Publications by authors named "Elizabeth J Carey"

74 Publications

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

Hepatology 2020 Nov 23. Epub 2020 Nov 23.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.

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.
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http://dx.doi.org/10.1002/hep.31652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141059PMC
November 2020

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.

J Clin Gastroenterol 2021 May-Jun 01;55(5):449-457

Division of Gastroenterology and Hepatology.

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.
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http://dx.doi.org/10.1097/MCG.0000000000001433DOI Listing
June 2020

The long-term outcomes of patients with immunoglobulin G4-related sclerosing cholangitis: the Mayo Clinic experience.

J Gastroenterol 2020 Nov 8;55(11):1087-1097. Epub 2020 Aug 8.

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 1st St SW, Rochester, MN, 55905, USA.

Background: The long-term outcomes of immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) are not well known.

Methods: The outcomes of patients with IgG4-SC at Mayo Clinic (1999-2018) were compared to an age- and gender-matched (1:1 ratio) group of patients with primary sclerosing cholangitis (PSC).

Results: We identified 89 patients with IgG4-SC; median age at diagnosis was 67 years, 81% were males, and the median follow-up was 5.7 years. Seventy-eight patients received prednisone for induction of remission, and 53 received at least one other immunosuppressive agent for maintenance of remission. Of the IgG4-SC group, 10 died (median time from diagnosis until death was 6.5 years): 2 due to cirrhosis, 3 due to cholangiocarcinoma (CCA), and 5 due to non-hepatobiliary causes. Eleven patients in the PSC group underwent liver transplantation, while none did in the IgG4-SC group. The incidence of a hepatobiliary adverse event (cirrhosis or CCA) was 3.4 times greater in the PSC compared to the IgG4-SC group (events per 1000 person-years: 52.6; 95% CI 38-73; vs. 15.6; 95% CI 7-32). The probability of development of a hepatobiliary adverse event within 10 years was 11% in the IgG4-SC compared to 45% in the PSC group (P = 0.0001). The overall survival tended to be higher in the IgG4-SC compared to the PSC group (10-year: 79% vs. 68%, respectively; P = 0.11).

Conclusions: In a cohort of IgG4-SC patients, 88% of whom were treated with immunosuppressive drugs, the risk of cirrhosis and CCA was significantly lower compared to an age- and gender-matched group with PSC.
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http://dx.doi.org/10.1007/s00535-020-01714-7DOI Listing
November 2020

Open-label prospective therapeutic clinical trials: oral vancomycin in children and adults with primary sclerosing cholangitis.

Scand J Gastroenterol 2020 Aug 7;55(8):941-950. Epub 2020 Jul 7.

Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Stanford University, Palo Alto, CA, USA.

Background: Oral vancomycin (OV) in primary sclerosing cholangitis (PSC) has been evaluated as a potential therapeutic agent. We report the long-term biochemical course and outcomes of patients with PSC treated with OV.

Methods: Patients were enrolled in 2 open-label clinical trials (ClinicalTrials.gov Identifier: NCT01802073 and NCT01322386) and offered OV at 50 mg/kg/day in 3 divided doses if weight <30kg, and 500 mg 3 times/day if weight ≥30kg. Patients with biliary strictures requiring stenting or awaiting liver transplant were excluded. Liver biochemistry, MRCP and histology were documented at baseline and while on OV. The primary outcome was a decrease in elevated gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), and/or alanine aminotransferase (ALT) from baseline.

Results: 30 subjects were enrolled, and 29 additional subjects who learned of the clinical trial requested OV (total  = 59; median age was 13.5 years [range, 1.5-44 years]; 64.4% were male; and 94.9% had inflammatory bowel disease [IBD]). The median treatment duration was 2.7 years (range, 0.2-14 years). Ninety-six percent (57/59), 81.3% (48/59), and 94.9% (56/59) experienced reduction of GGT, ALP, and ALT, respectively. Furthermore, 39% (23/59), 22% (13/59), and 55.9% (33/59) experienced normalization of GGT, ALP, and ALT, respectively, within the first 6 months of OV treatment. One patient underwent liver transplantation 8 years after beginning OV treatment, and one developed biliary strictures requiring endoscopic intervention. OV was well-tolerated by patients, and no patient developed treatment-related adverse events.

Conclusion: In PSC, OV was well-tolerated and was associated with improvement in liver chemistry. A randomized placebo-controlled clinical trial is warranted.
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http://dx.doi.org/10.1080/00365521.2020.1787501DOI Listing
August 2020

Azathioprine Monotherapy Is Equivalent to Dual Therapy in Maintaining Remission in Autoimmune Hepatitis.

Dig Dis Sci 2021 May 20;66(5):1715-1719. Epub 2020 May 20.

Division of Gastroenterology and Hepatology, Mayo Clinic in Arizona, 5777 E. Mayo Blvd, Phoenix, AZ, 85054, USA.

Background: Standard of care treatment for AIH includes prednisone monotherapy or dual therapy prednisone-azathioprine. However, many hepatologists alternatively use azathioprine monotherapy to avoid side effects of long-term corticosteroids.

Aims: To determine whether azathioprine monotherapy is comparable to dual prednisone-azathioprine for maintenance of remission in AIH.

Methods: A retrospective chart review of 260 individuals with AIH from a single institution was performed; 45 individuals were included. Exclusion criteria included concomitant PBC or PSC, use of alternative treatment regimen, and/or failure to reach remission. Treatment regimen received was guided by clinician standard of practice, not patients' clinical factors. Initial remission was defined as normalization of serum ALT for at least two consecutive blood draws. Data were analyzed for 5 years post-remission, recording outcome and dose of prednisone and/or azathioprine.

Results: 83% of individuals were female, and average age was 65 years. Median dose of prednisone and azathioprine for the dual-therapy group was 5 mg and 100 mg, respectively, while median azathioprine dose for the monotherapy group was 75 mg. Considering overall outcome, 93% of all patients maintained remission. 80% of the dual-therapy group, and 95% of the azathioprine monotherapy group maintained remission. Using Chi-square analysis to compare the maintenance of remission between dual therapy and azathioprine monotherapy, a p value of 0.28 was calculated.

Conclusions: AASLD guidelines recommend dual prednisone-azathioprine as standard of care for maintenance of remission in AIH. Our results suggest that azathioprine monotherapy is equivalent to prednisone-azathioprine. Azathioprine monotherapy offers a significant advantage in mitigating risks of long-term corticosteroid therapy.
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http://dx.doi.org/10.1007/s10620-020-06347-7DOI Listing
May 2021

Gender Differences in Hepatology Medical Literature.

Dig Dis Sci 2020 10 2;65(10):3014-3022. Epub 2020 Jan 2.

Comprehensive Transplant Center, Cedars Sinai Medical Center, 8900 Beverly Blvd, West Hollywood, CA, 90048, USA.

Background: Studies suggest that gender differences in academic medicine exist. Men frequently have better measures of performance such as number of publications, number of citations, remuneration, and funding.

Aims: To evaluate whether a gender disparity in authorship exists.

Methods: We recorded the gender of first and senior authors of original papers, editorials/reviews from liver-related manuscripts in Gastroenterology, Hepatology, Transplantation, American Journal of Gastroenterology, and Liver Transplantation from January 2014 to 2016.

Results: Of 2424 articles reviewed, we excluded 232 (10%) due to inability to determine gender. Among papers analyzed, 72.0% were original and 28.1% reviews/editorials with 65.1% of first authors being male and 34.9% female. Only 20.3% of papers with multiple authors had a female senior author. The proportion of male first and senior authorship between original papers and reviews/editorials was comparable. 72% of original papers had a male as first or senior author, but only 28% females. 71% of review/editorial papers had a male as first or senior author, but only 29% females. When the senior author of an original paper was female, 47.1% of first authors were male and 52.9% female. When the senior author was male, 67.1% of first authors were male and 32.9% female (p < 0.00001).

Conclusions: A significant gender difference exists in Hepatology publications. Female authorship mirrors the percentage of female AASLD membership; however, female senior authorship remains disproportionate. In general, funding for male authors is greater. Fewer women are first authors when the senior author is male, highlighting the importance of female mentorship in Hepatology.
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http://dx.doi.org/10.1007/s10620-019-06025-3DOI Listing
October 2020

A North American Expert Opinion Statement on Sarcopenia in Liver Transplantation.

Hepatology 2019 11 19;70(5):1816-1829. Epub 2019 Aug 19.

Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, AB, Canada.

Loss of muscle mass and function, or sarcopenia, is a common feature of cirrhosis and contributes significantly to morbidity and mortality in this population. Sarcopenia is a main indicator of adverse outcomes in this population, including poor quality of life, hepatic decompensation, mortality in patients with cirrhosis evaluated for liver transplantation (LT), longer hospital and intensive care unit stay, higher incidence of infection following LT, and higher overall health care cost. Although it is clear that muscle mass is an important predictor of LT outcomes, many questions remain, including the best modality for assessing muscle mass, the optimal cut-off values for sarcopenia, the ideal timing and frequency of muscle mass assessment, and how to best incorporate the concept of sarcopenia into clinical decision making. For these reasons, we assembled a group of experts to form the North American Working Group on Sarcopenia in Liver Transplantation to use evidence from the medical literature to address these outstanding questions regarding sarcopenia in LT. We believe sarcopenia assessment should be considered in all patients with cirrhosis evaluated for liver transplantation. Skeletal muscle index (SMI) assessed by computed tomography constitutes the best-studied technique for assessing sarcopenia in patients with cirrhosis. Cut-off values for sarcopenia, defined as SMI < 50 cm /m in male and < 39 cm /m in female patients, constitute the validated definition for sarcopenia in patients with cirrhosis. Conclusion: The management of sarcopenia requires a multipronged approach including nutrition, exercise, and additional pharmacological therapy as deemed necessary. Future studies should evaluate whether recovery of sarcopenia with nutritional management in combination with an exercise program is sustainable as well as how improvement in muscle mass might be associated with improvement in clinical outcomes.
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http://dx.doi.org/10.1002/hep.30828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819202PMC
November 2019

Primary Biliary Cholangitis and Primary Sclerosing Cholangitis.

Am J Gastroenterol 2019 10;114(10):1593-1605

Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Scottsdale, Arizona, USA.

Cholestatic liver diseases encompass a broad spectrum of pathologies, with the core injury occurring at the level of cholangiocytes and progressing to hepatic fibrosis and liver dysfunction. Primary biliary cholangitis and primary sclerosing cholangitis are the most significant progressive cholangiopathies in adults. Although rare, they commonly evolve to liver failure and need for liver transplantation. Despite recent advances in the basic knowledge of these cholangiopathies, the pathogenesis is still elusive. Targeted treatments to prevent disease progression and to preclude malignancy are not yet available. This review will address the general clinical features of both diseases, analyze their commonalities and differences, and provide a state-of-the art overview of the currently available therapeutics.
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http://dx.doi.org/10.14309/ajg.0000000000000268DOI Listing
October 2019

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

Scand J Gastroenterol 2019 May 26;54(5):633-639. Epub 2019 May 26.

a Division of Gastroenterology and Hepatology , Mayo Clinic , Rochester , MN , USA.

To assess if curcumin improves markers of cholestasis among subjects with primary sclerosing cholangitis (PSC). 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. 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. 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 ( = 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),  = .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. 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. 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.
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http://dx.doi.org/10.1080/00365521.2019.1611917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895452PMC
May 2019

Sarcopenia Predicts Post-transplant Mortality in Acutely Ill Men Undergoing Urgent Evaluation and Liver Transplantation.

Transplantation 2019 11;103(11):2312-2317

Department of Medicine, Division of Gastroenterology and Hepatology, University of California-San Francisco, San Francisco, CA.

Background: We examined the association between sarcopenia and post-transplant mortality in acutely ill inpatients with cirrhosis who underwent urgent liver transplantation.

Methods: Included were inpatients at 4 centers who were urgently listed as nonstatus 1 and transplanted from 2005 to 2017 with an abdominal computed tomography scan <90 days before transplantation. Skeletal muscle index (SMI) = total skeletal muscle cross-sectional area at the L3 vertebral level, normalized to height. Cox regression associated SMI with post-transplant mortality. Optimal search identified SMI cutoffs to detect survival.

Results: Of 126 inpatients, 63% were male patients, model for end-stage liver disease (MELDNa) was 32, and follow up was 5.1 years. Among men, 23% died. Median SMI was lower in men who died versus survived (45 versus 51 cm/m). SMI was associated with post-transplant mortality (hazard ratio [HR] = 0.96 per cm/m, 95% CI 0.92-0.99). Patients with SMI ≤ 48 cm/m versus >48 cm/m experienced higher rates of death at 1 year (86% versus 95%) and 3 years (73% versus 95%) (Log-rank P = 0.01). In MELD-adjusted analysis, sarcopenia was strongly associated with post-transplant mortality (HR = 4.39, 95% CI 1.49-12.97). Among women, 35% died. Median SMI was similar in women who died versus survived (45 versus 44 cm/m). SMI was not associated with post-transplant mortality (HR = 1.02, 95% CI 0.96-1.09). Optimal search did not identify any SMI cutoff that predicted post-transplant mortality.

Conclusions: Among patients who underwent urgent inpatient evaluation and liver transplantation, we identified an SMI cutoff value of 48 cm/m to predict post-transplant mortality in men. Our data support the use of SMI as a tool to capture the impact of muscle depletion on post-transplant mortality in acutely ill men with cirrhosis undergoing urgent liver transplantation.
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http://dx.doi.org/10.1097/TP.0000000000002741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783339PMC
November 2019

Frailty in liver transplantation: An expert opinion statement from the American Society of Transplantation Liver and Intestinal Community of Practice.

Am J Transplant 2019 07 8;19(7):1896-1906. Epub 2019 May 8.

Cirrhosis Care Clinic, Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada.

Frailty has emerged as a powerful predictor of outcomes in patients with cirrhosis and has inevitably made its way into decision making within liver transplantation. In an effort to harmonize integration of the concept of frailty among transplant centers, the AST and ASTS supported the efforts of our working group to develop this statement from experts in the field. Frailty is a multidimensional construct that represents the end-manifestation of derangements of multiple physiologic systems leading to decreased physiologic reserve and increased vulnerability to health stressors. In hepatology/liver transplantation, investigation of frailty has largely focused on physical frailty, which subsumes the concepts of functional performance, functional capacity, and disability. There was consensus that every liver transplant candidate should be assessed at baseline and longitudinally using a standardized frailty tool, which should guide the intensity and type of nutritional and physical therapy in individual liver transplant candidates. The working group agreed that frailty should not be used as the sole criterion for delisting a patient for liver transplantation, but rather should be considered one of many criteria when evaluating transplant candidacy and suitability. A road map to advance frailty in the clinical and research settings of liver transplantation is presented here.
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http://dx.doi.org/10.1111/ajt.15392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814290PMC
July 2019

De novo coccidioidomycosis among solid organ transplant recipients 1 or more years after transplant.

Am J Transplant 2019 09 26;19(9):2517-2524. Epub 2019 Mar 26.

Division of Infectious Diseases, Banner University Medical Center, University of Arizona, Tucson, Arizona.

Solid organ transplant recipients who contract coccidioidomycosis are at risk for complicated, protracted, disseminated, and severe disease. To date, no studies have described outcomes for patients who develop coccidioidomycosis only after the first posttransplant year. This study was a joint project of Mayo Clinic Hospital, Phoenix, Arizona, and the University of Arizona/Banner University Medical Center, Tucson, Arizona. We retrospectively reviewed electronic health records for patients with a history of solid organ transplant between January 1, 1998, and October 11, 2014, who developed coccidioidomycosis after the first transplant year. We identified 91 patients. Of those, 37/91 (40.7%) had pulmonary coccidioidomycosis (29/37 [78.4%] were symptomatic); and 5/91 (5.5%) had extrapulmonary disease (all were symptomatic). One patient (1.1%) died. Coccidioidomycosis was evident in 2/91 (2.2%) patients within 3 months of antirejection treatment. Many of the patients (51/91 [56.0%]) had asymptomatic coccidioidomycosis, 27 (27.9%) of whom were followed up closely but did not receive antifungal medication and had no sequelae. Although solid organ recipients taking low-level immunosuppression after the first posttransplant year appeared to have less symptomatic, disseminated, or fatal coccidioidal infection than historical cohorts, this remains an important infection with morbidity and mortality even after the first posttransplant year.
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http://dx.doi.org/10.1111/ajt.15324DOI Listing
September 2019

Poor performance of psoas muscle index for identification of patients with higher waitlist mortality risk in cirrhosis.

J Cachexia Sarcopenia Muscle 2018 12 29;9(6):1053-1062. Epub 2018 Sep 29.

Division of Gastroenterology and Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada.

Background: Sarcopenia, characterized by low muscle mass, associates with mortality in patients with cirrhosis. Skeletal muscle area in a single computed tomography image at the level of the third lumbar vertebrate (L3) is a valid representative of whole body muscle mass. Controversy remains regarding applicability of psoas muscle to identify patients at greater risk of mortality. We aimed to determine psoas muscle index (PMI) association with skeletal muscle index (SMI) and to evaluate the capacity of PMI to predict liver transplant waitlist mortality.

Methods: We evaluated listed adult patients with cirrhosis from 2012 to 2013 at four North American liver transplant centres. From L3 computed tomography images within 3 months of listing, we determined SMI and PMI expressed by cm /m . Low SMI was defined as SMI <39 cm /m in women and <50 cm /m in men as published by us earlier. Cut-offs for PMI to predict mortality were established using a receiver-operating characteristic analysis. Mortality predictors were determined using competing-risk analysis with reported results as subdistribution hazard ratios (sHRs).

Results: Of 353 waitlist candidates, 68% were men, mean age 56 ± 9 years, and Model for End-stage Liver Disease of 16 ± 8 points. Low SMI was present more frequently in men than women (51 vs. 36%, P = 0.02). Moderately strong correlation between SMI and PMI was observed (r > 0.7, P < 0.001). Low PMI (males < 5.1 cm /m ; females < 4.3 cm /m ) yielded poor and moderate concordance with low SMI in men and women, respectively (Kappa coefficient 0.31 and 0.63). SMI (39 ± 9 vs. 43 ± 7 cm /m ; P = 0.009) and PMI (4.4 ± 1.3 vs. 5.2 ± 1.1 cm /m ; P = 0.001) were lower in women who died and/or were delisted (compared with non-deceased patients) whereas men who died and/or were delisted had only lower SMI (47 ± 7 vs. 51 ± 9 cm /m ; P = 0.003), but not PMI compared with non-deceased patients. In women, both SMI (sHR 0.94, P = 0.048) and PMI (sHR 0.58, P = 0.002) were predictors of mortality, while in men, SMI was significant (sHR 0.95, P = 0.001) and PMI showed a trend to be (sHR 0.85, P = 0.09) associated with mortality. Overall, 104 patients (29%) were misclassified between SMI and PMI categories. Using PMI cut-offs, 66% and 28% of low SMI men and women, who have a higher risk of mortality, were incorrectly classified as low risk.

Conclusions: Skeletal muscle index is a more complete and robust measurement than PMI, especially in men with cirrhosis. Low PMI identifies an incomplete subset of patients at increased risk of mortality indicated by low SMI. Given the poor performance of PMI, SMI should not be substituted by PMI.
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http://dx.doi.org/10.1002/jcsm.12349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240754PMC
December 2018

Primary Biliary Cholangitis: A New Era.

Clin Liver Dis 2018 08 31;22(3):xiii-xiv. Epub 2018 Mar 31.

Division of Hepatology, University of Miami Miller School of Medicine, 1500 Northwest 12th Avenue, Suite 1101, Miami, FL 33136, USA. Electronic address:

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http://dx.doi.org/10.1016/j.cld.2018.03.012DOI Listing
August 2018

Current Status of Liver Transplantation for Primary Biliary Cholangitis.

Clin Liver Dis 2018 08;22(3):613-624

Division of Gastroenterology and Hepatology, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, AZ 85054, USA. Electronic address:

Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease diagnosed with elevated alkaline phosphatase in the presence of antimitochondrial antibody. With the introduction and widespread use of ursodeoxycholic acid the proportion of PBC patients undergoing liver transplant (LT) has decreased. However, up to 40% of patients are ursodeoxycholic acid nonresponders and require second-line treatment or progress to end-stage liver disease requiring LT. Several scoring systems have been developed and validated to assess treatment response and transplant-free survival in patients. Although PBC is a favorable indication for LT, recurrence of PBC may occur and requires biopsy for diagnosis.
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http://dx.doi.org/10.1016/j.cld.2018.03.011DOI Listing
August 2018

NGM282 for Treatment of Patients With Primary Biliary Cholangitis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

Hepatol Commun 2018 Sep 30;2(9):1037-1050. Epub 2018 Aug 30.

NGM Biopharmaceuticals Inc. South San Francisco California.

Patients with primary biliary cholangitis (PBC) who had an inadequate response to ursodiol have few treatment options. Alkaline phosphatase (ALP) and bilirubin levels correlate with the risk of liver transplant or death in PBC patients. Fibroblast growth factor (FGF) 19 is a hormone that acts directly in the liver to regulate bile acid synthesis. We evaluated NGM282, an engineered analogue of FGF19, for the treatment of PBC. In this 28-day, double-blind, placebo-controlled phase 2 trial, 45 PBC patients who had an inadequate response to ursodiol were randomly assigned 1:1:1 to receive subcutaneous daily doses of either NGM282 at 0.3 mg (n = 14), 3 mg (n = 16), or placebo (n = 15). The primary endpoint was a change in ALP from baseline after 28 days of treatment. At day 28, ALP was significantly reduced with NGM282 treatment at both 0.3 mg (least-squares mean -51.0 IU/L [standard error (SE) 15.4]) and 3 mg (-66.0 IU/L [SE 16.0]) versus placebo (3.3 IU/L [SE 14.8]), with least-squares mean differences of -54.3 IU/L (95% confidence interval -104.2 to -4.5; = 0.0149) and -69.3 IU/L (95% confidence interval -120.5 to -18.3; = 0.0030), respectively. Fifty percent (7 of 14) of patients receiving NGM282 0.3 mg and 46% (6 of 13) of those receiving NGM282 3mg achieved 15% or greater reduction in ALP levels from baseline, compared with 7% (1 of 15) of patients receiving placebo. NGM282 also significantly reduced serum concentrations of transaminases and immunoglobulins. Most adverse events were grade 1 (mild) to grade 2 (moderate) in severity, with gastrointestinal disorders more frequent in the NGM282 treatment groups. No worsening of pruritus was observed with NGM282 treatment. NGM282 administered for 28 days resulted in significant improvements in ALP and transaminase levels compared with placebo, with an acceptable safety profile in patients with PBC. ( 2018; 00:000-000).
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http://dx.doi.org/10.1002/hep4.1209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128239PMC
September 2018

Primary sclerosing cholangitis in children versus adults: lessons for the clinic.

Expert Rev Gastroenterol Hepatol 2018 Oct 1;12(10):1025-1032. Epub 2018 Oct 1.

a Division of Gastroenterology and Hepatology , Mayo Clinic , Phoenix , AZ , USA.

Introduction: Primary sclerosing cholangitis (PSC) is a rare cholestatic disorder that presents with multifocal biliary strictures. PSC has a variable course but often leads to progressive liver disease, and most patients will eventually require liver transplantation. PSC has a strong association with inflammatory bowel disease and autoimmune liver disease. Areas covered: The objective of this article is to compare and contrast the clinical features and natural history of PSC in children to adults. We performed a PubMed search of the English literature using keywords 'primary sclerosing cholangitis', 'PSC', 'children', and 'pediatric.' Expert commentary: While certain features of PSC are similar in the pediatric and adult population, there are unique features of pediatric PSC. More longitudinal studies are needed to better understand the natural history of pediatric PSC. It is conceivable that treatment for PSC that will alter the course of disease may become available in the future.
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http://dx.doi.org/10.1080/17474124.2018.1521719DOI Listing
October 2018

Patient and Caregiver Attitudes and Practices of Exercise in Candidates Listed for Liver Transplantation.

Dig Dis Sci 2018 12 3;63(12):3290-3296. Epub 2018 Sep 3.

Division of Gastroenterology and Hepatology, Mayo Clinic in Arizona, 5777 E. Mayo Blvd, Phoenix, AZ, 85054, USA.

Background: Impaired physical capacity increases peri-liver transplant complications. Patient perceptions regarding exercise prior to transplantation are not known.

Aims: This study aimed to assess patient and caregiver activity levels, perceptions of willingness to exercise, and of provider advice.

Methods: Consecutive patients listed for liver transplant and caregivers presenting for routine outpatient visits were evaluated over a 3-month interval. Anonymous surveys adapted to patients and caregivers addressed the importance and safety of exercise, type and duration of exercise performed, barriers, willingness to wear a monitoring device, and perceived provider recommendations. Responses were logged on a Likert scale from 1 to 5.

Results: Three hundred and sixty-eight responses were received. Most participants perceived exercise as important. Patients exercised three times per week for 30 min. Eighty percent endorsed walking (median response: 2-agree; IQR 1-2). Most did not jog, swim, cycle, or strength train. Fatigue, reported by 70%, was the major barrier (2, IQR 1-3). Over 90% of caregivers endorsed exercise as important (1-strongly agree, IQR 1-2) and encouraged exercise (median response 2, IQR 1-2). Over 60% of patients (median response 2, IQR 1-3) and caregivers (median response 2, IQR 2-3) felt providers encouraged exercise.

Conclusions: Patients and caregivers are willing to exercise to optimize physical fitness prior to liver transplantation.
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http://dx.doi.org/10.1007/s10620-018-5271-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532051PMC
December 2018

Dominant strictures in primary sclerosing cholangitis: A multicenter survey of clinical definitions and practices.

Hepatol Commun 2018 Jul 4;2(7):836-844. Epub 2018 May 4.

Division of Gastroenterology and Hepatology Mayo Clinic Scottsdale AZ.

Dominant strictures (DSs) of the biliary tree occur in approximately 50% of patients with primary sclerosing cholangitis (PSC) and may cause significant morbidity. Nevertheless, the definition and management of DSs lacks consensus. We aimed to better understand current perceptions and practices regarding PSC-associated DSs. We conducted an anonymous, 23-question, survey-based study wherein electronic surveys were distributed to 131 faculty in the Division of Gastroenterology and Hepatology at the three Mayo Clinic campuses (Rochester, Scottsdale, and Jacksonville) as well as the affiliated practice network. Responses were aggregated and compared, where applicable, to practice guidelines of the American Association for the Study of Liver Diseases and European Association for the Study of the Liver. A total of 54 faculty (41.2%) completed the survey, of whom 24 (44.4%) were hepatologists, 21 (38.9%) gastroenterologists, and 9 (16.7%) advanced endoscopists. One of the major study findings was that there was heterogeneity among participants' definition, evaluation, management, and follow-up of DSs in PSC. The majority of participant responses were in accordance with societal practice guidelines, although considerable variation was noted. Despite the prevalence and morbidity of DSs in PSC, clinical perceptions and practices vary widely among hepatologists, gastroenterologists, and advanced endoscopists who manage these patients, even within a single health care system. Further studies are needed to address these variations, develop general and evidence-based consensus, and increase adherence to societal guidelines. ( 2018;2:836-844).
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http://dx.doi.org/10.1002/hep4.1194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6049068PMC
July 2018

Progress in Primary Biliary Cholangitis.

N Engl J Med 2018 Jun;378(23):2234-2235

From the Mayo Clinic, Phoenix, AZ.

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http://dx.doi.org/10.1056/NEJMe1804945DOI Listing
June 2018

Surveillance for hepatobiliary cancers in patients with primary sclerosing cholangitis.

Hepatology 2018 06 19;67(6):2338-2351. Epub 2018 Apr 19.

Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ.

Primary sclerosing cholangitis (PSC) is a risk factor for cholangiocarcinoma (CCA) and gallbladder carcinoma (GBCa). Surveillance for GBCa is recommended, but the clinical utility of surveillance for other hepatobiliary cancers (HBCa) in PSC, namely CCA and hepatocellular carcinoma (HCC), remains unclear. We aimed to determine whether surveillance is associated with better survival after diagnosis of HBCa in patients with PSC. Medical records of PSC patients seen at the Mayo Clinic Rochester from 1995 to 2015 were reviewed. Patients were included if they had ≥1 year of follow-up and developed HBCa. Patients were categorized according to their surveillance status (abdominal imaging, carbohydrate antigen 19-9, and alpha-fetoprotein). The primary endpoints were HBCa recurrence, HBCa-related death, and all-cause mortality. Overall survival was assessed by the Kaplan-Meier survival method; HBCa-related survival was assessed using competing risk regression. Tests of significance were two-tailed, and a P value <0.05 was considered statistically significant. From 1995 to 2015, a total of 79 of 830 PSC patients were diagnosed with HBCa. Cumulative follow-up was 712 and 283 person-years pre- and post-HBCa diagnosis, respectively. Seventy-eight percent of patients (54/79) developed CCA, 21% (17/79) HCC, 6% (5/79) GBCa, 3% (2/79) both CCA and HCC, and 1% (1/79) both HCC and GBCa. Fifty-one percent (40/79) were under HBCa surveillance, and 49% (39/79) were not. Patients in the surveillance group had significantly higher 5-year overall survival (68% versus 20%, respectively; P < 0.001) and significantly lower 5-year probability of experiencing an HBCa-related adverse event (32% versus 75%, respectively; P < 0.001) compared with the no-surveillance group.

Conclusion: This study demonstrates that HBCa surveillance significantly improves outcomes, including survival, in patients with PSC. (Hepatology 2018;67:2338-2351).
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http://dx.doi.org/10.1002/hep.29730DOI Listing
June 2018

Curcumin in Hepatobiliary Disease: Pharmacotherapeutic Properties and Emerging Potential Clinical Applications.

Ann Hepatol 2017 November-December,;16(6):835-841

Division of Gastroenterology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA Division of Gastroenterology, Department of Medicine, Olive View-UCLA Medical Center, Sylmar, CA, USA.

Curcumin, an aromatic phytoextract from the turmeric (Curcuma longa) rhizome, has been used for centuries for a variety of purposes, not the least of which is medicinal. A growing body of evidence suggests that curcumin has a broad range of potentially therapeutic pharmacological properties, including anti-inflammatory, anti-fibrotic, and anti-neoplastic effects, among others. Clinical applications of curcumin have been hampered by quality control concerns and limited oral bioavailability, although novel formulations appear to have largely overcome these issues. Recent in vitro and in vivo studies have found that curcumin's cytoprotective and other biological activities may play a role in an array of benign and malignant hepatobiliary conditions, including but not limited to non-alcoholic fatty liver disease, cholestatic liver disease (e.g. primary sclerosing cholangitis), and cholangiocarcinoma. Here we provide an overview of fundamental principles, recent discoveries, and potential clinical hepatobiliary applications of this pleiotropic phytocompound.
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http://dx.doi.org/10.5604/01.3001.0010.5273DOI Listing
January 2018

Ibrutinib-induced acute liver failure.

Leuk Lymphoma 2018 02 11;59(2):512-514. Epub 2017 Jul 11.

a Division of Gastroenterology and Hepatology , Mayo Clinic , Phoenix , AZ , USA.

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http://dx.doi.org/10.1080/10428194.2017.1346251DOI Listing
February 2018

Advances in primary sclerosing cholangitis.

Lancet Gastroenterol Hepatol 2016 09 10;1(1):68-77. Epub 2016 Aug 10.

College of Health Solutions, Arizona State University, Phoenix, AZ, USA. Electronic address:

Primary sclerosing cholangitis is a chronic, progressive cholangiopathy that frequently affects men and is associated with inflammatory bowel disease. Although the cause of the disease is still debated, a genetic association and link to immune-mediated disease triggered by environmental factors are thought to contribute. The disease can present as isolated imaging abnormalities, biochemical changes, cholangiocarcinoma, or end-stage complications such as cirrhosis. Symptoms of primary sclerosing cholangitis include fatigue, jaundice, pruritus, or steatorrhoea. Differentiation of primary sclerosing cholangitis can be challenging because other chronic cholangiopathies can present similarly; however, the distinction is necessary to optimise disease surveillance. Management involves assessment for comorbid inflammatory bowel disease and exclusion of other associated cholangiopathic disorders. Patients with primary sclerosing cholangitis have a poor prognosis; progression to liver cirrhosis is common, and an increased risk of hepatobiliary and colorectal cancers is present in those with inflammatory bowel disease. Although much research involves locating an active therapy that can alter the disease course, the only available treatment is liver transplantation, and risk for disease recurrence remains. Use of ursodeoxycholic acid can improve alkaline phosphatase and bilirubin concentrations but does not alter the disease course. In this Review, we summarise aetiological theories, provide an update on hepatobiliary malignancies that require surveillance, and discuss exciting areas of investigation for potential treatment.
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http://dx.doi.org/10.1016/S2468-1253(16)30010-3DOI Listing
September 2016

The Long Winding Road to Transplant: How Sarcopenia and Debility Impact Morbidity and Mortality on the Waitlist.

Clin Gastroenterol Hepatol 2017 Oct 8;15(10):1492-1497. Epub 2017 Apr 8.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Electronic address:

Frailty and sarcopenia are common complications of cirrhosis. Frailty has been described as an increased susceptibility to stressors secondary to a cumulative decline in physiologic reserve; this decline occurs with aging or is a result of the disease process, across multiple organ systems. Sarcopenia, a key component of frailty, is defined as progressive and generalized loss of skeletal muscle mass and strength. The presence of either of these complications is associated with increased morbidity and mortality, as these are tightly linked to decompensation and increased complication rates. Recognition of these entities is critical. Studies have shown improvement in muscle strength and function lead to reduced mortality, suggesting both frailty and sarcopenia are modifiable risk factors. In this review we outline the prevalence of frailty and sarcopenia in cirrhosis and the impact on clinical outcomes such as decompensation, hospitalization, and mortality. Existing and potential novel therapeutic approaches for frailty and sarcopenia are also reviewed.
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http://dx.doi.org/10.1016/j.cgh.2017.04.004DOI Listing
October 2017

Old and new treatments for primary biliary cholangitis.

Liver Int 2017 04;37(4):490-499

Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA.

Primary biliary cholangitis (formerly primary biliary cirrhosis) is a rare progressive cholestatic liver disease, whose hallmark features include a persistently elevated alkaline phosphatase level, presence of anti-mitochondrial antibodies and characteristic histology. Since 1998, ursodeoxycholic acid (UDCA), a bile acid, has been the only available therapeutic agent. Primary biliary cholangitis is associated with the development of end-stage liver disease, increased morbidity and mortality. UDCA has been shown to improve serum biochemistries, histology and delay the need for liver transplantation. The clinical issue is that approximately 25%-40% of patients do not respond to this standard therapy. In recent years, many trials have investigated alternative and adjunctive treatments, leading to the recent approval of obeticholic acid, an analogue of chenodeoxycholic acid, which has shown significant and sustained reductions in alkaline phosphatase levels in combination with UDCA. Obeticholic acid has rapidly been embraced as a new agent to improve the biochemical profile in refractory patients, in addition to being approved for use as monotherapy in patients who cannot tolerate UDCA. There are several other studies and targets which are being investigated. This review is intended to highlight the benefits of UDCA, educate the reader on the newly available obeticholic acid, and to summarize the many ongoing trials and therapeutic targets being investigated in attempts to control and cure primary biliary cholangitis.
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http://dx.doi.org/10.1111/liv.13294DOI Listing
April 2017

Emerging treatments for primary sclerosing cholangitis.

Expert Rev Gastroenterol Hepatol 2017 May 22;11(5):451-459. Epub 2017 Feb 22.

a Division of Gastroenterology and Hepatology , Mayo Clinic , Phoenix , AZ , USA.

Introduction: Primary sclerosing cholangitis (PSC) is a chronic, cholestatic, idiopathic liver disease that can progress to end-stage liver disease, cirrhosis and cholangiocarcinoma. PSC is an uncommon and highly heterogeneous disease, associated with inflammatory bowel disease and a complex pathophysiology. To date, no medical therapies have proved effective. The only available treatment for end-stage PSC is liver transplant, but recurrence is a significant complication. Areas covered: This review will explore previously tested treatments, discuss current treatment strategies and present viewpoints about future emerging therapies in PSC. We searched PubMed using the noted keywords. We included data from full-text articles published in English. Further relevant articles were identified from the reference lists of review articles. Expert commentary: The development of new therapies in PSC has been challenging. However, with greater awareness of the disease nowadays, new insights into the disease may help in the design of future therapeutic agents in PSC and ultimately in effective therapies.
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http://dx.doi.org/10.1080/17474124.2017.1293524DOI Listing
May 2017

A multicenter study to define sarcopenia in patients with end-stage liver disease.

Liver Transpl 2017 05;23(5):625-633

Center for Liver Diseases, Liver Research Center, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA.

Sarcopenia is associated with increased wait-list mortality, but a standard definition is lacking. In this retrospective study, we sought to determine the optimal definition of sarcopenia in end-stage liver disease (ESLD) patients awaiting liver transplantation (LT). Included were 396 patients newly listed for LT in 2012 at 5 North American transplant centers. All computed tomography scans were read by 2 individuals with interobserver correlation of 98%. Using image analysis software, the total cross-sectional area (cm ) of abdominal skeletal muscle at the third lumbar vertebra was measured. The skeletal muscle index (SMI), which normalizes muscle area to patient height, was then calculated. The primary outcome was wait-list mortality, defined as death on the waiting list or removal from the waiting list for reasons of clinical deterioration. Sex-specific potential cutoff values to define sarcopenia were determined with a grid search guided by log-rank test statistics. Optimal search methods identified potential cutoffs to detect survival differences between groups. The overall median SMI was 47.6 cm /m : 50.0 in men and 42.0 in women. At a median of 8.8 months follow-up, mortality was 25% in men and 36% in women. Patients who died had lower SMI than those who survived (45.6 versus 48.5 cm /m ; P < 0.001), and SMI was associated with wait-list mortality (hazard ratio, 0.95; P < 0.001). Optimal search method yielded SMI cutoffs of 50 cm /m for men and 39 cm /m for women; these cutoff values best combined statistical significance with a sufficient number of events to detect survival differences between groups. In conclusion, we recommend that an SMI < 50 cm /m for men and < 39 cm /m for women be used to define sarcopenia in patients with ESLD awaiting LT. Liver Transplantation 23 625-633 2017 AASLD.
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http://dx.doi.org/10.1002/lt.24750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762612PMC
May 2017

Hyperglycemia during the immediate period following liver transplantation.

Future Sci OA 2016 Mar 27;2(1):FSO97. Epub 2016 Jan 27.

Division of Endocrinology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA; Division of Preventive, Occupational & Aerospace Medicine, Mayo Clinic, Scottsdale, AZ 85259, USA; Division of Endocrinology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA; Division of Preventive, Occupational & Aerospace Medicine, Mayo Clinic, Scottsdale, AZ 85259, USA.

Aim: High blood glucose levels in the hospital are common among transplant recipients.

Methods: Retrospective analysis, stratified by diagnosis of pretransplant diabetes mellitus (DM).

Results: Of 346 patients, 96 had pretransplant DM (insulin, n = 60; no insulin, n = 36) and 250 did not. Patients with pretransplant DM had higher inpatient mean glucose levels and more hyperglycemia and hypoglycemia (all p < 0.01). For patients without pretransplant DM, the need for insulin at discharge increased 23% for every 5-year age increase (odds ratio: 1.23; 95% CI: 1.06-1.44; p = 0.007) and 51% for every five units of glucose measurements >180 mg/dl (OR: 1.51; 95% CI: 1.23-1.95; p < 0.01).

Conclusion: Inpatient hyperglycemia was common in liver transplant recipients. Hospital practitioners must anticipate the need to teach self-management skills to liver transplant recipients.
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http://dx.doi.org/10.4155/fsoa-2015-0010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5138006PMC
March 2016

The Microbiome and Primary Sclerosing Cholangitis.

Semin Liver Dis 2016 09 20;36(4):340-348. Epub 2016 Dec 20.

Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with detrimental sequela. In many patients, PSC progresses to end-stage liver disease and hepatobiliary cancer. There is no medical therapy that is proven to halt or reverse the progression of PSC. Approximately 70 to 80% of PSC patients have inflammatory bowel disease, usually ulcerative colitis. The etiology of PSC is poorly understood. Several lines of evidence suggest that the intestinal microbiota plays an important role in the etiopathogenesis of PSC. Stemming from this theory, several antibiotics have been tried in PSC, some of which had shown promising results. Fecal microbiota transplantation is a novel therapy, and is currently being investigated as a potential therapeutic strategy in PSC along with probiotics. In this article, the authors discuss the current knowledge of the intestinal microbiota in PSC.
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http://dx.doi.org/10.1055/s-0036-1594007DOI Listing
September 2016