Case 1: Cholestatic jaundice in an infant with Down syndrome

A term male infant with Down syndrome was admitted to the neonatal intensive care unit at birth for possible sepsis, given suspected maternal chorioamnionitis and the need for resuscitation (including 2 min of positive-pressure ventilation) at delivery. Shortly after admission, he developed seizures requiring treatment with phenobarbital and fosphenytoin/phenytoin for three weeks. Magnetic resonance imaging revealed that a large infarct provoked his seizures. Blood and cerebrospinal fluid cultures were negative. His cerebrospinal fluid leukocyte count was elevated (88×106/L). Because meningitis could not be definitively excluded, he received ampicillin and gentamicin for two weeks. There were no cardiac or gastrointestinal malformations, nor was there bone marrow pathology. The infant was doing well but developed mild scleral icterus, dark urine and intermittent pale stools during the fourth week of life. There was no diarrhea or vomiting. Direct bilirubin was markedly elevated (111 μmol/L, normal 0.6 μmol/L to 20.1 μmol/L). His total bilirubin was 155 μmol/L. There was no family history of liver disease. He had never received parenteral nutrition. On examination, he exhibited features consistent with Down syndrome. He had scleral icterus and jaundice. His abdomen was soft and nontender. His liver was palpable 4 cm below the costal margin, with no splenomegaly. His examination was otherwise normal. Table 1 outlines laboratory investigations. Liver enzyme levels were mildly elevated. A TORCH screen was negative. Abdominal ultrasound showed a normal gall bladder, with no choledochal cyst. Slit-lamp examination, chest radiograph and echocardiogram were normal. Hepatobiliary scintigraphy after phenobarbital did not show excretion into the duodenum. Summary of laboratory investigations Laboratory investigations were conducted to rule out various causes of cholestasis. Most tests were conducted between four to six weeks of age. The results for each investigation are shown, with a range of normal listed for quantitative investigations. Considered to be protective; Hyperoxaluria was deemed secondary to fat malabsorption according to consultation with a clinical biochemist. ↑ Elevated value; ↓ Low value. CMV Cytomegalovirus; Ig Immunoglobin Summary of laboratory investigations Laboratory investigations were conducted to rule out various causes of cholestasis. Most tests were conducted between four to six weeks of age. The results for each investigation are shown, with a range of normal listed for quantitative investigations. Considered to be protective; Hyperoxaluria was deemed secondary to fat malabsorption according to consultation with a clinical biochemist. ↑ Elevated value; ↓ Low value. CMV Cytomegalovirus; Ig Immunoglobin A percutaneous liver biopsy was performed using ultrasound guidance. Histopathology revealed intrahepatic cholestatic liver changes (Figure 1A), paucity of interlobular bile ducts in the portal areas (Figure 1B), small bile ductule with absence of bile plugs (Figure 1C) and early bile ductular reaction in the periportal areas. This was consistent with nonsyndromic paucity of intrahepatic bile ducts. Liver biopsy. An ultrasound-guided percutaneous liver biopsy was conducted at six weeks of age. Nine portal areas were identified.ALiver biopsy showing intrahepatic cholestatic changes with liver cell swelling (star), bile stasis (arrowhead), apoptosis (dotted arrow) and giant cell transformation (solid arrow).BPortal area in the liver showing absence of interlobular bile duct.CA rare portal area showing a small bile duct (solid arrow) with no evidence of bile plug.DPeriportal areas showing bile ductular reaction with proliferation of cholangioles (cytokeratin 7 immunostain, brown colour) He was started on ursodeoxycholic acid (15 mg/kg/day) and fat-soluble vitamin supplements. The direct bilirubin peaked at 152 μmol/L at six weeks of age. He was discharged home at seven weeks of age. His scleral icterus, jaundice, liver enzyme and bilirubin levels gradually improved over the next few weeks. His stool colour normalized around two months of age. His direct bilirubin was 121 μmol/L at two months of age and 8 μmol/L at three months of age. Ursodeoxycholic acid and fat-soluble vitamins were discontinued. His alanine aminotransferase (ALT) level increased to a maximum of 111 U/L at two months of age, and then decreased to 49 U/L at four months of age. By nine months of age, his ALT had normalized to 25 U/L. His interim growth is acceptable (third percentile for weight and 15th percentile for height on WHO growth chart). He remained well at last follow-up. Nonsyndromic paucity of intrahepatic bile ducts (NSPIBD) is characterized by a paucity of interlobular bile ducts on liver biopsy in the absence of clinical features of Alagille syndrome. Liver biopsy findings are identical in the two conditions. NSPIBD can be idiopathic or associated with metabolic diseases (alpha-1-antitrypsin deficiency), viral infections (notably cytomegalovirus or rubella) or chromosomal disorders such as Down syndrome. Its incidence and prevalence have not been precisely established. Treatment for NSPIBD consists of supportive management of cholestasis. The reported prognosis is variable, ranging from complete resolution to mortality in infancy. The clinician must differentiate NSIPBD from Alagille syndrome (Online Mendelian Inheritance in Man, code 118450), a well-described autosomal dominant syndrome with a prevalence of approximately one in 70,000 (1). In case series, Alagille syndrome is more common than NSIPBD. Alagille syndrome is characterized by cholestasis caused by bile duct paucity, congenital heart disease (peripheral pulmonic stenosis), characteristic facies, skeletal abnormalities (butterfly vertebrae) and ocular abnormalities (posterior embryotoxon). Neonates with Down syndrome are at an increased risk for developing cholestasis. In a retrospective study involving 206 infants with Down syndrome, 3.9% developed neonatal cholestasis (2). This represents a 100-fold increase over the general population incidence. NSPIBD has been reported in infants with Down syndrome. However, cholestasis in infants with Down syndrome is more likely to result from congenital hypothyroidism, transient myeloproliferative disorder or parenteral nutrition. Clinicians evaluating a child with cholestatic jaundice must consider a broad differential diagnosis. Neonatal cholestasis can result from infections, genetic and metabolic conditions, toxins, endocrine disorders or anatomical obstruction. NSPIBD is a rare cause of neonatal cholestasis. The diagnosis is made using liver biopsy in the absence of clinical features of Alagille syndrome. The diagnosis of NSPIBD should be entertained in infants with cholestasis who have consistent clinical and laboratory findings. Infants with Down syndrome are at increased risk for developing cholestatic jaundice. Causes of cholestasis in this patient population include congenital hypothyroidism, transient myeloproliferative disorder and parenteral nutrition. The authors thank Dr Ernest Cutz, Senior Staff Pathologist at The Hospital for Sick Children in Toronto, for his consultation on this case.

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