Neonatal Cholestasis

Background

• Neonatal cholestasis is elevated direct (conjugated) bilirubin in a neonate caused by reduced bile formation or bile flow.
• Causes may be intrahepatic or extrahepatic.
  • The most common causes are biliary atresia (33%-50%) and idiopathic neonatal hepatitis (10%-15%).
  • Other important etiologies include choledochal cysts, TORCH and other viral infections, congenital hypothyroidism, gestational alloimmune liver disease (GALD), alpha-1 antitrypsin deficiency, metabolic/inborn errors of metabolism, genetic syndromes such as Alagille, cystic fibrosis, and trisomies 13, 18, and 21, medications, and prolonged total parenteral nutrition support.
• 15%-20% of infants with biliary atresia have other congenital anomalies.

Evaluation

• Early diagnosis and identification of the underlying cause is important to provide early supportive treatment, optimal nutritional care, prevent complications, and improve outcome.
• Neonates may present with persistent, recurrent, or new-onset jaundice.
  • Most will appear otherwise well, but may have acholic (pale) stools or dark urine.
  • Infants with liver failure, generalized infections, metabolic disorders, or intestinal blockage may present with irritability, poor feeding, vomiting, diarrhea lethargy, failure to thrive, oliguria, delayed stooling, and/or hypotonia.
• Total and direct bilirubin should be measured in infants with jaundice persisting beyond 2-3 weeks. Evaluation should occur sooner if the infant develops symptoms or appears ill (Strong recommendation).
• Elevated direct bilirubin is defined as:
  • > 1 mg/dL (17.1 mcmol/L) when total serum bilirubin ≤ 5 mg/dL (85.5 mcmol/L)
  • > 20% of total when total serum bilirubin > 5 mg/dL
• Initial testing in infants with elevated direct bilirubin may include:
  • liver synthetic function and enzymatic tests
  • thyroid and galactosemia screening and a review of neonatal screening performed
  • cholesterol and triglycerides
  • blood cultures, urine for culture and congenital cytomegalovirus (CMV), TORCH serology, and hepatitis A, B, and C serology
  • sweat test
  • galactose-1-phosphate uridyl transferase
  • plasma and urine amino acids, cortisol (preferably after 4 hour fast) urine organic acids (succinyl acetone)
  • urine for color and presence of bilirubin, reducing substances, and organic and amino acids
  • assessment of stool for acholic (pale) color
• A liver ultrasound is recommended for any infant with cholestasis of unknown etiology as it may indicate a choledochal cyst, gall stones, sludge in the biliary tree or gallbladder, ascites, cystic or obstructive dilatation of the biliary system, or an echogenic area at porta hepatis (triangular cord sign) which may indicate biliary atresia (Strong recommendation).
• A liver biopsy is recommended for most infants with cholestasis of unknown etiology (Strong recommendation), and is more sensitive in infants ≥ 6 weeks old for identifying biliary atresia.

Management

• Initial management involves the recognition and treatment of diseases amenable to specific therapy.
• Patients with acholic stools persisting for ≥ 2 days or with any other findings suggestive of neonatal cholestasis should be referred urgently to a gastroenterologist for evaluation and management.
• Refer the infant to a pediatric surgeon if biliary atresia or extrinsic biliary obstruction is identified.
  • Infants with biliary atresia should be referred as soon as the diagnosis is confirmed, as the success of hepatoportoenterostomy decreases dramatically if performed after 90 days.
  • Choledochal cysts and bile duct perforations also require surgical intervention.
  • Cholelithiasis and patients with poor bile drainage such as in progressive familial intrahepatic cholestasis and Caroli disease may also benefit from surgical intervention to relieve obstruction and improve biliary drainage.
  • A liver transplant may be indicated for unrestored bile flow, persistent liver dysfunction, cirrhosis after hepatoportoenterostomy for biliary atresia (most common reason), and acute liver failure of any cause.
• Medical treatments may include:
  • IV immunoglobulin with or without exchange transfusion for gestational alloimmune liver disease (GALD) may improve the outcome in infants with liver failure
  • providing medication for specific infectious and endocrinological etiologies
  • consideration of cholestyramine, phenobarbital, or ursodeoxycholic acid to remove bilirubin from the liver, but are difficult to use and not first-line therapy
• Dietary interventions for patients with cholestasis include:
  • increasing caloric intake in patients with steatorrhea
  • supplementing fat-soluble vitamins (A,D,E,K)
  • provision of fat as medium-chain triglycerides
• Patients should be closely monitored for growth restriction, malabsorption, vitamin deficiency, and for complications such as portal hypertension, cirrhosis, coagulopathy, and metabolic bone disease.
• The prognosis depends on the underlying cause of cholestasis.