Hepatic steatosis is the initial stage of non-alcoholic fatty liver disease (NAFLD) and may predispose to more severe hepatic disease, including hepatocellular carcinoma. Endoplasmic reticulum (ER) stress has been recently implicated as a novel mechanism that may lead to NAFLD, although the genetic factors invoking ER stress are largely unknown. During a screen for liver defects from a zebrafish insertional mutant library, we isolated the mutant cdipthi559Tg/+ (hi559). CDIPT is known to play an indispensable role in phosphatidylinositol (PtdIns) synthesis. Here we show that cdipt is expressed in the developing liver and its disruption in hi559 mutants abrogates de novo PtdIns synthesis, resulting in hepatomegaly at 5-dpf. The hi559 hepatocytes display features of NAFLD, including macrovesicular steatosis, ballooning, and necroapoptosis. Gene set enrichment of microarray profiling revealed significant enrichment of ER stress response (ERSR) genes in hi559 mutants. ER stress markers, including atf6, hspa5, calr, xbp1, are selectively upregulated in the mutant liver. The hi559 expression profile showed significant overlap with that of mammalian hepatic ER stress and NAFLD. Ultrastructurally, the hi559 hepatocytes display marked disruption of ER architecture with hallmarks of chronic unresolved ER stress. Induction of ER stress by tunicamycin in wild-type larvae results in a fatty liver similar to hi559, suggesting that ER stress could be a fundamental mechanism contributing to hepatic steatosis. Conclusion: Cdipt-deficient zebrafish exhibit hepatic ER stress and NAFLD pathologies, implicating a novel link between PtdIns, ER stress, and steatosis. The tractability of hi559 mutant provides a valuable tool to dissect ERSR components, their contribution to molecular pathogenesis and evaluation of novel therapeutics of NAFLD.

The NOD2 SNP rs2066844 associates with combined liver and intestinal failure in subjects with short-gut syndrome, who require combined liver-intestine transplantation, and secondarily with early rejection and septic deaths.

A seven-yr-old boy presented with persistent oxygen requirement following a respiratory infection. Physical exam was remarkable for orthodeoxia and digital clubbing. Laboratory evaluation showed elevated A-a oxygen gradient of 48 mmHg and mildly elevated transaminases. Sonography showed a 13 cm multilobulated liver mass and a biopsy revealed histological findings consistent with focal nodular hyperplasia. MAA scan revealed 23% right to left shunting. Abdominal CTA and MRV demonstrated the absence of the intrahepatic portal vein with an extrahepatic portocaval shunt. Abernethy malformation is a rare anomalous intra- or extrahepatic communication between portal blood flow and systemic venous return. In rare cases, Abernethy malformation results in HPS. Ours is the sixth case report to describe the co-existence of these two entities. Surgical correction of anomalous hepatic vasculature or liver transplant is imperative to restoration of lung function and also to prevent progression of possible malignant liver tumors. We describe the second patient with Abernethy and HPS who underwent liver transplant with complete resolution of HPS.

Aberrant right subclavian artery with a left aortic arch is rare, but it is the most common congenital aortic arch anomaly. It can present as an incidental finding later in life or be symptomatic at a young age. Here, we describe a case of an aberrant right subclavian artery discovered in a 4 month old with respiratory distress and feeding difficulties. She underwent an extensive aerodigestive evaluation including bronchoscopy, both flexible and rigid, upper GI endoscopy, modified barium swallow with esophageal sweep, chest imaging, CT thorax and echocardiogram. The final decision per the management team was to observe the patient in order to allow more growth. She ultimately improved with age and remains asymptomatic.