Long–Term Ursodeoxycholic Acid Delays Histological Progression in Primary Biliary Cirrhosis

Angulo, Paul; Batts, Kenneth P.; Therneau, Terry M.; Jorgensen, Roberta A.; Dickson, E. Rolland; Lindor, Keith D.

doi:10.1002/hep.510290301

Cited by 206 publications

(65 citation statements)

References 26 publications

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“…It is possible that the use of ursodeoxycholic acid may alter the natural history of PBC so that transplantation may be deferred. 12 We have not been able to examine the effect of pretransplantation treatment with ursodeoxycholic acid on the timing and outcome after transplantation because some patients had been treated with ursodeoxycholic acid but discontinued the treatment before referral. An alternative explanation is that the high numbers of patients grafted for PBC in the early stages of the evolution of transplantation program treated those with very advanced disease, and the greater awareness of transplantation has ensured that now patients are referred before reaching the end-stage of disease.…”

Section: Resultsmentioning

confidence: 99%

Transplantation for Primary Biliary Cirrhosis: Retrospective Analysis of 400 Patients in A Single Center

et al. 2001

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Orthotopic liver transplantation (OLT) is an effective treatment for patients with advanced primary biliary cirrhosis (PBC). We have conducted a retrospective analysis of 400 consecutive patients transplanted for PBC between 1983 and 1999. Mean follow-up was 56 months. The proportion of patients grafted for PBC fell progressively, from 35% in 1990 (n ‫؍‬ 80) to 21% in 1999 (n ‫؍‬ 111); comparison of patients grafted in the 2 decades showed that the median age increased from 53 to 56 years and the median serum bilirubin at transplantation fell from 270 mol/L to 132 mol/L. The overall actuarial patient and graft survival at 1, 5, and 10 years is 83%, 78%, and 67% and 82%, 75%, and 61%, respectively. The net gain in 5-year survival compared with predicted survival in the absence of transplantation fell from 37% (range, 82%-90%) to 16% (range, 91%-99%). Multiple organ failure (16.1%) and sepsis (9.6%) were the major causes of early deaths (<6 months). Recurrent PBC, diagnosed on allograft histology, was found in 68 (17%) patients, at a mean time of 36 months. We were unable to identify any pretransplantation donor or recipient factor, which identified those patients at risk of recurrence, although recurrence was much earlier and more frequently seen in patients receiving tacrolimus (P ‫؍‬ .04). PBC remains a good indication for liver transplantation, with excellent survival rates. The age at transplantation increased although patients tended to be grafted earlier. Survival rates have increased although there is a reduction in the survival benefit. Recurrence may be common, but does not seem to affect medium-term graft survival. (HEPATOLOGY 2001;33:22-27.)Orthotopic liver transplantation (OLT) in humans was first successfully reported by Starzl in 1968 1 ; in the early years, few patients were transplanted and survival rates were poor. With increasing experience; better selection; improved surgical, anesthetic, and microbiological techniques; and the introduction of potent immunosuppressive agents, results have improved considerably. As results have improved, patients have been offered transplantation when they are less ill and more likely to withstand the stresses of the procedure and the postoperative period.Primary biliary cirrhosis (PBC) has been one of the most common indications for liver transplantation in adults. 2 Although the pathogenesis remains uncertain and medical therapy, at best, only slows progression of the disease, the natural history is well understood and there are several prognostic models that have been developed to predict not only survival in the absence of transplantation but also survival after transplantation. 3,4 The indications for transplantation are relatively well defined: either a poor quality of life, usually because of intractable lethargy or pruritus, or an anticipated length of life less than 1 year. 5

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Section: Resultsmentioning

confidence: 99%

Transplantation for Primary Biliary Cirrhosis: Retrospective Analysis of 400 Patients in A Single Center

et al. 2001

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“…In contrast to classical immunosuppressors, UDCA is particularly useful in primary biliary cirrhosis (PBC), a chronic cholestatic disease of unknown pathogenesis that is associated with characteristic autoimmune phenomena (4)(5)(6)(7)(8)(9). When adequate UDCA therapy - i.e., daily administration of high doses of this hydrophilic bile acid - is initiated at early stages (I-II) of the disease, about 60% of PBC patients normalize their biochemical parameters and reach a survival comparable to that in the general population (8,9).…”

Section: Introductionmentioning

confidence: 99%

Combination of ursodeoxycholic acid and glucocorticoids upregulates the AE2 alternate promoter in human liver cells

Arenas¹,

Hervías²,

Úriz³

et al. 2008

J. Clin. Invest.

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Primary biliary cirrhosis (PBC) is a cholestatic disease associated with autoimmune phenomena and alterations in both biliary bicarbonate excretion and expression of the bicarbonate carrier AE2. The bile acid ursodeoxycholic acid (UCDA) is currently used in treatment of cholestatic liver diseases and is the treatment of choice in PBC; however, a subset of PBC patients respond poorly to UDCA monotherapy. In these patients, a combination of UDCA and glucocorticoid therapy appears to be beneficial. To address the mechanism of this benefit, we analyzed the effects of UDCA and dexamethasone on AE2 gene expression in human liver cells from hepatocyte and cholangiocyte lineages. The combination of UDCA and dexamethasone, but not UDCA or dexamethasone alone, increased the expression of liver-enriched alternative mRNA isoforms AE2b1 and AE2b2 and enhanced AE2 activity. Similar effects were obtained after replacing UDCA with UDCA conjugates. In in vitro and in vivo reporter assays, we found that a UDCA/dexamethasone combination upregulated human AE2 alternate overlapping promoter sequences from which AE2b1 and AE2b2 are expressed. In chromatin immunoprecipitation assays, we demonstrated that combination UCDA/dexamethasone treatment induced p300-related interactions between HNF1 and glucocorticoid receptor on the AE2 alternate promoter. Our data provide a potential molecular explanation for the beneficial effects of the combination of UDCA and glucocorticoids in PBC patients with inadequate response to UDCA monotherapy.

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“…Approximately 70% of patients also have salivary gland involvement (2). The only widely used medical treatment, ursodeoxycholate (UDCA), is only moderately effective in preventing progression to cirrhosis (3)(4)(5). Interestingly, Gershwin and others (6)(7)(8) have determined that over 90% of patients with PBC produce autoantibodies specific for a conformation-dependent epitope of the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), a ubiquitous mitochondrial matrix protein associated with the inner mitochondrial membrane.…”

Section: Introductionmentioning

confidence: 99%

Bcl-2–dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis

Odin¹,

Huebert²,

Casciola‐Rosen³

et al. 2001

J. Clin. Invest.

101

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The close association between autoantibodies against pyruvate dehydrogenase-E2 (PDC-E2), a ubiquitous mitochondrial protein, and primary biliary cirrhosis (PBC) is unexplained. Many autoantigens are selectively modified during apoptosis, which has focused attention on apoptotic cells as a potential source of "neo-antigens" responsible for activating autoreactive lymphocytes. Since increased apoptosis of bile duct epithelial cells (cholangiocytes) is evident in patients with PBC, we evaluated the effect of apoptosis on PDC-E2. Autoantibody recognition of PDC-E2 by immunofluorescence persisted in apoptotic cholangiocytes and appeared unchanged by immunoblot analysis. PDC-E2 was neither cleaved by caspases nor concentrated into surface blebs in apoptotic cells. In other cell types, autoantibody recognition of PDC-E2, as assessed by immunofluorescence, was abrogated after apoptosis, although expression levels of PDC-E2 appeared unchanged when examined by immunoblot analysis. Both overexpression of Bcl-2 and depletion of glutathione before inducing apoptosis prevented this loss of autoantibody recognition, suggesting that glutathiolation, rather than degradation or loss, of PDC-E2 was responsible for the loss of immunofluorescence signal. We postulate that apoptotic cholangiocytes, unlike other apoptotic cell types, are a potential source of immunogenic PDC-E2 in patients with PBC.

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Long–Term Ursodeoxycholic Acid Delays Histological Progression in Primary Biliary Cirrhosis

Cited by 206 publications

References 26 publications

Transplantation for Primary Biliary Cirrhosis: Retrospective Analysis of 400 Patients in A Single Center

Transplantation for Primary Biliary Cirrhosis: Retrospective Analysis of 400 Patients in A Single Center

Combination of ursodeoxycholic acid and glucocorticoids upregulates the AE2 alternate promoter in human liver cells

Bcl-2–dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis

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