Don’t be Mellow When an Infant is Yellow: Deciphering Cholestasis Catherine J. Goodhue, MN, RN, CPNP-PC Research Program Manager Division of Pediatric Surgery
Disclosure • Research Coordinator of an NIH-funded U01 Grant entitled: Establishment of CHLA’s ChiLDREN (Childhood Liver Disease Research and Education Network) Clinical Center
Objectives At the end of this presentation, the participant will be able to: 1. Describe at least 3 functions of the liver 2. Identify the most critical differential diagnoses for cholestatic jaundice in the newborn period 3. Discuss the long-term treatment for an infant with cholestatic jaundice
Functions of the Liver • Regulates distribution and metabolism of all nutrients from GI tract • Bile production • Detoxification • Assists immune system – filtering bacteria and other “bugs” • Assists in maintaining normal blood circulation
What is Bilirubin? • Formed from degradation of hemoglobin – Newborns produce twice as much bilirubin as adults • Heme converted to biliverdin heme oxygenase in RES • Biliverdin reduced to unconjugated bilirubin and bound to albumin and sent to liver • In liver, unconjugated bilirubin is conjugated with glucuronic acid • Most goes into bile and excreted into small intestine
Physiologic Jaundice of Newborns • Phase one – Term infants – lasts up to 5 days with rapid rise of serum bilirubin up to 12 mg/dL – Preterm infants – lasts up to 7 days with rapid rise of serum bilirubin up to 15 mg/dL • Phase two – bilirubin levels decline ~ 2mg/dL over 2 weeks – Preterm infants – can last more than 1 month – With exclusive breast feedings, can last more than 1 month
Pathologic Jaundice Neonatal Jaundice Unconjugated hyperbilirubinemia Conjugated hyperbilirubinemia Pathologic Physiologic jaundice Hepatic Post-hepatic of neonates Hemolytic Non-hemolytic 1 in 2500 live births Intrinsic Extrinsic
All jaundiced infants should have a fractionated bilirubin at 2 weeks of age • Measure both conjugated and unconjugated bilirubin - conjugated should < 30% total bilirubin
Defining Cholestasis • Physiologic definition : measurable decrease in bile flow • Pathological definition : histological presences of bile pigment in hepatocytes and bile ducts • Clinical definition : accumulation in blood and extrahepatic tissues of substances normally excreted in bile From Suchy, Sokol, Balistreri. Liver Disease in Children, 2001
Signs and Symptoms of Cholestasis • Jaundice • Icterus • Pruritus • Dark urine • Elevated bilirubin level • Elevated liver enzymes
Case Study: Sandra
Differential Diagnosis of Cholestasis Neonatal hepatitis • Cholestatic syndromes • Idiopathic – PFIC – Viral – BRIC – Bacterial – Metabolic disorders • Bile duct obstruction • Alpha 1 antitrypsin deficiency – Cholangiopathies – CF – • Biliary atresia Bile acid synthesis defects – • Alagille’s Toxic • • Choledochal cysts Drugs – Other – TPN – • Cholelithiasis Miscellaneous • • Tumors/masses Shock/hypoperfusion – ECMO – From Suchy et al., 2001
Evaluation of Cholestasis Timely referral to Pediatric Detailed H & P • • Hepatologist/GI and/or Pregnancy history – Pediatric Surgeon Family history – Abdominal ultrasound Neonatal course – – Serologies for infections Extrahepatic anomalies – – Sweat chloride Stool color – – Alpha 1 antitrypsin level and Laboratory testing – • phenotype Fractionated bilirubin – Metabolic screen – AST , ALT , Alk phos – Serum iron and ferritin – Liver function tests – Genetic testing – CBC – X-rays – Bacterial cultures – HIDA scan – Liver biopsy – From Suchy et al., 2001 IOC –
More Common Causes of Conjugated Hyperbilirubinemia • TPN-cholestasis • Idiopathic neonatal hepatitis • Alpha-1-antitrypsin deficiency • Bile acid synthesis defects • Progressive familial intrahepatic cholestasis • Alagille ’ s syndrome • Biliary atresia
TPN-associated Cholestasis • Short gut/prematurity • TPN developed by Ravdin, Roads, Dudrick 1960s • Progressive hyperbilirubinemia assoc with prolonged TPN use • Treatment Reversible in most instances with – discontinuation of TPN Cycling of TPN – Homocysteine – Parenteral Omega-3 fatty acids –
Idiopathic Neonatal Hepatitis • Unresolved conjugated hyperbilirubinemia • “Giant cell hepatitis” • Diagnosis of exclusion after metabolic, infectious, genetic, or obstructive causes of cholestasis • Up to 20% progressive, familial and worse prognosis
Idiopathic Neonatal Hepatitis Cont • 40% of cholestatic infants have INH • Male: female 2:1 • Present with jaundice and acholic stools • Recovery rates range from 60-80% for sporadic cases; familial 20-40% recovery rate
Alpha 1 Antitrypsin Deficiency • Inborn error of metabolism mutant α1-AT accumulates in the endoplasmic reticulum – leaving trypsin-mediated proteolysis uninhibited in connective tissues • 1 in 2,000 live births in U.S. • Homozygous α1-AT deficiency associated with pulmonary emphysema, chronic liver disease, and hepatocellular carcinoma
A1AT Continued • Diagnosis • Treatment – Prolonged jaundice – Supportive management of liver dysfunction – Neonatal hepatitis syndrome – Avoidance of cigarette smoking – Mild elevation AST/ALT in toddlers – Liver transplant if liver failure – Portal hypertension in child/teen – Severe liver dysfunction in child/teen – HSP
Bile Acid Synthesis Defects • 1 in 100,000 • Enzyme dysfunction at various steps of bile acid biosynthesis accumulation of atypical hepatotoxic bile acid precursors. – 6 identified – • Diagnosis: mass spectrometry of urine • Treatment: cholic acid therapy downregulation of intrinsic bile acid synthesis – reduction in the accumulation of toxic bile acid precursors –
Progressive Familial Intrahepatic Cholestasis • Rare inherited diseases resulting from defects in bile synthesis and secretion • Estimated prevalence is 1 in 70,000 • Clinical manifestations : – Cholestasis may progress from intermittent to persistent – Pruritus may/may not be associated with jaundice; absence of jaundice may lead to delay in diagnosis – Malabsorption of fat soluble vitamins is common
Alagille Syndrome • Cholestasis- paucity of intrahepatic bile ducts, cardiac defects, characteristic facies, eye findings, renal anomalies, and butterfly vertebrae • Autosomal dominant • 1 in 100,000 live births • Mutations in JAG1 (Notch signaling) • Prognosis dependent on severity of CV & hepatic disease • 15% progress to end-stage liver failure -> transplantation
Biliary Atresia • Progressive obliterative idiopathic cholangiopathy – Most common cause of chronic cholestasis in infants – Jaundice & acholic stools • 1:8,000-1:12,000 live births • F>M • Seasonal clustering • Lethal if untreated
Diagnosis of Biliary Atresia • Conjugated hyperbilirubinemia • Mildly elevated ALT , AST with normal AST:ALT ratio • Elevated GGT • Ultrasound • HIDA scan • Liver Biopsy
Ultrasound Findings - BA • Absent or small gallbladder • Cyst at the porta hepatis • Increased echogenicity • Nondilated intrahepatic ducts and nonvisualized CBD
HIDA Scan • Hepatic Technetium 99 Tc m c iminodiacetic acid • Non-excretion into small intestine
Liver Biopsy - BA Portal inflammation Bile plugs Ductular proliferation
Intraoperative Cholangiogram
Kasai Procedure Kasai and Shujitsu, 1959 Kasai, M., S. Kimura, et al. J Ped Surg, 1968 Excision of fibrotic mass in hilum of liver Drainage - Roux-en-Y portoenterostomy
Dissection of biliary remnant
Bile Pooling at Portal Plate
Timing of Diagnosis/Treatment is Key! From Ohi R. Biliary Atresia: A Surgical Perspective. Clin Liver Disease 2000
Post-operative Management • Antibiotic cholangitis prophylaxis • Post-operative steroids unproven • Analgesics • Oral bile acid therapy • Vitamin supplements/monitor vitamin levels • Possible anti-pruritus therapy • Monitor bilirubin/liver function tests • Other therapies – Probiotics – unproven – Herbal remedies – unproven – Omega 3 supplements - unproven
Fat Soluble Vitamins • Vitamin A – Integral for vision, immune function and growth • Vitamin D – Integral for bone health, immune function, growth, and prevention of chronic disease • Vitamin E – Powerful antioxidant, prevents damage to cells • Vitamin K – Component of many proteins in body including those involved in clotting and bone formation
Primary Care Management • Ensure regular follow-up with hepatologist/GI • Follow-up with surgeon as directed • Keep childhood vaccines up to date • Annual flu shot • Follow growth and nutritional status – Anthropometric measurements – Possible dietary consults if not gaining adequate weight – Avoid obesity • Avoid unnecessary medications and remedies (OTC and rx)
Family Education • Contact MD if: – Unexplained fever – Recurrent/worsening jaundice – Swollen belly or extremities – Abnormal bleeding – Can’t or won’t eat – Pale stools
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