COMMENTARY

Top Highlights in Hepatology: The Liver Meeting 2014

The Liver Meeting 2014: American Association for the Study of Liver Diseases (AASLD)

William F. Balistreri, MD

Disclosures

January 07, 2015

In This Article

Biliary Atresia

Biliary atresia is a rapidly progressive fibroinflammatory and obliterative disease of the extrahepatic bile ducts that occurs in 1 in 8000 to 15,000 patients; it is the most common indication for liver transplantation in the pediatric population. Although the etiology of biliary atresia remains obscure, increasing evidence suggests that environmental factors, such as infection or toxic exposure, might initiate biliary injury in genetically susceptible patients. Several studies reported insight into the potential mechanisms of biliary atresia obtained from studies of animal models.

Supporting the role of an environmental toxin as a biliary atresia trigger has been the occurrence of epidemic biliary atresia-like syndrome in newborn Australian livestock. Coincident with each epidemic was maternal consumption of Dysphania plant species that were not part of the animal's normal diet owing to drought conditions.

Zhao and colleagues[21] imported and fractionated two species of Dysphania plants from pastures grazed on during the most recent outbreak, and used a zebrafish biliary secretion assay to isolate a novel extrahepatic biliary toxin that they named "biliatresone." Confocal immunofluorescence microscopy and histologic analyses showed that exposure to biliatresone caused selective destruction of the extrahepatic bile ducts in zebrafish larvae in a dose- and time-dependent manner.

To identify genetic modifiers of biliatresone and to elucidate its mechanism of action, the investigators examined its activity in mutant larvae with intrahepatic biliary defects. One mutant, ductbend, showed heightened sensitivity to the toxin. Mutant larvae treated with the toxin at a dose that did not affect their wild-type siblings had typical toxin-induced extrahepatic defects.

Genetic mapping experiments localized the ductbend locus to a region within zebrafish chromosome 22 that has conserved synteny to two independent biliary atresia susceptibility loci (10q24.2, 16p13.3), thus linking biliatresone-induced toxicity to the pathogenesis of human biliary atresia. The close proximity of the zebrafish homologs of the nonlinked human biliary atresia susceptibility loci, suggests that genes within this large chromosomal segment could be coregulated in biliary cells.

Waisbourd-Zinman and colleagues[22] demonstrated abnormal cilia associated with biliary atresia, and they hypothesized that disruption of the microtubule network is a key element in the pathophysiology of biliary atresia. They suggested that the resultant loss of polarity and architectural disruption ultimately leads to ductal obstruction.Treatment of cultured cholangiocytes with the toxin (biliatresone) resulted in a dose-dependent loss of spheroid lumens, with redistribution of apical polarity markers. Loss or redistribution of polarity markers was also observed in human biliary atresia livers.

These results suggest that biliatresone, which causes biliary atresia in a zebrafish model and is probably responsible for outbreaks of biliary atresia in livestock, acts by compromising cholangiocyte polarity and therefore luminal integrity. In vivo, this is a potential cause of lumen obstruction and may be an important part of the pathophysiology of biliary atresia. The mechanism of action of the toxin appears to involve Notch pathway members and Sox proteins.

The investigators aim to further define the molecular pathway and determine the reason for its specificity toward cholangiocytes. These results establish a new animal model to study biliary atresia and the genetic susceptibility to biliary atresia, and also provide important insights into the sequence of events underlying the development of this enigmatic disease.

Interleukin-1 Signaling Regulates Bile Duct Injury and Obstruction

Human and experimental data have indicated a key role of the innate immune system in the pathogenesis of biliary atresia.

Mizuochi and colleagues[23] explored whether activation of the inflammasome is a mechanism used by innate immunity to target the bile duct epithelium. They quantified mRNA for key inflammasome molecules in liver biopsies obtained at the time of diagnosis of biliary atresia and at different stages of bile duct injury in the rhesus rotavirus model of disease.

Disruption of the inflammasome by the loss of interleukin (IL)-1R1 signaling suppressed the activation of dendritic cells and their ability to activate NK cells, and prevented obstruction of bile ducts in experimental biliary atresia. These data identify a regulatory role of IL-1R1 in pathogenesis of bile duct injury, and as a potential novel therapeutic approach to treat the disease.

Lysosomal Acid Lipase Deficiency: Enzyme Replacement Therapy

Lysosomal acid lipase (LAL) deficiency is a progressive multisystem disease that is an underappreciated cause of cirrhosis, severe dyslipidemia, and early-onset atherosclerosis. Sebelipase alfa, a recombinant human LAL enzyme, was shown to reduce aminotransferase levels, improve the serum lipid profile, and reduce the hepatic fat fraction.[24] After 20 weeks, ALT normalization was achieved in 31% of the treated group and 7% of the placebo group; there was also significant improvement in many other important disease-related abnormalities, including marked reductions in low-density lipoprotein cholesterol. The safety profile appears favorable, and infusions were generally well tolerated.

IL-113: Critical Mediator of Parenteral Nutrition-Associated Cholestasis

Hepatic macrophage activation by endotoxin absorbed from injured intestine promotes parenteral nutrition-associated cholestasis (PNAC) in mice. Furthermore, intestinal microbiota and TLR4 signaling promote transcriptional suppression of the hepatic bile salt export pump Abcb11/BSEP, the bilirubin exporter Abcc2/MRP2, and the sterol exporter Abcg5/8. This is associated with accumulation of cholestasis-inducing, parenteral nutrition-derived phytosterols. However, the signaling pathways regulating these alterations in gene expression remain undefined.

El Kasmi and colleagues[25] elucidated the role of cytokine signaling pathways as mediators of PNAC. They report that hepatic IL-113 signaling is a critical mediator in the pathogenesis by promoting cholestasis and phytosterol accumulation through direct suppression of hepatocyte gene expression of Abcb11, Abcc2, and Abcg5/8. Pharmacologic targeting of IL-1 signaling, through specific IL-1 receptor antagonists, may be a viable therapeutic strategy for PNAC and other cholestatic liver injuries.

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