Bile Acid Profiles in Primary Sclerosing Cholangitis and Their Ability to Predict Hepatic Decompensation.

BACKGROUND AND AIMS: Altered bile acid (BA) homeostasis is an intrinsic facet of cholestatic liver diseases, but clinical usefulness of plasma BA assessment in primary sclerosing cholangitis (PSC) remains understudied. We performed BA profiling in a large retrospective cohort of patients with PSC and matched healthy controls, hypothesizing that plasma BA profiles vary among patients and have clinical utility. APPROACH AND RESULTS: Plasma BA profiling was performed in the Clinical Biochemical Genetics Laboratory at Mayo Clinic using a mass spectrometry based assay. Cox proportional hazard (univariate) and gradient boosting machines (multivariable) models were used to evaluate whether BA variables predict 5-year risk of hepatic decompensation (HD; defined as ascites, variceal hemorrhage, or encephalopathy). There were 400 patients with PSC and 302 controls in the derivation cohort (Mayo Clinic) and 108 patients with PSC in the validation cohort (Norwegian PSC Research Center). Patients with PSC had increased BA levels, conjugated fraction, and primary-to-secondary BA ratios relative to controls. Ursodeoxycholic acid (UDCA) increased total plasma BA level while lowering cholic acid and chenodeoxycholic acid concentrations. Patients without inflammatory bowel disease (IBD) had primary-to-secondary BA ratios between those of controls and patients with ulcerative colitis. HD risk was associated with increased concentration and conjugated fraction of many BA, whereas higher G:T conjugation ratios were protective. The machine-learning model, PSC-BA profile score (concordance statistic [C-statistic], 0.95), predicted HD better than individual measures, including alkaline phosphatase, and performed well in validation (C-statistic, 0.86). CONCLUSIONS: Patients with PSC demonstrated alterations of plasma BA consistent with known mechanisms of cholestasis, UDCA treatment, and IBD. Notably, BA profiles predicted future HD, establishing the clinical potential of BA profiling, which may be suited for use in clinical trials.

Early Cholangiocarcinoma Detection With Magnetic Resonance Imaging Versus Ultrasound in Primary Sclerosing Cholangitis.

BACKGROUND AND AIMS: Early detection of perihilar cholangiocarcinoma (CCA) among patients with primary sclerosing cholangitis (PSC) is important to identify more people eligible for curative therapy. While many recommend CCA screening, there are divergent opinions and limited data regarding the use of ultrasound or magnetic resonance imaging (MRI) for early CCA detection, and it is unknown whether there is benefit in testing asymptomatic individuals. Our aims were to assess the diagnostic performances and prognostic implications of ultrasound and MRI-based CCA detection. APPROACH AND RESULTS: This is a multicenter review of 266 adults with PSC (CCA, n = 120) who underwent both an ultrasound and MRI within 3 months. Images were re-examined by radiologists who were blinded to the clinical information. Respectively, MRI had a higher area under the curve compared with ultrasound for CCA detection: 0.87 versus 0.70 for the entire cohort; 0.81 versus 0.59 for asymptomatic individuals; and 0.88 versus 0.71 for those listed for CCA transplant protocol. The absence of symptoms at CCA diagnosis was associated with improved 5-year outcomes including overall survival (82% vs. 46%, log-rank P < 0.01) and recurrence-free survival following liver transplant (89% vs. 65%, log-rank P = 0.04). Among those with asymptomatic CCA, MRI detection (compared with ultrasound) was associated with reduction in both mortality (hazard ratio, 0.10; 95% confidence interval, 0.01-0.96) and CCA progression after transplant listing (hazard ratio, 0.10; 95% confidence interval, 0.01-0.90). These benefits continued among patients who had annual monitoring and PSC for more than 1 year before CCA was diagnosed. CONCLUSIONS: MRI is superior to ultrasound for the detection of early-stage CCA in patients with PSC. Identification of CCA before the onset of symptoms with MRI is associated with improved outcomes.

Primary Sclerosing Cholangitis Risk Estimate Tool (PREsTo) Predicts Outcomes of the Disease: A Derivation and Validation Study Using Machine Learning.

Improved methods are needed to risk stratify and predict outcomes in patients with primary sclerosing cholangitis (PSC). Therefore, we sought to derive and validate a prediction model and compare its performance to existing surrogate markers. The model was derived using 509 subjects from a multicenter North American cohort and validated in an international multicenter cohort (n = 278). Gradient boosting, a machine-based learning technique, was used to create the model. The endpoint was hepatic decompensation (ascites, variceal hemorrhage, or encephalopathy). Subjects with advanced PSC or cholangiocarcinoma (CCA) at baseline were excluded. The PSC risk estimate tool (PREsTo) consists of nine variables: bilirubin, albumin, serum alkaline phosphatase (SAP) times the upper limit of normal (ULN), platelets, aspartate aminotransferase (AST), hemoglobin, sodium, patient age, and number of years since PSC was diagnosed. Validation in an independent cohort confirms that PREsTo accurately predicts decompensation (C-statistic, 0.90; 95% confidence interval [CI], 0.84-0.95) and performed well compared to Model for End-Stage Liver Disease (MELD) score (C-statistic, 0.72; 95% CI, 0.57-0.84), Mayo PSC risk score (C-statistic, 0.85; 95% CI, 0.77-0.92), and SAP <1.5 × ULN (C-statistic, 0.65; 95% CI, 0.55-0.73). PREsTo continued to be accurate among individuals with a bilirubin <2.0 mg/dL (C-statistic, 0.90; 95% CI, 0.82-0.96) and when the score was reapplied at a later course in the disease (C-statistic, 0.82; 95% CI, 0.64-0.95). Conclusion: PREsTo accurately predicts hepatic decompensation (HD) in PSC and exceeds the performance among other widely available, noninvasive prognostic scoring systems.

Liver Stiffness Measured by Either Magnetic Resonance or Transient Elastography Is Associated With Liver Fibrosis and Is an Independent Predictor of Outcomes Among Patients With Primary Biliary Cholangitis.

GOALS: We aimed to describe the diagnostic and prognostic performance of transient elastography (TE) and magnetic resonance elastography (MRE) in patients with primary biliary cholangitis (PBC). BACKGROUND: The diagnostic performance of TE and MRE in detecting advanced fibrosis in PBC and in predicting outcomes independent of existing serologic prognostic markers is incompletely understood. MATERIALS AND METHODS: Five hundred thirty-eight consecutive patients with PBC at 3 centers with liver stiffness (LS) measurements by TE (n=286) or MRE (n=332) were reviewed. LS cutoffs for predicting fibrosis stages were determined by receiver operating characteristic curves among those with a liver biopsy (TE, n=63; MRE, n=98). Cox proportional hazard regression modeling was used to identify associations between covariates and hepatic decompensation. RESULTS: The optimal LS thresholds for predicting histologic stage F4 were 14.40 kPa (area under the curve=0.94) for TE and 4.60 kPa (area under the curve=0.82) for MRE. Both TE and MRE outperformed biochemical markers for the prediction of histologic advanced fibrosis. Optimal LS thresholds to predict hepatic decompensation were 10.20 kPa on TE and 4.30 kPa on MRE. LS by TE and MRE (respectively) remained predictors of hepatic decompensation after adjusting for ursodeoxycholic acid responsiveness [hazard ratio (HR), 1.14; 95% confidence interval (CI), 1.05-1.24 and HR, 1.68; 95% CI, 1.28-2.19] and the GLOBE score (HR, 1.13; 95% CI, 1.07-1.19 and HR, 2.09; 95% CI, 1.57-2.78). CONCLUSION: LS measurement with either TE or MRE can accurately detect advanced fibrosis and offers additional prognostic value beyond existing serologic predictive tools.

Changes in Liver Stiffness, Measured by Magnetic Resonance Elastography, Associated With Hepatic Decompensation in Patients With Primary Sclerosing Cholangitis.

BACKGROUND & AIMS: Single measurements of liver stiffness (LS) by magnetic resonance elastography (MRE) have been associated with outcomes of patients with primary sclerosing cholangitis (PSC), but the significance of changes in LS over time are unclear. We investigated associations between changes in LS measurement and progression of PSC. METHODS: We performed a retrospective review of 204 patients with patients who underwent 2 MREs at a single center between January 1, 2007 and December 31, 2018. We collected laboratory data and information on revised Mayo PSC risk and model for end-stage liver disease scores, the PSC risk estimate tool, and levels of aspartate transferase at the time of each MRE. The ΔLS/time was determined by the change in LS between the second MRE compared to the first MRE divided by the time between examinations. The primary endpoint was development of hepatic decompensation (ascites, variceal hemorrhage or hepatic encephalopathy). RESULTS: The median LS measurement was 2.72 kPa (interquartile range, 2.32-3.44 kPa) and the overall change in LS was 0.05 kPa/y. However, ΔLS/y was 10-fold higher in patients anticipated to have cirrhosis (0.31 kPa/y) compared to patients with no fibrosis (0.03 kPa/y). The median LS increased over time in patients who ultimately developed hepatic decompensation (0.60 kPa/y; interquartile range, 0.21-1.26 kPa/y) vs but remained static in patients who did not (reduction of 0.04/y; interquartile range, reductions of 0.26 to 0.17 kPa/y) (P < .001). The ΔLS/y value associated with the highest risk of hepatic decompensation was Δ0.34 kPa/y (hazard ratio [HR], 13.29; 95% CI, 0.23-33.78). After we adjusted for baseline LS and other risk factors, including serum level of alkaline phosphatase and the Mayo PSC risk score, ΔLS/y continued to be associated with hepatic decompensation. The optimal single LS cut-off associated with the hepatic decompensation was 4.32 kPa (HR, 60.41; 95% CI, 17.85-204.47). A combination of both cut-off values was associated with risk of hepatic decompensation (concordance score, 0.93; 95% CI, 0.88-0.98) CONCLUSIONS: A single LS measurement and changes in LS over time are independently associated with hepatic decompensation in patients with PSC. However, changes in LS occur slowly in patients without advanced fibrosis or hepatic decompensation.

Efficacy and safety of curcumin in primary sclerosing cholangitis: an open label pilot study.

Goals: To assess if curcumin improves markers of cholestasis among subjects with primary sclerosing cholangitis (PSC). Background: PSC is a chronic cholestatic liver disorder for which there is no established medical therapy. Preclinical data suggest curcumin may have a beneficial effect in PSC. Study: Subjects with PSC and a serum alkaline phosphatase (SAP) greater than 1.5 times the upper limit of normal (ULN) received curcumin 750 mg orally twice daily for 12 weeks in an open-label pilot study. The primary composite endpoint was proportion of subjects who had a reduction of SAP to less than 1.5 times ULN or a 40% reduction in SAP between baseline and week 12. Secondary endpoints included changes in serum aspartate aminotransferase, total bilirubin, Mayo PSC risk score and self-reported health questionnaires. Results: Two-hundred and fifty-eight patients with PSC were screened and 15 subjects were enrolled and all completed 12 weeks of therapy. The most common reason for subject exclusion was SAP less than 1.5 times the ULN (n = 98). Curcumin did not result in a significant median (interquartile range) change in SAP times the ULN [3.43 (2.10-4.32) to 2.46 (1.89-4.41), p = .36], and only 20% (3/15) subjects achieved the primary endpoint. Similarly, there was no significant change in the secondary endpoints. There were no serious adverse events reported. Conclusion: While curcumin was well tolerated, it was not associated with significant improvements in cholestasis or symptoms. Moreover, this study also illustrates that a low SAP is common among those with PSC. Abbreviations PSC: Primary sclerosing cholangitis; IBD: inflammatory bowel disease; CCA: cholangiocarcinoma; SAP: serum alkaline phosphatase; ULN: upper limit of normal; UDCA: ursodeoxycholic acid; CRP: c-reactive protein; AST: aspartate aminotransferase; ALT: alanine aminotransferase; INR: international normalized ratio; FIS: fatigue impact scale; AE: adverse events; PREsTo: PSC risk estimate tool; IQR: interquartile range; ELF: enhanced liver fibrosis.

Combination Therapy of All-Trans Retinoic Acid With Ursodeoxycholic Acid in Patients With Primary Sclerosing Cholangitis: A Human Pilot Study.

GOALS: To perform an exploratory pilot study of all-trans retinoic acid (ATRA) combined with ursodeoxycholic acid (UDCA) in patients with primary sclerosing cholangitis (PSC). BACKGROUND: PSC is a progressive disorder for which there is no accepted therapy. Studies in human hepatocyte cultures and in animal models of cholestasis indicate that ATRA might have beneficial effects in cholestatic disorders. STUDY: ATRA (45 mg/m/d, divided and given twice daily) was combined with moderate-dose UDCA in patients with PSC who had incomplete response to UDCA monotherapy. The combination was administered for 12 weeks, followed by a 12-week washout in which patients returned to UDCA monotherapy. We measured alkaline phosphatase (ALP), alanine aminotransferase (ALT), bilirubin, cholesterol, bile acids, and the bile acid intermediate 7α-hydroxy-4-cholesten-3-one (C4) at baseline, week 12, and after washout. RESULTS: Fifteen patients completed 12 weeks of therapy. The addition of ATRA to UDCA reduced the median serum ALP levels (277±211 to 243±225 U/L, P=0.09) although this, the primary endpoint, did not reach significance. In contrast, median serum ALT (76±55 to 46±32 U/L, P=0.001) and C4 (9.8±19 to 7.9±11 ng/mL, P=0.03) levels significantly decreased. After washout, ALP and C4 levels nonsignificantly increased, whereas ALT levels significantly increased (46±32 to 74±74, P=0.0006), returning to baseline. CONCLUSIONS: In this human pilot study, the combination of ATRA and UDCA did not achieve the primary endpoint (ALP); however, it significantly reduced ALT and the bile acid intermediate C4. ATRA appears to inhibit bile acid synthesis and reduce markers of inflammation, making it a potential candidate for further study in PSC (NCT 01456468).

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 subject's 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.

Performance of magnetic resonance elastography in primary sclerosing cholangitis.

BACKGROUND AND AIM: Liver stiffness (LS) measured by magnetic resonance elastography (MRE) is emerging as an important biomarker in chronic liver diseases. We examined the diagnostic performance of MRE, factors associated with an increased LS and the prognostic value of LS as measured by MRE among patients with primary sclerosing cholangitis (PSC). METHODS: We performed a retrospective review of 266 patients with PSC to examine whether LS was associated with the primary endpoint of hepatic decompensation (ascites, variceal hemorrhage and hepatic encephalopathy). The ability of MRE to differentiate stages of fibrosis was examined in a subset of patients who underwent a liver biopsy (n = 20). RESULTS: An LS of 4.93 kPa was the optimal point to detected F4 fibrosis (sensitivity, 1.00; 95% confidence interval (CI), 0.40-1.00; specificity, 0.94; 95%CI, 0.68-1.00). While a serum alkaline phosphatase <1.5 times the upper limit of normal excluded the presence of advanced LS, it was not associated with the primary endpoint (hazard ratio, 0.26; 95%CI, 0.01-1.33). However, LS was associated with the development of decompensated liver disease (hazard ratio, 1.55; 95%CI, 1.41-1.70). The optimal LS thresholds that stratified patients at a low, medium and high risk for hepatic decompensation were <4.5, 4.5-6.0 and >6.0 kPa (respectively). CONCLUSION: Magnetic resonance elastography is able to detect cirrhosis with high specificity and an alkaline phosphatase <1.5 times the upper limit of normal makes the presence of advanced LS unlikely. Moreover, LS obtained by MRE is predictive of hepatic decompensation in PSC.

Biliary multifocal chromosomal polysomy and cholangiocarcinoma in primary sclerosing cholangitis.

OBJECTIVES: Polysomy detected by fluorescence in situ hybridization (FISH) is associated with cholangiocarcinoma (CCA) in patients with primary sclerosing cholangitis (PSC). However, a subset of PSC patients with polysomy do not manifest CCA even after long-term follow-up. It is unknown if patients with chromosomal gains detected by FISH in multiple areas of the biliary tree (i.e., multifocal polysomy, MFP) are more likely to be diagnosed with CCA than patients with unifocal polysomy (UFP). Therefore, our aim is to determine whether patients with MFP are more likely to manifest CCA compared with patients with other chromosomal abnormalities including UFP and other FISH subtypes. METHODS: We performed a retrospective review of PSC patients without a mass lesion who underwent FISH testing at our institution from 1 January 2005 to 1 July 2013. RESULTS: Three-hundred and seventy-one PSC patients were included. Compared with patients with UFP, those with MFP were more likely to have weight loss (32 vs. 9%), suspicious cytology (45 vs. 13%) and develop serial polysomy (91 vs. 35%). MFP was associated with CCA (hazard ratio (HR), 82.42; 95% confidence interval (CI), 24.50-277.31) and was the strongest predictor of cancer diagnosis. Suspicious cytology (HR, 26.31; 95% CI, 8.63-80.24) and UFP (HR, 13.27; 95% CI, 3.32-53.08) were also predictive of CCA. MFP, UFP and suspicious cytology remained associated with CCA in the multivariable model. CONCLUSIONS: Compared with other FISH subtypes, MFP is the strongest predictor of CCA. However, patients with UFP and suspicious cytology (regardless of FISH status) are also at an increased risk for CCA.

Recall processes for biliary cytology in primary sclerosing cholangitis.

PURPOSE OF REVIEW: Patients with primary sclerosing cholangitis (PSC) are at an increased risk for cholangiocarcinoma (CCA). Distinguishing benign from malignant biliary strictures with routine biliary cytology in this population is challenging. In this review, we examine the strengths and limitations of biliary cytology, review the application of other techniques to help minimize these limitations and present a pragmatic approach to address biliary cytology findings when encountered in PSC. RECENT FINDINGS: Limitations of biliary cytology and other diagnostic studies have driven the development of new techniques and applications of existing technologies to improve our ability to diagnose CCA in PSC. Polysomy when detected on fluorescence in-situ hybridization (FISH) is an independent predictor for the development of CCA. The application of imaging techniques and serologic testing such as carbohydrate antigen 19-9 may further enhance our ability to risk stratify patients. Recent studies suggest that proteomics may allow for the identification of novel biomarkers that could enhance our ability to detect CCA. SUMMARY: Given the inherent challenge of establishing a diagnosis of CCA, providers should apply a multifaceted approach that involves biliary cytology, FISH, serologic testing and advanced imaging techniques when CCA is suspected in patients with PSC.

Long-term outcomes of patients with primary biliary cirrhosis and hepatocellular carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is an aggressive tumor that frequently develops in patients with primary biliary cirrhosis (PBC). We determined the mortality of patients with PBC who develop HCC, and which interventions (surgery, radiofrequency ablation, chemoembolization, alcohol injection, or transplantation) increase survival times. We investigated whether the Milan criteria predict outcomes of these patients and are effective in selection for liver transplantation. METHODS: We evaluated data from 38 patients who had a confirmed diagnosis of PBC and HCC between March 1993 and February 2011. Patients were grouped based on whether or not they met the Milan criteria. Survival was assessed using the Kaplan-Meier analysis. RESULTS: Eighteen of the 38 patients (47.3%) died during the follow-up period; 49.4% survived for 5 years and 31.7% survived for 10 years. Thirty-five patients (92.0%) underwent one or a combination of interventions. Liver transplantation improved survival (risk ratio, 0.06; P < .0001), whereas surgery approached significance in causing deterioration (risk ratio, 2.87; P = .07). Mortality did not appear to be affected by meeting the Milan criteria (P = .84). CONCLUSIONS: Five- and 10-year survival times for patients with PBC who developed HCC were 49.4% and 31.7%, respectively. Patients who meet the Milan criteria receive liver transplantation as often as those who do not; we did not observe a difference in survival time between groups. Patients with PBC who develop HCC appear to benefit from aggressive therapies.

Pathogenesis and management of pruritus in cholestatic liver disease.

Patients with cholestatic liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis and intrahepatic cholestasis of pregnancy commonly complain of pruritus. The underlying pathogenesis remains obscure with several mediators possibly playing an important role; these include lysophosphatidic acid, bile salts, opioids, histamine and progesterone metabolites. We describe in this review novel insights into the pathogenesis and management of pruritus in patients with cholestasis.

Potential Role of Inflammation-Promoting Biliary Microbiome in Primary Sclerosing Cholangitis and Cholangiocarcinoma.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a major risk factor for cholangiocarcinoma (CCA). We investigated biliary and fecal microbiota to determine whether specific microbes in the bile or stool are associated with PSC or CCA. METHODS: Bile was obtained from 32 patients with PSC, 23 with CCA with PSC, 26 with CCA without PSC, and 17 controls. Over 90% of bile samples were from patients with perihilar CCA. Stool was obtained from 31 patients with PSC (11 were matched to bile), 16 with CCA with PSC (10 matched to bile), and 11 with CCA without PSC (6 matched to bile). Microbiota composition was assessed using 16SrRNA-marker-based sequencing and was compared between groups. RESULTS: Bile has a unique microbiota distinguished from negative DNA controls and stool. Increased species richness and abundance of Fusobacteria correlated with duration of PSC and characterized the biliary microbiota in CCA. Stool microbiota composition showed no significant differences between groups. CONCLUSIONS: We identified a unique microbial signature in the bile of patients with increased duration of PSC or with CCA, suggesting a role for microbiota-driven inflammation in the pathogenesis and or progression to perihilar CCA. Further studies are needed to test this hypothesis.

Moexipril for treatment of primary biliary cirrhosis in patients with an incomplete response to ursodeoxycholic acid.

Blockade of angiotensin II synthesis attenuates hepatic fibrosis in different experimental models of chronic liver injury. We evaluated the safety and efficacy of moexipril, an angiotensin-converting enzyme inhibitor, in patients with primary biliary cirrhosis (PBC) who have had a suboptimal response to ursodeoxycholic acid (UDCA). Twenty PBC patients on UDCA (13-15 mg/kg/day) therapy with an elevation of serum alkaline phosphatase at least twice the upper limit of normal were treated with oral moexipril 15 mg/day for one year. No significant changes in serum alkaline phosphatase (379 +/- 32 vs. 379 +/- 51), bilirubin (0.8 +/- 0.1 vs. 0.9 +/- 0.1), aspartate aminotransferase (60 +/- 8 vs. 63 +/- 9), and Mayo risk score (3.55 +/- 0.2 vs. 3.62 +/- 0.2) was associated with the treatment. Fatigue and health-related quality of life scores during treatment demonstrated a trend toward improvement. Moexipril was not clinically beneficial to PBC patients responding suboptimally to UDCA.

A national study of personal accomplishment, burnout, and satisfaction with work-life integration among advance practice nurses relative to other workers.

BACKGROUND: There is a high prevalence of burnout among health care professionals, but little remains known about burnout and satisfaction with work-life integration (WLI) among advance practice nurses (APNs). PURPOSE: To evaluate burnout and satisfaction with WLI among APNs compared with other US workers. METHODS: A national sample of APNs and a probability-based sample of US workers completed a survey that measured burnout and satisfaction with WLI. RESULTS: Of the 976 (47%) APNs who completed the survey 64% had high personal accomplishment, 36.6% had symptoms of overall burnout, and 60.6% were satisfied with their WLI. In multivariable analysis, work hours (for each additional hour odds ratio [OR] 1.03, 95% confidence interval [CI] 1.02-1.04, p < .001) and working in an outpatient setting (overall p = .03; referent hospital: outpatient, OR 1.80, 95% CI 1.17-2.18; other/unknown, OR 1.41, 95% CI 0.90-2.22, p = .13) were independently associated with having higher odds of burnout. Work hours were also independently associated with lower odds of satisfaction with WLI (for each additional hour OR 0.94, 95% CI 0.94-0.95, p < .001). Advance practice nurses were not more likely to have burnout or have greater struggles with WLI than other workers. IMPLICATIONS FOR PRACTICE: Findings from this study suggest APNs have high levels of personal accomplishment and a favorable occupational health profile. Advance practice nurses do not appear at higher risk of burnout or dissatisfaction with WLI than other US workers.

An update on primary sclerosing cholangitis epidemiology, outcomes and quantification of alkaline phosphatase variability in a population-based cohort.

BACKGROUND: Contemporary primary sclerosing cholangitis (PSC) population-based cohorts describing the epidemiology, natural history, and long-term fluctuations in serum alkaline phosphatase (SAP) and their prognostic relevance are lacking. Therefore, we investigated the incidence and natural history of PSC and quantified SAP fluctuations among those with PSC in Olmsted County, Minnesota over the last 41 years. METHODS: The Rochester Epidemiology Project was used to identify 56 subjects diagnosed with PSC between 1976 and 2017 in Olmsted County. The primary endpoint (n = 19) included liver transplantation, hepatic decompensation, and cholangiocarcinoma. RESULTS: The age- and sex-adjusted incidence of PSC (per 100,000 person years) nearly doubled from 2001 to 2017 compared to 1976-2000 (1.47; 95% CI 0.99-1.96 versus 0.79; 95% CI 0.42-1.16, p = 0.02). This increase paralleled a rise in patients with markers of a milder phenotype at the time of diagnosis: normal SAP (26.32% versus 0%, p < 0.01) and lower Mayo PSC risk score [0.36 (- 0.57 to 1.55) versus - 0.50 (- 1.25 to 0.35), p = 0.03]. Intra-individual SAP fluctuates with a median coefficient of variation of 36.20%. SAP normalization and dropping below 1.5 × upper limit of normal (ULN) occurs at a rate of 5% and 10% per year, respectively. SAP less than 1.5 × ULN was associated with a lower risk of PSC-related complications (hazard ratio 0.11; 95% CI 0.03-0.42). CONCLUSIONS: The patients with PSC are increasingly being diagnosed with a milder phenotype. While a lower SAP is associated with improved outcomes, the high intra-individual variation of SAP levels calls into question the practice of using a single SAP value as a surrogate endpoint in clinical trials.

Complications of endoscopic retrograde cholangiopancreatography in primary sclerosing cholangitis.

OBJECTIVES: Endoscopic retrograde cholangiopancreatography (ERCP) is commonly performed in patients with primary sclerosing cholangitis (PSC). The risk of complications associated with this procedure is not well established in these patients. The aim of this retrospective study was to compare the risk of ERCP complications in PSC vs. non-PSC patients. METHODS: We identified all Mayo Clinic patients who underwent ERCP in 2005. Procedural and clinical data were collected. Complications were defined as hospitalizations for pancreatitis, cholangitis, perforation, and bleeding. RESULTS: A total of 168 patients with PSC and 981 patients without PSC had at least one ERCP examination in the calendar year 2005. PSC patients were younger (48 years+/-15 vs. 60 years+/-19, P<0.000) and had a higher prevalence of portal hypertension (31.5% vs. 4%, P<0.0001). PSC patients had more biopsies (39% vs. 15%, P<0.0001), brushings (37% vs. 8%, P<0.001), balloon dilatations (48% vs. 15%, P<0.0001), duct cytology (20% vs. 3%, P<0.0001) and intraductal ultrasounds (11% vs. 5%, P=0.007) than non-PSC patients. The duration of the procedure was longer in the PSC group (51 min+/-29 vs. 40 min+/-28, P<0.0001). The overall rate of complications in patients with PSC when compared to non-PSC patients was not significantly different (18/168 (11%) vs. 76/981(8%), P=0.2). The incidence of cholangitis was higher in the PSC group (4% vs. 0.2%, P<0.0002) despite routine use of antibiotics before the procedure in PSC patients. The duration of the procedure was longer in PSC patients who developed cholangitis (86 min+/-28 vs. 51 min+/-29, P=0.02). The risks of complications such as pancreatitis, perforation, and bleeding were not significantly different between the two groups despite their demographic and procedural variations. The duration of hospitalization due to complications was also not significantly different between the two groups. CONCLUSIONS: Complications requiring hospitalizations occur in over 10% of PSC patients undergoing ERCP. Cholangitis occurs more often in PSC patients and correlates with the length of the procedure. Further studies to confirm the role of aggressive prophylactic antibiotics in patients with PSC who undergo prolonged procedures are warranted.

Minocycline in the treatment of patients with primary sclerosing cholangitis: results of a pilot study.

OBJECTIVES: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of young adults that is associated with significant morbidity and mortality. No effective medical therapy is available. Minocycline has been found to exert biological effects independent of its antimicrobial properties, including anti-inflammatory activities such as inhibition of inducible nitric oxide synthase, upregulation of interleukin 10, and direct suppressive effect on B- and T-cell function. Minocycline may also inhibit cell death pathways by reducing both proapoptotic and proinflammatory enzyme activation. We sought to investigate the safety and efficacy of minocycline among patients with PSC. METHODS: We evaluated the efficacy of minocycline in patients with PSC in a pilot study. Sixteen patients with PSC were enrolled. Minocycline, 100 mg orally twice daily, was given for 1 year. RESULTS: A statistically significant improvement in serum alkaline phosphatase activity (330 U/l vs. 265 U/l, P=0.04) and Mayo risk score (0.55 vs. 0.02, P=0.05) occurred with treatment. Serum bilirubin and albumin remained essentially unchanged while on treatment. CONCLUSIONS: The results of this pilot study indicate that minocycline is reasonably well tolerated and potentially effective in patients with PSC. These findings might be explained by the anti-inflammatory and antiapoptotic properties of minocycline. Though the data presented are too preliminary to support the clinical use of minocycline in the treatment of PSC at this time, its use should be further investigated.

Current and promising therapy for primary biliary cholangitis.

INTRODUCTION: Primary biliary cholangitis is a chronic, cholestatic liver disease that may progress to cirrhosis with complications of end-stage liver disease. Approved treatment options include ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) but novel therapies are being investigated. AREAS COVERED: In this review, the authors describe the current pharmacotherapy for the treatment of primary biliary cholangitis (PBC) and for management of side effects such as pruritus and fatigue based on the currently available literature. EXPERT OPINION: Patients diagnosed with PBC should be offered treatment with UDCA at 13-15 mg/kg per day if liver enzymes are elevated. If they do not meet the defined criteria of response, adjunctive therapy should be considered. This may include OCA at 5 mg per day for patients without cirrhosis or investigational therapy. Management of the most common side effects, pruritus, and fatigue, is nuanced and includes lifestyle modifications as well as pharmacological approaches. Several tools such as the Mayo Risk Score and GLOBE are available for prognostic modeling. Ultimately, patients with PBC may end up requiring liver transplantation and referral to a transplant center may also be needed.