Snapshot A 3-day old newborn girl is evaluated in the hospital for jaundice that was first visible only in her face as seen in the image, but has gradually progressed to the trunk and extremities. She was born at 35 weeks' gestation to a healthy mother with an uncomplicated pregnancy course. On physical examination, her muscle tone is weak in the upper extremities and she has an altered cry. A total serum bilirubin level is measured and is found to be elevated and in the 99th percentile. Introduction Overview congenital hyperbilirubinemia may be due to either accumulation of conjugated or unconjugated bilirubin in newborns Congenital HyperbilirubinemiaUnconjugated HyperbilirubinemiaSyndromePathophysiologyCharacteristicsGilbert syndromeDefect in glucuronyl transferase5% of populationIncrease in serum unconjugated bilirubinJaundice presents in stressful situationsBenignno treatment necessaryCrigler-Najjar syndromeDeficiency of glucuronyl transferaseMarkedly increased serum unconjugated bilirubinType 1severe jaundice,death from kernicterus is common by 1 year of age; liver transplant is curativeType 2less severe; responds to treatment with phenobarbitalConjugated HyperbilirubinemiaDubin-Johnson syndromeDefective liver excretion of bilirubinIncrease in serum conjugated bilirubinBenignno treatment necessaryLiver turns blackRotor syndromeImpaired hepatic uptake and defective excretion of bilirubinIncrease in serum conjugated bilirubinBenignno treatment necessarymilder than Dubin-Johnson syndromeLiver does not turn black Epidemiology Incidence Gilbert syndrome 3-7% of individuals Crigler-Najjar syndrome 1 in 750,000-1,000,000 newborns Dubin-Johnson and Rotor syndrome rare, incidence unknown ETIOLOGY Pathophysiology significant unconjugated congenital hyperbilirubinemia ↑ bilirubin production due to pathological hemolysis ↓ bilirubin clearance due to inherited genetic defects that impair bilirubin conjugation i.e., Gilbert syndrome and Crigler-Najjar syndromes (see table below) conjugated congenital hyperbilirubinemia impaired liver excretion of bilirubin i.e., Dubin-Johnson and Rotor syndromes (see table below) Genetics mutations Gilbert syndrome and Crigler-Najjar syndrome UGT1A1 gene encodes for a protein that catalyzes the conjugation of bilirubin with glucuronic acid Presentation Symptoms jaundice signs of bilirubin encephalopathy (kernicterus) decreased feeding lethargy abnormal muscle tone high-pitched cry fever seizures Physical exam scleral icterus jaundice that may have cephalocaudal progression brown discoloration of the urine (conjugated hyperbilirubinemia) abnormal muscle tone and seizures (bilirubin encephalopathy) Studies Serum bilirubin level increased levels of total serum bilirubin typically ranges from 1-5 mg/dL in Gilbert syndrome direct bilirubin concentration of ≥ 10 μmol/L may indicate conjugated hyperbilirubinemia direct bilirubin is < 15% of total serum bilirubin in Crigler-Najjar syndrome Complete blood cell count screen for hemolysis Differential Physiologic neonatal jaundice (benign congenital hyperbilirubinemia) key distinguishing factor resolves after 1-2 weeks after birth caused by turnover of fetal erythrocytes and immature ability of infant's liver to metabolize bilirubin Treatment Medical phenobarbital treatment for Crigler-Najjar syndrome type 2 (detectable but low UGT1A1 activity) ↑ liver enzyme synthesis Surgical liver transplant curative for Crigler-Najjar syndrome type 1 Complications Kernicterus incidence rare may occur from bilirubin encephalopathy in Crigler-Najjar syndrome type I treatment plasma exchange transfusion long-term phototherapy Prognosis Gilbert syndrome benign good prognosis Crigler-Najjar syndrome patients often die within a few years of life Dubin-Johnson syndrome benign good prognosis Rotor syndrome benign good prognosis with milder presentation compared to Dubin-Johnson syndrome