Review article: the evidence that vancomycin is a therapeutic option for primary sclerosing cholangitis.

BACKGROUND AND AIMS: PSC is an autoimmune biliary inflammatory disorder that is often associated with inflammatory bowel disease (IBD), with 50%-75% of patients with PSC having coexisting IBD, most commonly ulcerative colitis. Currently, no medical therapies have been shown to improve the disease course or slow its progression. However, ongoing research has resulted in a growing interest in the use of antibiotics for treatment of PSC, of which vancomycin is the most studied. In this review, we summarise the current evidence on the use of vancomycin in PSC and comment on future research areas of interest. METHODS: A comprehensive PUBMED and EMBASE literature search for articles on vancomycin, PSC, therapeutic options and microbiome was performed. RESULTS: Two randomised clinical trials, three case series and two case reports were included in the study. These include uncontrolled data from at least 98 patients that include promising improvements in biochemistry and imaging. Optimal dosing regimens are unclear. CONCLUSION: Vancomycin is one of the most studied antibiotics used in the treatment of PSC with promising results. There is not currently sufficient evidence to support treatment recommendations. Further research is needed to establish if vancomycin is a PSC treatment.

An update on primary sclerosing cholangitis:from pathogenesis to treatment.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology despite advances in medical research that have focused on uncovering its pathogenesis. Recent developments in the diagnosis of PSC including technological advances in magnetic resonanace cholangiography and the recognition of distinct clinical subtypes have led to more frequent early detection and appropriate therapy when indicated. Continued work in the areas of identifying genetic predisposing factors and novel molecular therapeutic targets are expected to create new opportunities for treating patients suffering from this chronic illness. In this review we highlight recent advances in PSC pathogenesis, diagnosis and management.

Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis - a pilot study.

BACKGROUND: Emerging data suggest that oral antibiotics may have therapeutic effects in primary sclerosing cholangitis (PSC), but published studies are limited. AIMS: To investigate the safety and efficacy of oral vancomycin and metronidazole in patients with PSC. METHODS: Thirty-five patients with PSC were randomised in a double-blind manner into four groups: vancomycin 125 mg or 250 mg four times/day, or metronidazole 250 mg or 500 mg three times/day for 12 weeks. The primary endpoint was decrease in alkaline phosphatase (ALK) at 12 weeks. Secondary end points included serum bilirubin and Mayo PSC risk score; pruritus; and adverse effects (AEs). Nonparametric tests were used for analysis. RESULTS: The primary endpoint was reached in the low-dose (-43% change in ALK, P = 0.03) and high-dose (-40%, P = 0.02) vancomycin groups, with two patients in the former experiencing ALK normalisation. Bilirubin decreased significantly in the low-dose metronidazole group (-20%, P = 0.03) and trended towards significance in the low-dose vancomycin group (-33%, P = 0.06). Mayo PSC risk score decreased significantly in the low-dose vancomycin (-0.55, P = 0.02) and low-dose metronidazole group (-0.16, P = 0.03). Pruritus decreased significantly in the high-dose metronidazole group (-3.4, P = 0.03). AEs led to medication discontinuation in six patients, four of whom were receiving metronidazole. CONCLUSIONS: Both vancomycin and metronidazole demonstrated efficacy; however, only patients in the vancomycin groups reached the primary endpoint, and with less adverse effects. Larger, longer-term studies are needed to further examine the safety and efficacy of antibiotics as a potential treatment for patients with primary sclerosing cholangitis (clinicaltrials.gov NCT01085760).

Colonic neoplasia in young patients with inflammatory bowel disease and primary sclerosing cholangitis.

AIM: Current guidelines recommend annual surveillance for colorectal cancer (CRC) in all patients with inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC). The aim of our study was to validate the need for annual surveillance for colon neoplasia in patients ≤45 of age with a combined diagnosis of PSC and IBD. METHOD: We identified patients, ≤45 years of age with a combined diagnosis of PSC and IBD, who were seen at the Mayo Clinic between 1995 and 2010. We then reviewed the medical records of the patients who developed colonic neoplasia defined as cancer, high-grade dysplasia (HGD) or dysplasia-associated lesion or mass (DALM). RESULTS: In the population of 784 patients ≤45 years of age with a combined diagnosis of PSC and IBD, 10 (1.3%) of 784 developed colonic neoplasia during the follow-up period. Seven patients had colon cancer, one had HGD and two had a DALM. CONCLUSION: Colonic neoplasia is uncommon in young patients (≤45 years of age) with a combined diagnosis of PSC and IBD. We suggest delaying surveillance in young patients and propose that studies should be carried out to clarify the cost-effectiveness of annual or biannual surveillance colonoscopies according to patient age.

The safety and efficacy of oral docosahexaenoic acid supplementation for the treatment of primary sclerosing cholangitis - a pilot study.

BACKGROUND: Primary sclerosing cholangitis (PSC) is characterised by progressive inflammatory and fibrotic destruction of the biliary ducts. There are no effective medical therapies and presently high dose ursodeoxycholic acid is no longer recommended due to significant adverse events in a recent clinical trial. Cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction is associated with PSC in both children and adults. Since CFTR dysfunction leads to altered fatty acid metabolism, specifically reduced docosahexaenoic acid (DHA), we hypothesised that DHA supplementation might be an effective therapy for patients with PSC. AIM: To determine the safety and efficacy of oral DHA supplementation for the treatment of PSC. METHODS: We conducted a 12 month open-label pilot study to evaluate safety of oral DHA and its effects on serum alkaline phosphatase as a primary outcome measure in 23 patients with PSC. DHA was administered orally at 800 mg twice per day. Secondary outcomes included changes in other liver function tests and fibrosis biomarkers. RESULTS: A 1.7-fold increase in serum DHA levels was observed with supplementation. The mean alkaline phosphatase level (±S.E.) at baseline was 357.8 ± 37.1 IU compared to 297.1 ± 23.7 IU (P < 0.05) after 12 months of treatment. There were no changes in other liver function tests and fibrosis biomarkers. No adverse events were reported. CONCLUSIONS: Oral DHA supplementation is associated with an increase in serum DHA levels and a significant decline in alkaline phosphatase levels in patients with PSC. These data support the need for a rigorous trial of DHA therapy in PSC.

High-dose ursodeoxycholic acid increases risk of adverse outcomes in patients with early stage primary sclerosing cholangitis.

BACKGROUND: Ursodeoxycholic acid (UDCA) in a dose of 28-30 mg/kg/day increases the likelihood of clinical deterioration of primary sclerosing cholangitis (PSC) patients. AIM: To compare the risk of adverse clinical endpoints in patients with varying disease status. METHODS: We reviewed records from patients previously enrolled in a study evaluating the effects of high dose (28-30 mg/kg/day) UDCA in PSC. Patients were grouped according to treatment (UDCA vs. placebo) and baseline disease status (histological stage of PSC, total serum bilirubin). Development of clinical endpoints including death, liver transplantation, cirrhosis, oesophageal varices and cholangiocarcinoma was sought. RESULTS: A total of 150 patients were included of whom 49 patients developed endpoints. There was an increased development of endpoints among patients using UDCA vs. placebo (14 vs. 4, P=0.0151) with early histological disease (stage 1-2, n=88) but not with late stage (stage 3-4, n=62) disease (17 vs. 14, P=0.2031). Occurrence of clinical endpoints was also higher in patients receiving UDCA vs. placebo (16 vs. 2, P=0.0008) with normal bilirubin levels (total bilirubin ≤1.0 mg/dL) but not in patients with elevated bilirubin levels (15 vs. 16, P=0.6018). Among patients not reaching endpoints 31.7% had normalisation of their alkaline phosphatase levels when compared to 14.3% in patients who reached endpoints (P=0.073). CONCLUSION: The increased risk of adverse events with UDCA treatment when compared with placebo is only apparent in patients with early histological stage disease or normal total bilirubin.

Current therapies for nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in adults and children in many regions of the world. Although a relatively benign condition in some, for others the disease will progress to cirrhosis and end-stage liver disease with associated complications including hepatocellular cancer. Pharmaceutical therapies have had mixed results and none are accepted as standard therapy. Depending on the metric used to assess response (biochemical or histological), there are some therapies which may afford benefit. Others, however, have caused less than desirable adverse effects. Unfortunately, no particular treatment has emerged as safe and highly effective. The cornerstones of management of this problematic condition should include exercise and efforts at weight reduction through dietary changes and increased physical activity. Weight reduction does indeed seem to be beneficial in this setting, as evidenced by studies including those evaluating the effect of bariatric surgery. Less is known, however, about the effort of exercise in and of itself as a treatment strategy, even in the absence of a reduction in body weight. In this paper, we review the literature pertaining to the current state of NAFLD management with an emphasis on pharmacotherapy.

Recurrent primary biliary cirrhosis after liver transplantation.

Recurrent primary biliary cirrhosis (PBC) is an important clinical outcome after liver transplantation (LT) in selected patients. Prevalence rates for recurrent PBC (rPBC) reported by individual LT programs range between 9% and 35%. The diagnostic hallmark of rPBC is histologic identification of granulomatous changes. Clinical and biochemical features are frequently absent with rPBC and cannot be used alone for diagnostic purposes. Some of the risk factors of rPBC may include recipient factors such as age, gender, HLA status and immunosuppression, as well as donor factors such as age, gender and ischemic time, although controversy exists. Most patients have early stage disease at the time of diagnosis, and there may be a role for therapy with ursodeoxycholic acid. While short- and medium-term outcomes remain favorable, especially if compared to patients transplanted for other indications, continued follow-up may identify reduced long-term graft and patient survival.

Review article: nuclear receptors and liver disease--current understanding and new therapeutic implications.

BACKGROUND: The important role of nuclear receptors and their contribution to liver function in both physiological and pathological conditions has come to attention in recent years and has advanced our understanding of several liver diseases. These findings led to the introduction of targeting nuclear receptors as treatment strategies for various liver diseases. AIMS: To review the new insights brought by the study of nuclear receptors to our understanding of the molecular basis of various liver diseases, and to summarize some of the recent studies that evaluated the efficacy of targeting nuclear receptor as a new approach in treating liver diseases. METHODS: Review of articles, using PubMed and article references. RESULTS: Nuclear receptor ligands in patients with liver diseases have been associated with a variety of toxicities. Some clinical results have not met the expectations predicted from animal experiments. Mechanistic explanations at the molecular level are needed for preventing toxicity and improving outcomes from nuclear receptor ligands. CONCLUSION: The use of various nuclear receptor ligands in liver diseases is a promising approach that can benefit many patients suffering from these devastating diseases. However, we are far from a full understanding of the molecular mechanisms by which these receptors work.

Clinical trial: randomized controlled study of zidovudine and lamivudine for patients with primary biliary cirrhosis stabilized on ursodiol.

BACKGROUND: A human betaretrovirus has been characterized in patients with primary biliary cirrhosis (PBC). Uncontrolled studies using combination anti-retroviral therapy have reported significant biochemical and histological improvement. AIM: To conduct a double blind, randomized controlled trial as a proof of principal to link infection with PBC. METHODS: Fifty-nine patients with an alkaline phosphatase level>1.5 upper limits of normal stabilized on ursodeoxycholic acid therapy were randomized to either 300 mg zidovudine and 150 mg lamivudine B.I.D. or placebo for 6 months. RESULTS: None of the patients normalized alkaline phosphatase and no significant differences were observed in normalizing serum aminotransferase levels. Significant differences were observed in the antiviral versus placebo arms with improvements in serial alkaline phosphatase (p<0.04), ALT (p<0.03) and AST (p<0.04) as well as clinical score (p<0.02). After 6 months, 25% of patients in the placebo arm and 4% in the antiviral arm had evidence of virus in serum. CONCLUSIONS: The study endpoints for normalizing hepatic biochemistry were too stringent to show efficacy for zidovudine and lamivudine therapy despite the demonstrable impact on clinical and biochemical improvement. Accordingly, more potent anti-viral regimens will be required to confirm the efficacy of antiviral therapy in PBC patients with human betaretrovirus infection.

Primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic syndrome of unknown etiology frequently associated with inflammatory bowel disease and characterized by diffuse inflammation and fibrosis of the intra and/or extrahepatic bile ducts. Recent studies seem to favor autoimmunity in the context of a genetic predisposition as the most likely underlying mechanism for the development of the disease, however our knowledge on the pathogenesis of PSC is still incomplete and further work is needed. The most common manifestations are fatigue, pruritus, jaundice and abdominal pain; however, the increasing use of invasive cholangiography has led to diagnosing this condition in a high proportion of asymptomatic patients. PSC usually follows a progressive course leading to biliary cirrhosis with complications of portal hypertension and hepatic failure. Patients with PSC also may develop a number of other complications, including bacterial cholangitis, dominant biliary strictures, conditions of chronic cholestasis, colorectal cancer and cholangiocarcinoma. Currently, no medical therapy aimed at disrupting disease progression is available, although high-dose ursodeoxycholic acid and other medicines are being evaluated in clinical trials. A better understanding of the pathogenesis of the disease will serve as a guide for evaluating new medical approaches. Liver transplantation is the only therapeutic alternative that improves survival in patients with end-stage PSC. Prognostic models are useful in determining the timing of liver transplantation.

Development of autoimmune hepatitis in the setting of long-standing primary biliary cirrhosis.

Primary biliary cirrhosis and autoimmune hepatitis, the most common autoimmune liver diseases in adults, are frequently easily differentiated by a combination of clinical, biochemical, and histological features along with the presence of highly sensitive and characteristic serum autoantibodies. Patients presenting with "overlapping" features of both conditions simultaneously are not uncommon. However, patients who switch over time from one disease to another have remained largely unrecognized. We report here two cases from the spectrum of autoimmune liver disease, patients who had well-defined primary biliary cirrhosis for a number of years and then developed the classic picture of superimposed autoimmune hepatitis. The importance of its recognition and the appropriate management modifications are discussed.

Incomplete response to ursodeoxycholic acid in primary biliary cirrhosis: is a double dosage worthwhile?

OBJECTIVE: The aim of this study was to assess the safety and efficacy of high-dose ursodeoxycholic acid (UDCA, 28-32 mg/kg/day) in patients with primary biliary cirrhosis (PBC) who had shown an incomplete response to the standard dose (13-15 mg/kg/day). METHODS: A total of 25 patients with PBC who had been on UDCA (13-15 mg/kg/day) therapy for 24-141 months and had shown persistent elevation of ALP activity at least two times the upper limit of normal were enrolled. The dose of UDCA was increased to 30 (28-32) mg/kg/day and given for 1 yr. RESULTS: A significant but marginal improvement in serum ALP activity (707+/-52 vs 571+/-32, p = 0.001) was noted at 1 yr of treatment with high-dose UDCA. However, levels of total bilirubin (1.1+/-0.2 vs 1.0+/-0.2, p = 0.1), AST (58+/-9 vs 54+/-1, p = 0.1), albumin (4.1+/-0.7 vs 4.0+/-0.08, p = 0.1), or Mayo risk score (4.13+/-0.3 vs 4.12+/-0.3, p = 0.2) remained essentially unchanged. Normalization of liver tests did not occur in any patient, and adverse events were not recorded in any case. CONCLUSIONS: Although UDCA at a dose of 28-32 mg/kg/day is well tolerated, this dosage does not seem to benefit most patients with PBC responding incompletely to a dose of 13-15 mg/kg/day. The results of this pilot study would seem to discourage further controlled trials of high-dose UDCA in suboptimal responders to the standard dose of UDCA.

Nutritional and metabolic considerations in the etiology of nonalcoholic steatohepatitis.

The aim of this study was to determine if a relationship exists between nonalcoholic steatohepatitis (NASH) and serum levels of free fatty acids, choline deficiency, or celiac disease. Forty-seven patients with liver biopsy proven NASH were enrolled. Total serum free fatty acids and anti-endomysial antibodies were determined in all patients, while plasma free and phospholipid-bound choline were determined in 29 patients. Total serum free fatty acid concentration correlated significantly with female gender and serum albumin concentration. Patients with severe fibrosis on liver biopsy had significantly greater serum concentration of free fatty acids than patients without severe fibrosis. Plasma free and phospholipid-bound choline levels were normal and no significant correlation was found between the concentration of plasma free or phospholipid bound choline, and the severity of liver damage. Only one of the 47 patients with NASH had a positive titer for the anti-endomysial antibody. In conclusion, increased serum concentrations of free fatty acids were found in NASH and were associated with development of more severe liver disease. Neither choline deficiency nor celiac sprue by anti-endomysial antibody testing was associated with NASH.

Bone disease in primary biliary cirrhosis: independent indicators and rate of progression.

BACKGROUND/AIMS: To identify indicators of osteoporosis and to determine the rate of bone loss in patients with primary biliary cirrhosis (PBC). METHODS: Bone mineral density of the lumbar spine and hip was measured at annual intervals over 7 years of follow-up in 176 patients with PBC. RESULTS: Osteoporosis (t-score below -2.5) was found in 20% of patients and occurred 32.1 times more frequently in patients with PBC than expected. Patients with histologic stage 3 or 4 disease had a 5.4-fold increased risk of osteoporosis compared to patients with stage 1 or 2. Age, body mass index, advanced stage (3 or 4), and history of fractures were the only independent indicators of osteoporosis. After 3 years of follow up, the rate of bone loss in patients with stage 1 or 2 increased and equaled that seen in patients with stage 3 or 4. Serum bilirubin level was the only variable independently associated with the rate of bone loss over time. CONCLUSIONS: Severity of the liver disease contributes significantly to the severity of bone disease in PBC. PBC patients who are older, thinner and have more advanced liver disease may have the most benefit from bone density measurements and treatment for their osteoporosis.

Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study.

OBJECTIVES: No effective therapy currently exists for patients with nonalcoholic steatohepatitis (NASH). Betaine, a naturally occurring metabolite of choline, has been shown to raise S-adenosylmethionine (SAM) levels that may in turn play a role in decreasing hepatic steatosis. Our aim was to determine the safety and effects of betaine on liver biochemistries and histological markers of disease activity in patients with NASH. METHODS: Ten adult patients with NASH were enrolled. Patients received betaine anhydrous for oral solution (Cystadane) in two divided doses daily for 12 months. Seven out of 10 patients completed 1 yr of treatment with betaine. RESULTS: A significant improvement in serum levels of aspartate aminotransferase (p = 0.02) and ALAT (p = 0.007) occurred during treatment. Aminotransferases normalized in three of seven patients, decreased by >50% in three of seven patients, and remained unchanged in one patient when compared to baseline values. A marked improvement in serum levels of aminotransferases (ALT -39%; AST -38%) also occurred during treatment in those patients who did not complete 1 yr of treatment. Similarly, a marked improvement in the degree of steatosis, necroinflammatory grade, and stage of fibrosis was noted at 1 yr of treatment with betaine. Transitory GI adverse events that did not require any dose reduction or discontinuation of betaine occurred in four patients. CONCLUSIONS: Betaine is a safe and well tolerated drug that leads to a significant biochemical and histological improvement in patients with NASH. This novel agent deserves further evaluation in a randomized, placebo-controlled trial.

Fat-soluble vitamin levels in patients with primary biliary cirrhosis.

OBJECTIVE: To determine the occurrence of fat-soluble vitamin deficiencies and to identify clinical factors that may predict vitamin deficiency in patients with primary biliary cirrhosis (PBC). METHODS: Review of our data from a randomized, placebo-controlled trial that evaluated the efficacy of UDCA in 180 patients with PBC. We use the first available measurements of vitamin levels in each study participant. Vitamin levels for A, D, and E were measured in serum. The prothrombin time (PT) was used as a surrogate marker for vitamin K. RESULTS: The proportion of patients with fat-soluble vitamin deficiencies in the treatment and placebo groups was similar and the data sets were combined. The proportion with vitamin A, D, E or K deficiency was 33.5%, 13.2%, 1.9%, and 7.8%, respectively. In multivariate analysis, the Mayo risk score, advanced histological stage, and total cholesterol were independently associated with vitamin A deficiency whereas serum albumin levels was independently associated with vitamin D deficiency. No factors were associated with vitamin E or K deficiency in multivariate analysis owing to the few vitamin E and K deficient patients. Factors predictive of vitamin K deficiency by univariate analysis included Mayo risk score, advanced histological stage, HDL, total bilirubin, AST, and albumin. The cut-off value of the Mayo risk score with the highest sensitivity and specificity for vitamin A deficiency was 5.0. CONCLUSION: Other than deficiency of vitamin A, deficiency of fat-soluble vitamins occurs uncommonly in patients with PBC. A Mayo risk score > or = 5 helps in selecting patients with PBC for surveillance for vitamin A deficiency.