tyrosinemia, hypothyroid, PFIC, CF Toxic/secondary causes TPN associated cholestasis History Congenital infections Prenatal ultrasound ABO incompatibility Neonatal infection UTI Dietary history Weight gain vomiting Stool pattern Delayed: CF, hypothyroid Diarrhea: infx, metabolic disease Stool and urine color Excessive bleeding Irritability or lethargy +family history Physical Exam Weight measurement General appearance Ill-appearing: infection, metabolic disease Well-appearing: biliary atresia Fundoscopic exam (congenital infection) Cardiac murmur Abdominal exam Ascites, abd wall veins, liver, spleen Stool/urine for color Skin exam Bruising, petechiae Dysmorphic features Broad nasal bridge, triangular facies, deep set eyes (Alagille) Laboratory Studies Total and direct bilirubin LFTs + GGTP Detects liver cell or bile duct injury PT/PTT, glucose, albumin Assessment of biosynthetic capacity of liver CBC, urine and blood culture Viral serologies (TORCH infections + HBsAg, CMV, HIV if indicated) UA for reducing substances TFTs Alpha-1-antitrypsin Sweat chloride or mutation analysis for CF gene NASPGHAN Recommendations: Imaging Studies Ultrasound: initial study recommended for patients with cholestasis of unknown etiology Evaluates for anatomic abnormalities Liver Biopsy Recommended for most infants with cholestasis of unknown etiology Differentiates b/w extra and intrahepatic processes, disorders of physiology from anatomy and can determine need for surgical vs. medical intervention Scintigraphy (HIDA), ERCP, MRCP Biliary Atresia 1:8,000-15,000 live births Accounts for 30% of all cases of cholestasis in infants Female>Male Asians>African Americans>Caucasian Most frequent cause of chronic end-stage liver disease in children Leading indication for liver transplantation in the pediatric population (40-50% of all liver transplants) Biliary Atresia: pathogenesis Bile duct obstruction due to inflammation and fibrous obliteration Perinatal or classic type (70-85%): obstruction begins after birth. Signs/symptoms develop within ~2-4 weeks of age. No associated abnormalities Embryonic type (15-30%): obstructive process begins in utero. Cholestatic symptoms present at birth. Associated with congenital anomalies: Situs inversus, polysplenia, malrotation, cardiac anomalies Unknown etiology: genetic, viral and host immune factors have been postulated Variations in Biliary Atresia Clinical Features History: Variable degrees of persistent jaundice, dark urine, light colored stools, +/-poor appetite * Usually Well- Appearing* Physical: Hepatomegaly, +/- splenomegaly appear well-nourised Usually with decreased fat stores and lean body mass Enlarged abdomen from HSM may give impression of normal weight for age Scleral icterus, abdominal wall veins (caput medusa) Labs: Total bilirubin rarely is >12mg/dL; CB is usually <8mg/dL Elevated GGTP w/ mild elevation of other LFTs Imaging Studies Ultrasound Absent gallbladder, triangular cord sign Low sensitivity; operator dependent Evaluates for other anatomic abnormalities Hepatobiliary scintigraphy (HIDA) High sensitivity: normal uptake, but no excretion of radionuclide tracer into biliary system or bowel in virtually all patients with BA (exceptions in very early disease) However, failure of excretion may be seen in both BA and neonatal hepatitis Sensitivity and Specificity increase with phenobarbital administration ERCP Invasive, not readily available, technically difficult in infants Intraoperative use is most common to confirm diagnosis and document site of obstruction MRCP May become an important tool for diagnosis Further studies are required Triangular Cord Sign Diagnosis Percutaneous Liver Biopsy: most reliable test for diagnosing biliary atresia Biopsy interpretation is pathologist dependent Accurate diagnosis made in 90-95% of cases Liver biopsies made early in the course of disease (<6 wks) may be indistinguishable from neonatal hepatitis Histologic findings: fibrotic portal tracts with ductular proliferation and bile plugs No bile duct proliferation seen in neonatal hepatitis Following biopsy, diagnosis is usually confirmed at laparotomy by intraoperative cholangiography Surgical Management Kasai Procedure: resection of the obliterated bile duct w/ creation of a Roux-n-Y hepatoportoenterostomy Timing of procedure predicts the prognosis <60 days- bile flow returned in 80-90% cases Only 30% with complete drainage >90 days- bile flow returned in ~20% cases Usually require a liver transplant within one year The experience of the center performing the Kasai if one of the most important factors determinig surgical outcome Post-operative Management Prophylactic Abx to prevent cholangitis Ursodiol: enhance bile flow No special diet needed unless concern with poor bile drainageMCT formula (ie Alimentum, Pregestimil) Fat-soluble vitamins: A, D, E, K +/- short term, high dose steroid therapy If Kasai Fails? +/- support for revision of Kasai procedure if fails Despite clinical improvement after a Kasai, 70-80% pts will eventually require liver transplantation Indications for Liver Transplant: operation not successful in restoring bile flow initially (~20%) late referrals (generally >120 days) develop end-stage liver dz despite bile drainage (ie portal htn, recurrent cholangitis, ascites, growth failure) Liver Transplant results: one-yr survival rates >90% b/c reduced size allografts and living-related donors Post-Kasai Complications Early: Ascending Cholangitis (50%) can lead to ongoing bile duct injury & re-obstruction fever, dec. bile secretion, worsening jaundice, leukocytosis Late: Portal Hypertension bleeding esophageal varices, ascites, hypoalbuminemia, fat-soluble vit def., malabsorbtion of long-chain triglycerides, encephalopathy Long term, malignancies screened for Hepatoblastoma, hepatocarcinoma, cholangiocarcinoma What happened to our patient? Kasai Procedure on 8/16/04 Complicated by cholangitis x 2 wks Portal hypertension Esophogeal varicessclerotherapy x 2 1/05: TB 32.3/ conjugated bilirubin 18.6 Now on the transplant list awaiting a liver Take-Home Message! Any Jaundice>2 weeks requires investigation ALWAYS ask for fractionated bilirubin (Total + Direct bilirubin) Early diagnosis and referral (<2 months old) is critical for the best outcome!