pulmicort and Cholangitis--Sclerosing

While bile acids are important for both digestion and signalling, hydrophobic bile acids can be harmful, especially when in high concentrations. Mechanisms for the protection of cholangiocytes against bile acid cytotoxicity include negative feedback loops via farnesoid X nuclear receptor (FXR) activation, the bicarbonate umbrella, cholehepatic shunting and anti-inflammatory signalling, among others. By altering or overwhelming these defence mechanisms, cholestatic diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) can further progress to biliary cirrhosis, end-stage liver disease and death or liver transplantation. While PBC is currently treated with ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), many fail treatment, and we have yet to find an effective therapy for PSC. Novel therapies under evaluation target nuclear and surface receptors including FXR, transmembrane G-protein-coupled receptor 5 (TGR5), peroxisome proliferator-activated receptor (PPAR) and pregnane X receptor (PXR). Modulation of these receptors leads to altered bile composition, decreased cytotoxicity, decreased inflammation and improved metabolism. This review summarizes our current understanding of the role of bile acids in the pathophysiology of cholestatic liver diseases, presents the rationale for already approved medical therapies and discusses novel pharmacologic therapies under investigation.

Topics: Bile Acids and Salts; Budesonide; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis, Sclerosing; Cholestasis; Drug Therapy, Combination; Elasticity Imaging Techniques; Humans; Immunosuppressive Agents; Liver; Liver Cirrhosis, Biliary; Receptors, Cytoplasmic and Nuclear; Ursodeoxycholic Acid

Primary sclerosing cholangitis is a chronic cholestatic disease of intrahepatic and extrahepatic biliary ducts, characterised by chronic periductal inflammation and sclerosis of the ducts, which results in segmental stenoses of bile ducts, cholestasis, fibrosis, and ultimately, liver cirrhosis. Patients with primary sclerosing cholangitis are at higher risk of cholangiocarcinoma as well as of colonic neoplasia, since primary sclerosing cholangitis is associated with inflammatory bowel disease in more than 80% of the patients. Several therapeutic modalities have been proposed for primary sclerosing cholangitis, like ursodeoxycholic acid, glucocorticosteroids, and immunomodulatory agents, but none has been successful in reversing the process of the disease. To date, liver transplantation is the only definite therapeutic solution for patients with advanced primary sclerosing cholangitis with liver cirrhosis.. To assess the beneficial and harmful effects of glucocorticosteroids for patients with primary sclerosing cholangitis.. We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, and LILACS from their inception until September 2009, as well as reference lists.. Randomised clinical trials comparing any dose or duration of glucocorticosteroids versus placebo, no intervention, or other immunosuppressive agents. We included trials irrespective of language, blinding, or publication status.. Authors extracted data independently and assessed the methodological quality by the generation of the allocation sequence, allocation concealment, double blinding, follow-up, incomplete outcome data reporting, selective reporting, baseline imbalance, and early stopping. The results of the meta-analyses were presented as relative risks (RR) or mean difference (MD), both with 95% confidence intervals (CI). The primary outcome measures were mortality and liver-related morbidity.. Two randomised clinical trials were eligible for inclusion. One trial compared biliary lavage with hydrocortisone versus saline in 17 patients. Hydrocortisone tended to increase adverse events (pancreatitis, cholangitis with septicaemia, paranoid ideas, fluid retention) (RR 3.43, 95% CI 0.51 to 22.9) and had no cholangiographic improvement, which led to termination of the trial. The other trial compared budesonide versus prednisone in 18 patients. Patients had statistically significant higher serum bilirubin concentration after treatment with prednisone compared with budesonide (MD 10.4 micromol/litre, 95% CI 1.16 to 19.64 micromol/litre). No other statistically significant effects on clinical or biochemical outcomes were reported on any of the evaluated interventions.. There is no evidence to support or refute peroral glucocorticosteroids for patients with primary sclerosing cholangitis. The intrabiliary application of corticosteroids via nasobiliary tube seems to induce severe adverse effects.

Topics: Anti-Inflammatory Agents; Budesonide; Cholangitis, Sclerosing; Humans; Hydrocortisone; Prednisone; Randomized Controlled Trials as Topic; Therapeutic Irrigation

Autoimmune hepatitis is a chronic liver disease of unknown aetiology characterized by interface hepatitis, hypergammaglobulinaemia and circulating autoantibodies. In the last decade a number of advancements have been made in the field of clinical and basic research: the simplified diagnostic criteria, the complete response defined as normalization of transaminase levels, the molecular identification of the antigenic targets of anti-liver cytosol antibody type 1 and anti-soluble liver antigen, the detection of anti-actin antibodies, the description of de novo autoimmune hepatitis after liver transplantation for non-autoimmune liver diseases, the characterization of autoimmune hepatitis with overlapping features of primary biliary cirrhosis or primary sclerosing cholangitis, the preliminary experience with novel treatment strategies based on cyclosporine, mycophenolate mofetil and budesonide, the role played by "impaired" regulatory T cells and the development of novel animal models of autoimmune hepatitis.

Topics: Animals; Autoantibodies; Autoantigens; Biomarkers; Budesonide; Cholangitis, Sclerosing; Cyclosporine; Glucocorticoids; Hepatitis, Autoimmune; Humans; Hypergammaglobulinemia; Immunity, Cellular; Immunoglobulin G; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Liver Transplantation; Mice; Mycophenolic Acid; Rats; Transaminases

Glucocorticosteroids have been suggested for primary sclerosing cholangitis, which is characterised by chronic inflammation and fibrosis in the intrahepatic and extrahepatic biliary tree.. To assess the beneficial and harmful effects of glucocorticosteroids for patients with primary sclerosing cholangitis.. We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials on The Cochrane Library, MEDLINE, EMBASE from their inception until March 2003, and reference lists.. Randomised clinical trials comparing any dose or duration of glucocorticosteroids versus placebo, no intervention, or other immunosuppressive agents. We included trials irrespective of language, blinding, or publication status.. Both reviewers extracted data independently and assessed the methodological quality by the generation of the allocation sequence, allocation concealment, double blinding, and follow-up. The results of the meta-analyses were presented as relative risks or weighted mean difference (WMD), both with 95% confidence intervals (CI). The primary outcome measures were mortality and liver-related morbidity.. Two randomised clinical trials were eligible for inclusion. One trial compared biliary lavage with hydrocortisone versus saline in 17 patients. A significant number of adverse events (pancreatitis; cholangitis with septicaemia; paranoid ideas; fluid retention) and no cholangiographic improvement led to termination of the trial. The other trial compared budesonide versus prednisone in 18 patients. Patients had significantly higher serum bilirubin concentration after treatment with prednisone compared with budesonide (WMD 10.4 micro mol/litre, 95% CI 1.16 to 19.64 micro mol/litre). No other significant effects on clinical or biochemical outcomes were identified for any of the evaluated interventions.. There is no evidence to support or refute peroral glucocorticosteroids for patients with primary sclerosing cholangitis.

Topics: Anti-Inflammatory Agents; Budesonide; Cholangitis, Sclerosing; Humans; Hydrocortisone; Prednisone; Randomized Controlled Trials as Topic

Topics: Anti-Inflammatory Agents; Budesonide; Cholagogues and Choleretics; Cholangitis, Sclerosing; Drug Therapy, Combination; Gastroenterology; Humans; Prednisone; Ursodeoxycholic Acid

PSC has characteristics of an (auto)immune-mediated disease: however, few studies have evaluated corticosteroid therapy for this disorder.. We performed an 8-wk double-blind randomized pilot study to assess the effects of additional treatment with 9 mg budesonide (n = 6) versus 3 mg budesonide (n = 6) versus 10 mg prednisone (n = 6) in patients who had been treated with UDCA (mean dose, 12 mg/kg/day) for at least 5 months without achieving biochemical remission. Pruritus and fatigue were evaluated using visual analog scales. Serum liver biochemistry was measured every 4 wk. At entry and at the end of the trial, adrenocorticotrophic hormone (ACTH) and dehydroepiandrosterone (DHEA) were measured to assess effects on the pituitary-adrenal axis. Duodenal bile was collected for assessment of biliary corticosteroid activity.. Pruritus decreased significantly more in the prednisone group compared to both the 3-mg and the 9-mg budesonide groups (p < 0.05). Alkaline phosphatase (mean: -23.4%; p = 0.03) and IgG (mean: -16.2%; p = 0.04) decreased in the prednisone group, whereas bilirubin, gamma-glutamyl transferase, aspartate aminotransferase, and alanine aminotransferase did not change significantly. No significant clinical or liver biochemical changes were observed in the 3-mg and 9-mg budesonide groups. Significantly larger drops in serum ACTH were found in the 10-mg prednisone group (-40.7%; p = 0.04) and 9-mg budesonide group (-36.6%; p = 0.02) compared to the 3-mg budesonide group (+ 19.0%). No significant differences in percentage change in baseline values for DHEA between the three treatment arms were found. Mononuclear cell proliferation assays did not demonstrate corticosteroid activity in bile. Autoimmune hepatitis was observed in one case (9 mg budesonide) when corticosteroids were tapered off.. The results of this pilot study suggest only minor beneficial short-term effects of prednisone but not budesonide on symptoms and serum liver tests in UDCA-treated PSC patients.

Topics: Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Adult; Alkaline Phosphatase; Anti-Inflammatory Agents; Bile; Budesonide; Cholagogues and Choleretics; Cholangitis, Sclerosing; Double-Blind Method; Fatigue; Female; Humans; Immunoglobulin G; Male; Middle Aged; Pilot Projects; Prednisone; Pruritus; Ursodeoxycholic Acid

This study was designed to evaluate the safety and estimate the efficacy of oral budesonide in patients with primary sclerosing cholangitis (PSC).. Twenty-one patients with PSC were treated with 9 mg daily of oral budesonide for 1 yr.. Significant, but marginally important, improvement in serum alkaline phosphatase (1,235 +/- 190 vs 951 +/-206 U/L, p = 0.003) and AST levels (119 +/- 14 vs 103 +/- 19 U/L, p = 0.02) was noted at the end of the treatment period. Serum bilirubin levels increased significantly in the 18 patients who completed 1 yr of treatment (1.1 +/- 0.1 vs 1.4 +/- 0.3, p = 0.01) and no significant changes in liver tests were noted 3 months after budesonide was discontinued. The Mayo risk score did not change significantly, and although a significant improvement in the degree of portal inflammation was noted at the end of the treatment period, the degree of fibrosis and stage of disease were not significantly affected. There was a marked loss of bone mass of the femoral neck (0.851 +/- 0.02 vs 0.826 +/- 0.02 g/cm2, p = 0.002) and lumbar spine (1.042 +/- 0.02 vs 1.029 +/- 0.02 g/cm2, p = 0.09) at 1 yr of treatment with budesonide. Two patients required evaluation for liver transplantation during treatment, and two patients developed cosmetic side effects.. Oral budesonide appears to be of minimal, if any, benefit and it is associated with a significant worsening of osteoporosis in patients with PSC.

Topics: Administration, Oral; Adult; Aged; Alkaline Phosphatase; Anti-Inflammatory Agents; Aspartate Aminotransferases; Bilirubin; Biomarkers; Biopsy; Budesonide; Cholangitis, Sclerosing; Disease Progression; Female; Humans; Male; Middle Aged; Pilot Projects; Prognosis; Safety

BACKGROUND Systemic IgG4-related disease is a rare disease that can affect the hepatobiliary system and may lead to tissue fibrosis and organ failure. Diagnostic criteria for IgG4-related disease are well established, and systemic glucocorticoids are recommended for initiation of treatment. Besides the beneficial properties of glucocorticoids, the long-term treatment with systemic steroids carries the risk of toxicity, especially in elderly patients, in whom IgG4-related disease is more common. Furthermore, disease relapses may occur during the tapering of steroids. Overall, the optimal treatment approach for maintenance therapy has not been clarified yet and is an area of current clinical research. CASE REPORT We present a patient with IgG4-related sclerosing cholangitis and histologically confirmed systemic (multi-organ) IgG4-related disease who was at increased risk of disease recurrence. The effects of immunosuppressants (prednisolone, 6-mercaptopurine, budesonide) on clinical symptoms, laboratory parameters (AST, ALT, AP, γGT, bilirubin), and imaging examinations (magnetic resonance cholangiography) were documented over 56 months. Control of IgG4-related sclerosing cholangitis was achieved - without systemic prednisolone - with the locally acting glucocorticoid budesonide in combination with low-dose 6-mercaptopurine. During treatment with 6-mercaptopurine, transient hepatotoxicity occurred, which was reversed by intermittent pausing and subsequent dose reduction. In addition, gangrenous cholecystitis occurred as a complication of immunosuppression and was treated by emergency cholecystectomy. CONCLUSIONS Budesonide could be a new treatment modality for IgG4-related sclerosing cholangitis. Systemic manifestations of immunoglobulin G4-related disease can be controlled with low-dose 6-mercaptopurine. Gangrenous cholecystitis may occur as a complication of immunosuppressive treatment.

Topics: Aged; Budesonide; Cholangitis, Sclerosing; Humans; Immunoglobulin G; Immunoglobulin G4-Related Disease; Mercaptopurine

Budesonide has been studied in patients with primary sclerosing cholangitis (PSC). This study was designed to evaluate the efficacy of oral budesonide on liver function tests in patients with PSC and pouchitis associated with ileal pouch-anal anastomosis (IPAA).. The study group consisted of 18 pouch patients with underlying ulcerative colitis (UC) and PSC who were treated with 9 mg daily of budesonide for their underlying pre-pouch ileitis and pouchitis for 1-3 months followed by 3-6 mg maintenance for another 9 months. Demographic and clinical variables were analyzed.. The mean age was 39.4±12.4 years (range, 21-59 years). There was no significant change in aspartate aminotransferase (AST) [median (interquartile range) (IQR) 32 (25, 43.8) vs. 35.5 (25.5, 53), p=0.35], alanine aminotransferase (ALT) [37.5 (25.5, 49.5) vs. 40 (30, 84.3), p=0.29], alkaline phosphatase [142.5 (98.5, 264.5) vs. 126 (94.3, 189.5), p=0.35], serum bilirubin [0.7 (0.4, 1.3) vs., 0.6 (0.4, 1.6), p=0.13] or albumin levels [4.3 (3.9, 4.4) vs. 4.2 (3.8, 4.4), p=0.22] at the end of the treatment period (1 year). The revised Mayo Risk Score did not change significantly and three patients required evaluation for liver transplantation during treatment. There was a significant improvement in the endoscopy subscores in the afferent limb and pouch after a year of budesonide treatment (p=0.001).. Oral budesonide appears to have no impact on liver function tests in pouch patients with PSC. However it significantly improved afferent limb and pouch inflammation in IPAA patients.

Topics: Adult; Anal Canal; Anastomosis, Surgical; Biomarkers; Budesonide; Cholangitis, Sclerosing; Colitis, Ulcerative; Colonic Pouches; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Glucocorticoids; Humans; Liver Function Tests; Male; Middle Aged; Pouchitis; Proctocolectomy, Restorative; Prospective Studies; Time Factors; Treatment Outcome; Young Adult

Autoimmune disorders (AID) have been shown to be associated with chronic antibiotic-refractory pouchitis (CARP). The role of anti-microsomal antibodies in ileal pouch disorders has not been investigated. The aims of the study were to investigate the prevalence of positive anti-microsomal antibody in symptomatic patients with ileal pouches and to investigate its clinical implications.. A total of 118 consecutive symptomatic patients with ileal pouches were included between January and October 2010. Anti-microsomal antibodies were measured at the time of presentation. Demographic, clinical, and laboratory characteristics were compared between patients with positive and negative anti-microsomal antibody.. There were 14 patients (11.9%) with positive serum anti-microsomal antibody. The mean age of patients in the antibody positive and negative groups were 41.8 ± 14.4 and 42.0 ± 14.0 years, respectively (p = 0.189). All 14 patients in the antibody positive group (100%) had some form of AID, as compared to 20 patients (19.2%) in the antibody negative group (p < 0.001). Four (28.6%) patients in the antibody positive group had at least one AID in addition to Hashimoto's thyroiditis in contrast to four (3.8%) in the antibody negative group (p = 0.003). In addition, five (35.7%) patients had associated primary sclerosing cholangitis (PSC) in the antibody positive group compared to nine (8.7%) in the antibody negative group (p = 0.012). Eleven patients (78.6%) in the antibody positive group required steroids for treatment of pouch related symptoms in contrast to 26/104 (25%) patients in the antibody negative group (p = 0.002).. Anti-microsomal antibodies were common in pouch patients presenting with symptoms. Patients with positive anti-microsomal antibodies were much more likely to have concurrent AID and PSC. These patients were more likely to require therapy with steroids.

Topics: Adult; Anti-Bacterial Agents; Anti-Inflammatory Agents; Autoantibodies; Autoimmune Diseases; Budesonide; Cholangitis, Sclerosing; Crohn Disease; Drug Resistance, Bacterial; Female; Hashimoto Disease; Humans; Male; Middle Aged; Pouchitis

Topics: Anti-Inflammatory Agents; Autoimmune Diseases; Budesonide; Cholagogues and Choleretics; Cholangitis, Sclerosing; Cholestasis, Intrahepatic; Disease-Free Survival; Drug Therapy, Combination; Humans; Liver Cirrhosis, Biliary; Liver Function Tests; Liver Transplantation; Syndrome; Ursodeoxycholic Acid