High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis

Smith, Timothy M.; Befeler, Alex S.

doi:10.1007/s11894-008-0021-z

Cited by 14 publications

(9 citation statements)

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“…Long‐term treatment of PSC patients with high‐dose ursodeoxycholic acid is associated with improvement in liver biochemistry and histology, although an effect on survival remains unproven,34–37 and it may be chemopreventive against carcinoma of the colon 38. Our current data do not suggest a protective effect against rPSC ( P = 0.614), but longer follow‐up may be needed for this to be realized.…”

Section: Discussionmentioning

confidence: 59%

A re-evaluation of the risk factors for the recurrence of primary sclerosing cholangitis in liver allografts

et al. 2009

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Previously, we have found that the absence of the colon after liver transplantation (LT) protects the patient from recurrent primary sclerosing cholangitis (rPSC). As our previous observation has not been confirmed in other series, we have reviewed our cohort of patients grafted for primary sclerosing cholangitis (PSC) with greater numbers and longer follow-up to reassess the rate, consequences, and risk factors for rPSC. We collected data on patients who underwent LT for PSC between January 1986 and April 2006. Data were collected for cytomegalovirus status, inflammatory bowel disease status, time of colectomy, type of colectomy, donor-recipient gender mismatch, recipient sex, extended donor criteria (EDC), and donor risk index. Accepted criteria were used to diagnose rPSC. Of a total of 230 consecutive adult patients, 61 (27%) underwent colectomy pre-/peri-LT, and 54 (23.5%) developed rPSC at a median of 4.6 (range, 0.5-12.9) years post-LT. A total of 263 deceased donor grafts were used, and 73 were EDC grafts. A diagnosis of rPSC was made in 61 of the 263 grafts (23%). The recurrence-free patient survival was significantly better (P Ͻ 0.05) in patients who underwent pre-/peri-LT colectomy and in those with non-EDC grafts. In conclusion, in this larger cohort of 230 patients and with longer follow-up of 82.5 (range, 0.0-238.6) months [in comparison with the previous report of 152 recipients with a follow-up of 52.8 (range, 1-146) months], we have shown that colectomy remains a significant risk factor for rPSC and that colectomy before and during initial LT for PSC confers a protective effect against rPSC in subsequent graft(s). Moreover, we have shown that EDC grafts are also a significant risk factor for rPSC. Liver Transpl 15:330-340, 2009. © 2009 AASLD. Received July 9, 2008 accepted September 23, 2008.Five years ago, we published a retrospective multivariable analysis of the risk factors associated with recurrent primary sclerosing cholangitis (rPSC) in liver allografts after transplantation and reported that the presence of an intact colon before transplantation was significantly associated with recurrence.

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Section: Discussionmentioning

confidence: 59%

A re-evaluation of the risk factors for the recurrence of primary sclerosing cholangitis in liver allografts

et al. 2009

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“…This realization has important implications for designing therapy in chronic cholestatic disorders such as primary biliary cirrhosis, which at present is limited to UDCA 9. UDCA's efficacy in other cholestatic disorders remains unproven and whether other agents can enhance the efficacy is unclear 26. The goals for this work were twofold: to elucidate the molecular mechanisms responsible for the impairment in GSH synthesis and to see how treatment may be improved.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of glutathione synthesis during cholestasis in mice

Yang¹,

Ramani²,

Xia³

et al. 2009

Hepatology

107

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Glutathione (GSH) provides important antioxidant defense and regulates multiple critical processes including fibrogenesis. There are conflicting literature studies regarding changes in GSH during cholestasis. Here we examined changes in the GSH synthetic enzymes during bile duct ligation (BDL) in mice and how treatment with ursodeoxycholic acid (UDCA) and/or S-adenosylmethionine (SAMe) affects the expression of these enzymes and liver injury. The hepatic expression of glutamate-cysteine ligase (GCL) subunits and GSH synthase (GS) increased transiently after BDL but fell to 50% of baseline by 2 weeks. Nuclear factor-erythroid 2-related factor 2 (Nrf2) trans-activates gene expression by way of the antioxidant response element (ARE), which controls the expression of all three genes. Despite increased Nrf2 nuclear levels, Nrf2 nuclear binding to ARE fell 2 weeks after BDL. Nuclear levels of c-Maf and MafG, which can negatively regulate ARE, were persistently induced during BDL and the dominant proteins bound to ARE on day 14. UDCA and SAMe induced the expression of GCL subunits and raised GSH levels. They increased nuclear Nrf2 levels, prevented c-Maf and MafG induction, and prevented the fall in Nrf2 nuclear binding to ARE. Combined treatment had additive effects, reduced liver cell death, and prevented fibrosis. Conclusion: GSH synthesis falls during later stages of BDL due to lower expression of GSH synthetic enzymes. UDCA and SAMe treatment prevented this fall and combined therapy was more effective on preserving GSH levels and preventing liver injury. (HEPATOLOGY 2009;49:1982-1991

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“…Liver biopsy can be essential in the diagnosis of small-duct PSC, but is not required for the diagnosis of largeduct PSC (Burak et al, 2003;Chapman, Fevery et al, 2010). Multiple studies show that using ursodeoxycholic acid (UDCA) at moderate to high dosages has been shown to improve liver histology and liver biochemistry (Smith & Befeler, 2007). Even though UDCA has not been demonstrated to improve either symptoms or mortality, it has been shown to reduce the incidence of colonic dysplasia, colorectal carcinoma and cholangiocarcinoma (Pardi et al, 2003).…”

Section: Primary Sclerosing Cholangitis (Psc)mentioning

confidence: 99%