Janice L. Petz

Randomised clinical trial: Vancomycin or metronidazole in patients with primary sclerosing cholangitis - A pilot study

Emerging data suggest that oral antibiotics may have therapeutic effects in primary sclerosing cholangitis (PSC), but published studies are limited.

Tacrolimus for the treatment of primary sclerosing cholangitis

Background: Results from a pilot investigation with tacrolimus for primary sclerosing cholangitis (PSC) demonstrated biochemical improvement without excessive drug toxicity. To date, no confirmatory study has been performed.

Mycophenolate Mofetil for the Treatment of Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology. Despite advances in understanding the pathophysiology underlying this disorder, no effective medical therapy has been identified for halting disease progression. The aim of this investigation was to determine the safety and estimated efficacy of mycophenolate mofetil (MMF) for the treatment of PSC. Thirty patients with PSC received MMF 1 g daily to a maximum of 3 g daily for 1 yr. Liver tests were determined at 3-month intervals with the Mayo risk score calculated at baseline and at the end of therapy. Twenty-three (77%) patients completed 1 yr of therapy. Significant but clinically marginal improvement in serum alkaline phosphatase level after 1 yr of therapy was observed (1135 ± 581 U/L vs 912 ± 463 U/L, p = 0.02). No other significant changes in liver biochemistries or Mayo risk score was observed. Seven patients (23%) discontinued MMF due to adverse events possibly related to therapy. Adverse reactions resolved spontaneously or with dose reduction in 10 (33%) patients. One patient developed pancreatitis, bacterial cholangitis, and sepsis during the eighth month of MMF therapy. No patient developed cytopenia on therapy. In conclusion, MMF does not appear to have clinically important benefits for PSC despite being tolerated by most patients. The results of this pilot study do not support further study of MMF as a single agent in the treatment of PSC.

Mycophenolate mofetil for the treatment of primary biliary cirrhosis in patients with an incomplete response to ursodeoxycholic acid

BACKGROUND & AIMS Despite evidence for therapeutic efficacy with ursodeoxycholic acid (UDCA) in primary biliary cirrhosis (PBC), only 30-50% of patients achieve complete biochemical remission within 1 year of therapy. Mycophenolate mofetil (MMF) is an immunosuppressive medication that inhibits T and B lymphocyte proliferation. The aim of this investigation was to determine the safety and estimated efficacy of MMF in patients with PBC. METHODS Twenty-five patients with incomplete responses to UDCA (defined as persistent elevation of serum alkaline phosphatase > or =2 times the upper limit of normal) received MMF 1 g daily to a maximum of 3 g daily with UDCA (13-15 mg/kg per day) for 1 year. Liver biochemistries were determined at 3-month intervals with Mayo Risk Score calculated at baseline and end of therapy. RESULTS Nineteen (76%) patients completed 1 year of therapy. Despite improvements in serum alkaline phosphatase (920 +/- 308 vs. 709 +/- 242 IU/L, P = 0.001) and AST (65 +/- 31 vs. 51 +/- 19 IU/L, P = 0.007) levels, these findings were clinically insignificant. Exploratory analysis revealed a strong correlation between advanced PBC defined by higher Mayo Risk Score and reduction in serum alkaline phosphatase levels (r = -0.74, P = 0.006). Six patients (24%) did not complete therapy; adverse drug events were responsible for study withdrawal in 3 individuals. Adverse reactions that resolved spontaneously or by dose reduction occurred in 13 patients. CONCLUSIONS MMF is not associated with important clinical benefits in PBC based on the results of this pilot investigation.

Parenteral bisphosphonates for osteoporosis in patients with primary biliary cirrhosis.

We aimed to describe the effects of parenteral bisphosphonates on bone mineral density (BMD) changes in primary biliary cirrhosis (PBC) patients with osteoporosis. Seventeen PBC patients with osteoporosis diagnosed between 1996 and 2005 were enrolled retrospectively. All patients received one of the following parenteral bisphosphonates: zoledronic acid, pamidronate disodium, or ibandronate sodium. The median (interquartile range) age of patients at osteoporosis diagnosis was 62.2 (56.4-67.9) and 94% were women. After treatment, percent change of lumbar spine bone mineral density (LS-BMD) and proximal femur BMD (PF-BMD) of patients with PBC was 2.9% and 0.4%, respectively. Eight patients (47%) showed a greater LS-BMD and/or PF-BMD with percent change of LS-BMD and PF-BMD of 8.7% and 0.8%, respectively. No serious adverse events were found. In PBC patients with osteoporosis, parenteral bisphosphonates can stabilize BMD for 47% of patients. More prospective studies are needed to evaluate the efficacy of specific parenteral bisphosphonates in patients with PBC and osteoporosis.

A Randomized, Placebo-Controlled Clinical Trial of Efficacy and Safety: Modafinil in the Treatment of Fatigue in Patients With Primary Biliary Cirrhosis

Background and Aims: Fatigue is a common symptom of primary biliary cirrhosis (PBC), and is associated with an impaired quality of life. Study Question: No studies have assessed the use of modafinil in fatigue related to PBC in a controlled manner. Study Design, Measures, and Outcomes: A randomized, double-blind, placebo-controlled study was conducted to determine the safety and efficacy of modafinil for the treatment of fatigue in PBC. Forty patients were randomized to modafinil (n = 20) or placebo (n = 20) for 12 weeks. A verbal report of fatigue for at least 6 months was required for enrollment. Modafinil was administered at 100 mg by mouth once daily; a change by 50 mg every 2 weeks (maximum: 200 mg once daily) was allowed, depending on the subjects response to treatment. The primary outcome was defined as a ≥50% improvement in fatigue severity [quantified by the Fisk Fatigue Impact Scale (FFIS)] after 12 weeks of treatment, compared with baseline values. Results: Thirty-three PBC patients completed the study. After 12 weeks of therapy, only 5 patients had a ≥50% reduction in FFIS scores: 3 patients (17.6%) in the modafinil arm and 2 (12.5%) in the placebo arm (P = 1.00). Change in median FFIS score was not statistically different between patients in the 2 treatment groups (P = 0.36). Modafinil was associated with minimal adverse events (headaches, diarrhea, and rash). Conclusions: In patients with PBC who have fatigue, treatment with modafinil for 12 weeks was safe and fairly well tolerated; however, it did not result in beneficial effects on fatigue compared with patients treated with placebo (CONSORT Table 1). ClinicalTrials.gov identifier NCT00943176.

306 Rifaximin Therapy for Patients With Primary Sclerosing Cholangitis—an Open Label Clinical Trial

Introduction Primary sclerosing cholangitis (PSC) is a chronic liver disease leading to biliary fibrosis and liver cirrhosis, eventually necessitating liver transplantation or resulting in death. In the absence of an effective treatment it is important to reliably predict survival. Previous studies indicated that improvement of alkaline phosphatase (ALP) during the disease course is associated with a better prognosis. Aim of this study was to evaluate if normalization of ALP within one year after diagnosis is associated with better event-free survival. Methods Patient charts from a large population-based PSC cohort were reviewed for laboratory results and the use of ursodeoxycholic acid (UDCA). Patients without documented ALP both at diagnosis, as well as 1 year after diagnosis (+/-3 months) were excluded. Clinical endpoints were development of cholangiocarcinoma, liver transplantation and PSC-related death. Univariable logistic regression analyses were performed to determine laboratory and clinical variables associated with outcome. Kaplan Meier survival curve was used to estimate event free survival between those who attained normalization of ALP within 1 year after diagnosis and those who did not. To correct for possible confounding co-variables on reaching an endpoint, Cox proportional hazard analysis was used. Results We included 247 patients with a median follow up of 95 months (range 12-347). Mean age at diagnosis was 40 years (± 13), 61% was male. In 75 patients (30%) ALP normalized within one year after diagnosis, in 172 patients (70%) ALP did not normalize. In the first group 7 patients (9%) reached an endpoint, compared to 38 (22%) in the second group (p=0.019). Patients in the first group had a significantly longer event-free survival than the second group (p=0.028, fig. 1). Univariable logistic regression showed that UDCA use and normalization of ALP within one year after diagnosis were significantly associated with outcome. In multivariate Cox regression analysis only ALP normalization within one year after diagnosis proved to be a significant predictor of long-term outcome. (Odds Ratio 0.43, 95% CI 0.19 0.97). Conclusion Normalization of ALP within the first year after diagnosis is associated with a better long-term survival in PSC patients. These results corroborate ALP as a candidate surrogate parameter in future PSC intervention studies. Furthermore ALP may serve as an important factor in prognostic modelling in PSC.

Sa1027 Plasma Cysteine Levels and Muscle Cramps in Patients With Cirrhosis

Background/Aims:Muscle cramps are common in patients with cirrhosis, particularly when diuretics are used for ascites. Its pathophysiologic mechanism remains uncertain. In this work, we conducted field testing of a questionnaire to measure the extent and severity of muscle cramps in patients with cirrhosis and explored plasma metabolomic biomarkers for muscle cramps. Methods: Patients with an established diagnosis of cirrhosis were prospectively contacted prior to their follow-up appointment in our liver clinic. Patients were asked to fill out a muscle cramps questionnaire (mMCQ) which asks about occurrence, frequency, location and impact (sleep and daily living) of muscle cramps. Blood samples were drawn after a minimum of 12 hours of fasting, which were promptly cold-centrifuged and plasma was separated for metabolomics assays. Results: In this on-going study, 109 patients have been contacted to date, of whom 46 patients have responded to the questionnaire (response rate=42% to date). The respondents were 57.8 ± 11.1 years of age and 59% were men. The mean MELD score was 12.8 ± 5.5. Approximately half (46%) reported history of hepatic encephalopathy and 6.5% refractory ascites requiring therapeutic paracentesis. In this patient cohort, the prevalence of muscle cramps was 76%. Of those who reported muscle cramps, 50% had moderate to severe symptoms (occuring at least daily or causing at least moderate disturbance of activities of daily living). To date, we have assayed 25 amino acid in the plasma samples (n=43), including taurine, threonine, serine, asparagine, glutamic acid, argininosuccinic acid, glutamine, proline, glycine, alanine, citruline, α-amino-N-butyric acid, valine, cysteine, methionine, isoleucine, leucine, tyrosine, phenyl alanine, β-alanine, ornithine, lysine, histidine, arginine, and allo-isoleucine. Of these, plasma cysteine levels were significantly different according to the severity of muscle cramps. In patients without muscle cramps the median plasma level was 59 nmol/mL with an interquartile range (IQR) of 52-75 nmol/mL, compared to those with cramps (median=82 nmol/mL, IQR=61-94). In the figure, patients with severe cramps had the highest cysteine levels (median 90 nmol/ mL, IQR=78-106) compared to those with mild cramps (median:73 nmol/mL, IQR=51-86). Conclusion: Muscle cramps are extremely common in patients with cirrhosis receiving ongoing care at a liver clinic. Plasma cysteine levels may be a potential biomarker for muscle cramps, as they correlate with their occurrence and severity.