Discordant Presentation of Biliary Atresia in Premature Monozygotic Twins

Abstract

Biliary atresia (BA) is a disease of progressive inflammation and fibrosis of the biliary tree in infants, involving complete occlusion of the extrahepatic bile ducts (1). Despite extensive research, the etiology and pathogenesis of BA are largely unknown (1). Twins with discordant pathology in BA represent a unique opportunity to study its etiology. The patient, twin A, is a former 1090-g, 27-4/7 week monozygotic boy, born to a healthy 36-year-old mother. Her pregnancy was complicated by premature rupture of membranes and gestational diabetes. A primary cesarean section was performed with an uncomplicated delivery. The patient developed unconjugated hyperbilirubinemia and jaundice (unconjugated bilirubin [U/L]/conjugated bilirubin [U/L] 4.7/0.1) on day of life (DOL) 1, which progressed to conjugated hyperbilirubinemia on DOL 3 (4.4/2.6). Liver function tests showed alanine transaminase 6 U/L, aspartate transaminase 101 U/L, alkaline phosphatase 331 U/L, and γ-glutamyl transpeptidase 1098 U/L. Normal stool color was noted. An ultrasound performed on DOL 4 was unremarkable. His jaundice improved during the next week, with hyperbilirubinemia of 6/1.7 at DOL 11 decreasing to 2.6/1.9 (Table 1). His jaundice was initially attributed to prematurity. Persistence of the jaundice was attributed to total parenteral nutrition (TPN) cholestasis. The patient remained in the neonatal intensive care unit with chronic lung disease and ventilator dependence; however, the conjugated hyperbilirubinemia persisted, so an ultrasound was repeated at DOL 57, demonstrating hepatic echogenicity and a small gallbladder without ductal dilatation. Laboratory data on DOL 74 showed increased conjugated hyperbilirubinema of 1.9/3.3 mg/dL, aspartate transaminase 80 U/L, alanine transaminase 43 U/L, γ-glutamyl transpeptidase 440 U/L, alkaline phosphatase 375 U/L, and a normal α1-antitrypsin. A third ultrasound performed on DOL 93 demonstrated hepatomegaly with increased echogenicity and a persistently small gallbladder without biliary dilatation. After receiving pretreatment with phenobarbital, a subsequent hepatobiliary iminodiacetic acid (HIDA) scan revealed decreased and delayed tracer uptake by the liver without excretion. A percutaneous liver biopsy showed bile duct proliferation, cholestasis and acute cholangitis, and cirrhosis consistent with extrahepatic obstruction.TABLE 1: Comparison of bilirubin values over timeExploratory laparotomy was performed on DOL 107. An atretic gallbladder and an enlarged, firm liver were noted. The remnant of the common bile duct was small and fibrotic, confirming the diagnosis. A Kasai portoenterostomy was performed. The patient was discharged 2 weeks after surgery following a benign postoperative course. At 8 months of age, the patient had an upper gastrointestinal hemorrhage treated with EGD and sclerotherapy. At 2 years of age, he underwent orthotopic liver transplantation secondary to portal hypertension. He had an uncomplicated post-transplant course and continues to do well at age 5. His brother, twin B, weighing 962 g at birth, also developed unconjugated hyperbilirubinemia (Table 1). He remained in the hospital until DOL 96 as a result of apnea of prematurity and prolonged oxygen requirements. He required TPN with intralipids until DOL 14, and intermittent nasal continuous positive airway pressure until DOL 53. Other than mild reactive airway disease, he has remained healthy with normal liver function tests. DISCUSSION The etiology and pathogenesis of BA remain elusive. Several hypotheses have been proposed, including intrauterine or perinatal viral infection, ischemia, and abnormalities in bile duct morphogenesis due to unknown genetic factors (1). A recent study has demonstrated that conjugated hyperbilirubinemia in BA patients is detectable in the immediate newborn period, as in our patient, suggesting that the injury of the extrahepatic biliary tree begins before or soon after birth (2). Although rare, the presence of BA in one or both twins provides a unique opportunity to further understand its etiology because intrauterine events usually affect both twins because of their shared environment. The development of the biliary system can be affected by vascular events early in gestation because the biliary system is fully formed by the 16th week (3). A detailed account of the mother's gestational history in this case did not reveal any indication of viral infection or vascular incident, nor was there any serologic evidence of infection in either twin. In theory, the occurrence of BA in twins may suggest genetic or epigenetic factors in the pathophysiology of the disease. In a review of the literature, 30 discrete sets of twins with BA were found, with only 2 sets of dizygotic twins demonstrating concordance for the disease (4,5). The remaining 28 were discordant, having only 1 twin diagnosed as having BA. Eight of the sets of discordant twins were dizygotic, and 7 were monozygotic (see supplemental references, https://links.lww.com/MPG/A160). Information was not available for the remaining 13 sets of twins. Because none of the monozygotic twins demonstrated concordance for BA, a purely genetic basis for the disease seems unlikely, although variable penetrance is possible. Epigenetic modification of genomic DNA could explain the discordance of BA in monozygotic twins. Epigenetics refer to modifications of gene expression resulting from events other than changes in the DNA sequence, such as methylation of selected DNA residues (6). In a particularly compelling study, Bezerra (7) found variable activation of genes, which differentiated the embryonic and perinatal forms of BA. To confirm this hypothesis, patterns of DNA methylation would need to be compared between monozygotic twins discordant for BA. Early diagnosis of BA is known to improve outcomes, particularly in infants younger than 30 days (8). The delay in diagnosis seen in this report was attributed to the infant's prematurity and a comparison to his twin. The early elevation of conjugated bilirubin was erroneously attributed to TPN administration because these levels decreased in concordance with the TPN wean and discontinuation; additionally, the unconjugated bilirubins were similar between the twins. Imaging was inconclusive because multiple ultrasounds were not suggestive of BA. Despite persistent conjugated hyperbilirubinemia, the contributory HIDA scan was delayed, attributable to the previous negative ultrasounds, the improvement in clinical status of the patient, and the continued comparison to the twin brother. Although twins with discordant pathology have been reported, this is the first report of premature monozygotic twins with discordant BA. This case demonstrates the difficulty of diagnosis of BA in premature babies, prompting early assessment by liver biopsy and/or HIDA scan with subsequent expeditious intraoperative diagnosis if indicated. This case supports the theory that epigenetic modifications could contribute to the pathogenesis of BA, suggesting that further studies in epigenetics are warranted in this rare but clinically significant disease of infancy.