Although physiologic jaundice of neonates is common, persistent neonatal cholestasis is life-threatening and has multiple etiologies. Among these etiologies, biliary atresia (BA) requires rapid diagnosis and treatment. In diagnosing BA, the surgical pathologist must recognize subtle histologic changes, often with only a small core liver biopsy. To aid in the differential diagnosis of neonatal cholestasis, we investigated Yes-associated protein (YAP), a regulator of organ size and bile duct development. We examined whether a YAP immunostain can highlight emerging hepatobiliary epithelium in BA (n = 28) versus other causes of persistent cholestasis (non-BA; n = 15) and thus serve as a useful diagnostic marker in persistent neonatal jaundice. We show significantly (P < .01) more high-grade (<2) fibrosis and ductular proliferation among BA versus non-BA cases. Likewise, there was significantly more high-grade (2-3/3) cytoplasmic and nuclear YAP staining in BA (97% and 89%) versus non-BA (20% and 13%). High-grade nuclear YAP staining was both sensitive (88%) and specific (87%) for the diagnosis of BA. In contrast to neonatal cholestasis, the differences in YAP localization in cholestatic/obstructed versus nonobstructed adult livers were not significant. Lastly, we found that pharmacologic inhibition of the YAP complex in both cholangiocyte and cholangiocarcinoma cell lines blocked compensatory bile duct proliferation, an early marker of BA that requires nuclear YAP expression, in a time- and dose-dependent manner. In summary, we show that YAP expression modulates both bile duct proliferation and liver damage/fibrosis while acting as a sensitive and specific marker in the differential diagnosis of persistent neonatal cholestasis.
Keywords: Bile duct obstruction; Bile ductular reaction; Biliary atresia; Hippo pathway; Neonatal cholestasis; Neurofibromatosis 2 (NF2); Verteporfin (VP); Yes-associated protein (YAP).
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