A four week old infant is brought into your primary care office.  She was born at 39w6d via uncomplicated home delivery and missed her newborn appointment.  Mom received appropriate prenatal care, and the pregnancy was uncomplicated.  The child’s birth weight was appropriate for age.  She has been breast feeding well and has continued to gain weight along the 30th percentile.  She has had no fevers or other signs of illness. On exam the child is markedly jaundiced with prominent icteric sclera.  You note that she has a firm, palpable liver edge.  She has no dysmorphic features or murmurs on exam.  She has a stool in the office which is a pasty white color.  You check a total serum bilirubin which is notable for direct hyperbilirubinemia.  You also obtain an abdominal ultrasound, which is notable for a triangular fibrous mass at the porta hepatis.  What is the most likely diagnosis?  

A. Choledochal cyst 

B. Physiologic jaundice

C. Alagille syndrome

D. Biliary atresia

E. Galactosemia

 

The correct answer is D, Biliary atresia.

 

Answer Choice D: Biliary Atresia

Biliary atresia is a form of direct hyperbilirubinemia.  The definition of direct hyperbilirubinemia can vary depending on laboratory systems.  In some systems, a direct bilirubin of more than 20% the total serum bilirubin is considered abnormal.  In other systems, any direct bilirubin greater than 1mg/dL is considered abnormal.  Due to variability in lab systems, the North American and Europeans Societies for Pediatric Gastroenterology, Hepatology and Nutrition recommend that any infant with a direct bilirubin > 1mg/dL are referred for further evaluation.   

Extrahepatic biliary atresia is the most common cause of neonatal cholestasis.  It typically presents with jaundice between 3-6 weeks of age.  These patients frequently have pasty white or acholic stools. Early referral to a pediatric gastroenterologist is key.  The ultrasound finding described in the question is suggestive of biliary atresia, but not diagnostic. The primary purpose of the ultrasound is to rule out a choledochal cyst, which was answer choice A.  A normal ultrasound does not rule out biliary atresia. Liver biopsy is diagnostic in 90-95% of cases and will demonstrate large duct obstruction, portal tract edema, bile ductular proliferation and the presence of bile plugs in bile ductules.  Patient’s then undergo intraoperative cholangiogram followed by a hepato-porto-enterostomy Kasai procedure which allows bile to drain into the intestine.  The younger the patient is at the time of the procedure the higher the success rate.  If these patients are not treated, they will most likely die from liver failure by 2 years of age. 

 

Answer Choice A: Choledochal Cyst

Choledochal cysts are cystic dilations of the bile duct which lead to obstruction and bile retention, which in turn leads to jaundice and liver enlargement.  There are five different types based on the site of the cyst or dilation.  They can be identified on ultrasound, and treatment is surgical.

 

Answer Choice B: Physiologic Jaundice

Physiologic jaundice is incorrect for several reasons.  First, all jaundice that persists past two weeks of life requires further investigation. Second, physiologic jaundice results in indirect hyperbilirubinemia.  In this case, the patient had direct hyperbilirubinemia which ALWAYS requires further investigation.  This is why it is essential to always obtain a fractionated serum total bilirubin; you cannot rely solely on transcutaneous bilirubin monitoring.  

 

Answer Choice C: Alagille Syndrome

Alagille syndrome is less likely in this patient.  While these patients do present with jaundice and acholic stools there are several other features to look for including

  1. Dysmorphic facies: prominent broad forehead, deep set eyes and a triangular chin
  2. Congenital heart disease, most commonly pulmonary stenosis
  3. Short stature and hypogonadism 
  4. Abnormalities of the eyes, kidneys, and butterfly vertebra 

This syndrome is inherited in an autosomal dominant fashion with variable penetrance and expressivity.  In contrast to biliary atresia, their liver size is normally normal in the neonatal period.  Histology demonstrates a paucity of normal intralobular bile ducts which are progressively lost with age.

 

We discuss more about galactosemia in our episode related to inborn errors of metabolism (Episode 15), but this is an unlikely etiology in this patient given the fact that they are overall clinically well appearing.  Children with biliary atresia are initially well appearing and are growing well, while infants with metabolic disorders or infections as the cause of their cholestatic jaundice are typically ill appearing and slow to gain weight.

 

References

1. Zallen GS, Bliss DW, Curran TJ, Marvin WH, silen, ML.  Biliary Atresia.  Pediatrics in Review Jul 2006, 27 (7) 243-248; DOI: 10.1542/pir.27-7-243.

2. Wang KS; Section on Surgery; Committee on Fetus and Newborn; Childhood Liver Disease Research Network. Newborn Screening for Biliary Atresia. Pediatrics. 2015 Dec;136(6):e1663-9. doi: 10.1542/peds.2015-3570. PMID: 26620065; PMCID: PMC4920543.

3. Suchy FJ. Neonatal Cholestasis.  Pediatrics in Review Nov 2004, 25 (11) 388-396; DOI: 10.1542/pir.25-11-388.

4. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004 Jul;114(1):297-316. doi: 10.1542/peds.114.1.297. Erratum in: Pediatrics. 2004 Oct;114(4):1138. PMID: 15231951.

5. Fawaz R, Baumann U, Ekong U, Fischler B, Hadzic N, Mack CL, McLin VA, Molleston JP, Neimark E, Ng VL, Karpen SJ. Guideline for the Evaluation of Cholestatic Jaundice in Infants: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2017 Jan;64(1):154-168. doi: 10.1097/MPG.0000000000001334. PMID: 27429428.

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