Jaundice Developing in a 13-Day-Old Baby With Down Syndrome

A 13-day old term female infant with trisomy 21 who previously had normal transcutaneous bilirubin screenings in the first few days of life develops jaundice overnight. She was born via planned Cesarean delivery to a 40-year-old female individual at 39 weeks’ gestation and required a hospitalization following birth for respiratory distress. Initially, during her neonatal intensive care unit stay, she was treated with intermittent low-flow nasal cannula support with 0.1 to 0.3 L of oxygen per hour. She was found to have a moderately sized atrial septal defect (ASD) and a large patent ductus arteriosus (PDA) that was diagnosed shortly after birth. She was started on furosemide (1 mg/kg) daily for suspected pulmonary edema.For the last 3 days, the patient has had poor oral feeding intake. Today, she weighs 5% less than her birth weight. Previously, she was tolerating full oral feeds at a rate of 150 mL/kg/d of human breast milk and is now only consuming around 100 mL/kg/d. Her physical examination this morning shows an alert and active infant with conjunctival icterus and jaundice of the face and body. Her facial features are distinct, with upward slanting of the palpebral fissures that appear consistent with trisomy 21. The lungs are clear to auscultation, with no audible murmurs, and the abdomen is nontender, nondistended, and soft to palpation. A soft liver tip is palpated at the right costal margin, and no splenomegaly is appreciated. Total serum bilirubin level obtained this morning is elevated to 15.6 mg/dL with a conjugated bilirubin of 8.5 mg/dL and an unconjugated bilirubin of 7.1 mg/dL. Additional laboratory tests show an elevated aspartate aminotransferase (AST) of 446 U/L, alanine aminotransferase (ALT) of 436 U/L, and alkaline phosphatase of 607 U/L. The international normalized ratio (INR) is normal at 1.0. Thyroid studies show a normal thyroid stimulating hormone of 1.82 μIU/mL and a free thyroxine 4 (T4) of 1.92 ng/dL. Complete blood count shows a normal white blood cell count of 11 × 109/L and hemoglobin level of 18.4 g/dL. Ammonia level is normal at 49 μmol/L.Jaundice is a commonly occurring condition in neonates, with unconjugated hyperbilirubinemia being the predominant etiology.1 Unconjugated hyperbilirubinemia is typically less pathological in nature, including causes such as benign neonatal jaundice, ABO incompatibility, hemolytic anemia, breast milk jaundice, and breast feeding jaundice.2 Although its etiology can be benign, unconjugated jaundice still needs to be closely monitored, as high levels can lead to Kernicterus. The American Academy of Pediatrics (AAP) recommends routine checking of bilirubin in every infant within 24 hours before discharge.3 Additionally, they advise measuring total and direct bilirubin levels in breastfed infants presenting with jaundice at age 3 to 4 weeks and in formula-fed infants at age 2 weeks.3 On the other hand, conjugated hyperbilirubinemia is defined as a conjugated bilirubin level greater than or equal to 2.0 mg/dL or greater than 20% of the total bilirubin level.4 It is always considered pathological and requires a thorough workup.5 Conjugated hyperbilirubinemia developing shortly after birth is referred to as neonatal cholestasis. Neonatal cholestasis affects around 1 infant out of every 2500 births.6 Cholestasis is often a result of hepatic injury and can be caused by the obstruction of bile flow, issues with transportation of bile, or systemic disease, which can affect bile formation.4 Biliary atresia, a form of extrahepatic biliary obstruction, is the most common cause of neonatal cholestasis present in approximately 25% to 35% of all cases of neonatal cholestasis.4,5 Other identifiable causes include congenital and acquired infections, parenteral nutrition-associated liver disease, endocrinopathies, drug- or toxin-induced hepatic injury, metabolic diseases (ie, alpha-1 antitrypsin, cystic fibrosis, galactosemia, tyrosinemia), choledochal cysts, heart failure, and genetic disorders such as Alagille syndrome and progressive familial intrahepatic cholestasis.4Initial workup for infants presenting with conjugated hyperbilirubinemia should include a thorough laboratory workup. Markers of liver synthetic function, including prothrombin time, ammonia, and albumin, are important to acquire because abnormal values indicate advanced hepatic injury and may warrant more rapid evaluation and intervention.4 AST and ALT are typically elevated to a variable degree but are not specific for a cause of cholestasis.4 Urinalysis and urine culture should also be part of the initial workup to rule out a urinary tract infection, as well as blood cultures if clinically indicated because infections can result in elevated conjugated bilirubin levels. It is also important to review the infant’s newborn screen to rule out inborn errors of metabolism.4 Liver Doppler ultrasonography should also be obtained as part of the initial workup to evaluate the liver, gallbladder, and bile ducts and assess for any vascular abnormalities that may be contributing to the clinical picture.7 In the case of our patient, initial laboratory tests showed a conjugated bilirubin level of 8.5 mg/dL and evidence of hepatic injury as depicted by the elevated liver enzymes. Liver synthetic function appeared normal given the appropriate INR level. Our team obtained a liver Doppler ultrasonography, which showed a dilated left portal vein with increased velocity involving its connection with the hepatic vein. This study was followed-up with an abdominal computed tomography (CT) scan, which identified multiple portosystemic shunts involving the left portal and left hepatic veins with an enlarged suprahepatic inferior vena cava and hepatic artery as a result of the shunting.The patient was diagnosed with a rare condition called a congenital portosystemic shunt (CPSS). CPSS is thought to occur in 1 out of 50 000 births and can be associated with genetic syndromes, most commonly trisomy 21.8,9 CPSS is caused by an abnormal connection between portal and systemic veins that forms due to a failure of involution of specific primordial vessels.10 This results in complete or partial diversion of portal blood flow away from the liver to the systemic venous system. CPSS can lead to cholestasis and complications such as end-stage liver disease liver tumors, portopulmonary hypertension, and pulmonary arteriovenous shunts.11 Imaging is critical for diagnosis, as it is uncommon, and clinical findings are often nonspecific.11 Liver ultrasonography with Doppler, which often shows enlargement of the portal or systemic venous system, is the preferred first-line imaging modality, as well as a useful tool for follow-up after treatment.12 CT or magnetic resonance imaging is then used to confirm the diagnosis, better characterize the vascular malformations, and guide future interventions if they are indicated.11 In most cases, intrahepatic shunts will close spontaneously within the first year of life. For this reason, interventions should only be considered in patients who are older than age 1 year or in patients with associated complications such as poor fetal hemodynamics, growth restriction, respiratory distress, and hepatic inflammation.13 Given our patient’s oxygen requirement and poor feeding, a decision was made to undergo procedural treatment in our patient’s case. Percutaneous closure often performed by an interventional radiologist is preferred over surgical management.11 During percutaneous closure, the vessel is treated by intravascular embolization, most often using plugs or coils. Most patients improve following shunt closure, with heart and liver complications typically resolving completely within months following the procedure.11Following further discussion between our team and our hepatology colleagues, the patient was taken for percutaneous shunt embolization by our interventional radiology team. Transhepatic portal venography demonstrated 2 small portosystemic shunts and a dominant shunt between the left portal vein and the hepatic vein (Figure 1). The dominant shunt was occluded with a 7-mm diameter embolic device plug on day of life (DOL) 24 (Figures 2, 3). The 2 smaller shunts were left untreated. Two days after the procedure, the patient’s bilirubin began to decrease (total bilirubin, 12.8 mg/dL; direct bilirubin, 7.8 mg/dL), and the patient was weaned to room air.Our patient was discharged home on DOL 33 with pulmonology, hepatology, cardiology, and special infant care clinical follow-up. Since discharge, the patient has been clinically stable and is doing well. She is gaining weight and developing appropriately. She remains asymptomatic and without jaundice. Most recent laboratory tests including INR, liver enzymes, ammonia level, conjugated and unconjugated bilirubin levels have all been within normal limits. Repeat liver ultrasonography showed interval closing of the small shunts that were not embolized and sustained closure of the main portosystemic shunt. Repeat follow-up echocardiogram showed a small PDA, moderate ASD, and no pulmonary hypertension, which were improved from admission and expected to resolve with time.Jaundice in early life should be evaluated by obtaining a fractionated serum bilirubin level to examine total, conjugated, and unconjugated bilirubin levels.Conjugated hyperbilirubinemia, defined as a conjugated bilirubin level greater than or equal to 2.0 mg/dL or greater than 20% of the total bilirubin level, is concerning and always requires further diagnostic testing and evaluation.CPSS should be considered in the differential diagnosis for conjugated hyperbilirubinemia.Liver Doppler ultrasonography is the preferred initial imaging modality used to identify CPSS.Small CPSSs can resolve on their own. However, symptomatic patients require intervention by a team of interventional radiologists.