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


January 07, 2015

In This Article

Primary Sclerosing Cholangitis

Although the etiology of PSC is unknown and probably multifactorial, it is clear that a better understanding of the mechanisms leading to this condition is needed to develop therapeutic strategies. Bile acid toxicity, death receptor signaling, altered gastrointestinal microflora, and environmental exposures have all been implicated in the pathogenesis of PSC. Several studies were directed to these postulates; two of the studies used a murine model with mice deficient in mdr2, a canalicular phospholipid flippase that leads to the excretion of low phospholipid "toxic" bile and causes rapid progression of cholestasis and biliary fibrosis resembling small duct PSC.

Absence of the Intestinal Microbiota

Tabibian and colleagues[4] explored the postulated role of the intestinal microbiota in the pathogenesis of PSC. They tested the hypothesis that germ-free mdr2-/- mice develop a distinct PSC phenotype compared with conventionally housed mdr2-/- mice.

Serum markers of cholestasis were significantly higher in the germ-free mdr2-/- mice. Primary bile acid profiles were similar; however, secondary bile acids were absent in the germ-free mice, consistent with the absence of intestinal microbiota. Hepatic fibrosis, ductular reaction, and ductopenia were significantly more severe in germ-free mdr2-/- mice, as was cholangiocyte senescence, a characteristic and potential mediator of progressive biliary disease.

These findings demonstrate the importance of the commensal microbiota and its metabolites in protecting against biliary injury and support further studies of their role as potential biomarkers and therapeutic targets in PSC.

Caspase Inhibitors

Death receptor signaling is modulated by cellular inhibitor of apoptosis (cIAP) proteins. Rizvi and colleagues[5] reported a novel role of cIAP-1 and -2 in the pathogenesis of PSC in the murine model of nonobliterative, fibrous cholangiopathy that exhibited cholangiographic alterations of segmental and peripheral bile ducts. These data also suggest another potential strategy (inhibition of caspase) for cytoprotection in PSC.

Role of Environmental Exposures

PSC may develop through immune-mediated mechanisms triggered by complex gene/environment interactions in susceptible individuals. Although tobacco use has been reported to have a negative association with PSC, other exposures, particularly dietary habits and food preparation methods, have not been well explored.

Eaton and colleagues[6] identified novel environmental exposures among patients with PSC.They reported that:

A history of smoking was inversely associated with PSC when inflammatory bowel disease (IBD) was present;

Persons with PSC, regardless of sex or IBD status, were less likely to eat fish, vegetables, and grilled/barbecued meat;

Those with PSC with and without IBD were more likely to consume steak/burgers that were well done;

Women with PSC were more likely to have recurrent urinary tract infections and less likely to receive estrogen replacement.

These findings offer insight into the complex interactions between genes and environmental exposures in PSC.

Novel Treatment Approaches

Bile acids retained in the liver are likely key drivers of liver injury and progression of fibrosis in patients with PSC. Blocking bile acid recycling by inhibiting the apical sodium-dependent bile acid transporter (ASBT) in the intestine is an attractive pharmacologic approach.

Keller and colleagues[7] described the effect of LUM001, a potent, minimally absorbed ASBT inhibitor, on serum bile acid levels and liver injury in a rat partial bile duct ligation model of cholestasis.Blocking the enterohepatic recirculation of bile acids with LUM001 attenuated the increase in serum bile acid levels and reduced the severity of cholestatic liver injury, suggesting that an ASBT inhibitor could provide a novel treatment for cholestatic liver disease by limiting the accumulation of toxic bile acids.

Simmons and colleagues[8] also reported that pharmacologic inhibition of the ileal ASBT blocks progression of liver disease in mdr2-/- mice.Treatment with SC-435 (an analogue of LUM001) increased the loss of bile acids in feces, improved animal growth rates, and reduced plasma biomarkers of cholestasis (serum bile acid levels) and hepatocellular injury. Concomitantly, mRNA expression of tumor necrosis factor alpha, a signature proinflammatory cytokine of murine sclerosing cholangitis, was reduced. Furthermore, expression levels of pro-fibrotic genes were significantly down-regulated in SC-435 treated vs mdr2-/- control mice. These two studies suggest that inhibition of ASBT could be a promising target for pharmacotherapy of PSC.

Another approach to reduce bile acid toxicity is to activate farnesoid X receptor (FXR) and retinoid X receptor (RXR) and repress CYP7A1 and therefore bile acid synthesis. All-trans retinoic acid (ATRA), which activates FXR and RXR in human hepatocytes, is a potent inhibitor of bile acid synthesis in humans. In animal models of biliary injury, ATRA improved hepatic inflammation and fibrosis when combined with ursodeoxycholic acid (UDCA). Twelve-week combination therapy with ATRA plus a moderate dose of UDCA significantly reduced serum parameters of cholestasis (alkaline phosphatase, ALT, and bile acids levels) in patients with PSC.[9] Side effects were frequent at the full ATRA dose. However, further evaluation of this combination therapy with a lower dose of ATRA, UDCA, and other new agents is recommended.

One potential new agent is obeticholic acid (OCA; 6-ethyl chenodeoxycholic acid), a highly potent, selective FXR agonist. OCA has been suggested to have a beneficial effect in a variety of liver diseases; for example, FXR-selective derivatives are under investigation as treatment for nonalcoholic steatohepatitis.[10]


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