Geniposide suppresses liver injury in a mouse model of DDC-induced sclerosing cholangitis.

Sclerosing cholangitis, characterized by biliary inflammation, fibrosis, and stricturing, remains one of the most challenging conditions of clinical hepatology. Geniposide (GE) has anti-inflammatory, hepatoprotective, and cholagogic effects. Whether GE provides inhibition on the development of sclerosing cholangitis is unknown. Here, we investigated the role of GE in a mouse model in which mice were fed with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) for 4 weeks to induce sclerosing cholangitis. The results demonstrated that the increased hepatic gene expressions of pro-inflammatory (IL-6, VCAM-1, MCP-1, and F4/80) and profibrogenic markers (Col1α1, Col1α2, TGF-ß, and α-SMA) in DDC feeding mice were reversed after treatment with GE. GE also suppressed expressions of CK19 and Ki67 in DDC-fed mice, suggesting that GE could ameliorate DDC-induced hepatocytes and cholangiocytes proliferation. In addition, GE significantly increased bile acids (BAs) secretion in bile, which correlated with induced expressions of hepatic FXR, BAs secretion transporters (BSEP, MRP2, MDR1, and MDR2), and reduced CYP7A1 mRNA expression. Furthermore, higher expressions of ileal FXR-FGF15 signaling and reduced ASBT were also observed after GE treatment. Taken together, these data showed that GE could modulate inflammation, fibrosis, and BAs homeostasis in DDC-fed mice, which lead to efficiently delay the progression of sclerosing cholangitis.

Loss of keratin 19 favours the development of cholestatic liver disease through decreased ductular reaction.

Keratins (K) are cytoprotective proteins and keratin mutations predispose to the development of multiple human diseases. K19 represents the most widely used marker of biliary and hepatic progenitor cells as well as a marker of ductular reaction that constitutes the basic regenerative response to chronic liver injury. In the present study, we investigated the role of K19 in biliary and hepatic progenitor cells and its importance for ductular reaction. K19 wild-type (WT) and knockout (KO) mice were fed: (a) 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC); (b) cholic acid (CA); (c) a choline-deficient, ethionine-supplemented (CDE) diet; or (d) were subjected to common bile duct ligation (CBDL). The bile composition, liver damage, bile duct proliferation, oval cell content and biliary fibrosis were analysed. In untreated animals, loss of K19 led to redistribution of the K network in biliary epithelial cells (BECs) but to no obvious biliary phenotype. After DDC feeding, K19 KO mice exhibited (compared to WTs): (a) increased cholestasis; (b) less pronounced ductular reaction with reduced ductular proliferation and fewer oval cells; (c) impaired Notch 2 signalling in BECs; (d) lower biliary fibrosis score and biliary bicarbonate concentration. An attenuated oval cell proliferation in K19 KOs was also found after feeding with the CDE diet. K19 KOs subjected to CBDL displayed lower BEC proliferation, oval cell content and less prominent Notch 2 signal. K19 deficiency did not change the extent of CA- or CBDL-induced liver injury and fibrosis. Our results demonstrate that K19 plays an important role in the ductular reaction and might be of importance in multiple chronic liver disorders that frequently display a ductular reaction.

Sclerosing cholangitis secondary to bleomycin-iodinated embolization for liver hemangioma.

Sclerosing cholangitis (SC) is a rarely reported morbidity secondary to transcatheter arterial chemoembolization (TACE) with bleomycin-iodinated oil (BIO) for liver cavernous hemangioma (LCH). This report retrospectively evaluated the diagnostic and therapeutic course of a patient with LDH who presented obstructive jaundice 6 years after TACE with BIO. Preoperative imaging identified a suspected malignant biliary stricture located at the convergence of the left and right hepatic ducts. Operative exploration demonstrated a full-thickness sclerosis of the hilar bile duct with right hepatic duct stricture and right lobe atrophy. Radical hepatic hilar resection with right-side hemihepatectomy and Roux-en-Y hepaticojejunostomy was performed because hilar cancer could not be excluded on frozen biopsy. Pathological results showed chronic pyogenic inflammation of the common and right hepatic ducts with SC in the portal area. Secondary SC is a long-term complication that may occur in LCH patients after TACE with BIO and must be differentiated from hilar malignancy. Hepatic duct plasty is a definitive but technically challenging treatment modality for secondary SC.

The effect of silver nitrate, chloroformic garlic extract, and normal saline in induction of sclerosing cholangitis in rabbits.

OBJECTIVE: To evaluate the effects of 0.5% silver nitrate, 20% chloroformic garlic extract, and 0.9% normal saline in induction of sclerosing cholangitis in the bile ducts of rabbits. METHODS: During a-6-months period from April to September 2006 in Shiraz University Laboratory Animal Research Center, we selected 3 equal groups of rabbits. We injected 0.5% silver nitrate, 20% chloroformic garlic extract, and 0.9% normal saline into the bile ducts of each group. The animals were euthanized, and autopsied after 4 months and the liver and bile ducts were removed and studied histopathologically. Cholangiography was undertaken to evaluate the presence and extent of any sclerosing cholangitis. RESULTS: Animals showed sclerosing cholangitis in silver nitrate group (7 [58%]), one (8%) in chloroformic garlic extract group and one (7%) in normal saline group. The difference between silver nitrate and chloroformic garlic extract groups were statistically significant and similar results were noticed between chloroformic garlic extract and normal saline groups. CONCLUSION: Twenty percent of chloroformic garlic extract had fewer complications such as sclerosing cholangitis, compared to other materials.