Michelle Lai

Circulating Microparticles as Disease-Specific Biomarkers of Severity of Inflammation in Patients with Hepatitis C or Nonalcoholic Steatohepatitis

BACKGROUND & AIMS Microparticles released into the bloodstream upon activation or apoptosis of CD4(+) and CD8(+) T cells correlate with inflammation as determined by histologic analysis in patients with chronic hepatitis C (CHC). Patients with nonalcoholic fatty liver (NAFL) or nonalcoholic steatohepatitis (NASH) can be differentiated from those with CHC based on activation of distinct sets of immune cells in the liver. METHODS We compared profiles of circulating microparticles from patients with NAFL and NASH (n = 67) to those of CHC (n = 42), with healthy individuals (controls) using flow cytometry; the profiles were correlated with inflammation grade and fibrosis stage based on histologic analyses. We assessed the ability of the profiles to determine the severity of inflammation and fibrosis based on serologic and histologic analyses. RESULTS Patients with CHC had increased levels of microparticles from CD4(+) and CD8(+) T cells; the levels correlated with disease severity based on histologic analysis and levels of alanine aminotransferase. Patients with NAFL or NASH had significant increases in numbers of microparticles from invariant natural killer T cells and macrophages/monocytes (CD14(+)), which mediate pathogenesis of NASH. Microparticles from CD14(+) and invariant natural killer T cells correlated with levels of alanine aminotransferase and severity of NASH (based on histology). Levels of microparticles could differentiate between patients with NAFL or NASH and those with CHC, or either group of patients and controls (area under the receiver operating characteristic curves ranging from 0.56 to 0.99). CONCLUSIONS Quantification of immune cell microparticles from serum samples can be used to assess the extent and characteristics of hepatic inflammation in patients with chronic liver disease.

Efficacy and safety of pharmacological agents in managing osteoporosis in the old old: Review of the evidence

INTRODUCTION Osteoporosis and fracture risk increase exponentially in postmenopausal females. This places a significant burden in terms of morbidity, mortality and costs that are likely to increase with an ageing population. Despite this there is very limited data on pharmacological management of osteoporosis in this high risk group. OBJECTIVES OF THIS REVIEW: To review the published literature on the clinical efficacy and safety of specific anti osteoporosis treatments in the reduction in fracture risk in females >or=75 years of age. The following major endpoints were used in this review: SEARCH METHODS FOR IDENTIFICATION OF STUDIES: We performed an electronic search of Medline (1970 to June 2007) and the Cochrane Library (1996 to June 2007). Our search strategy included MeSH terms for osteoporosis and treatments. We reviewed the reference list of identified articles for additional relevant published trials. RESULTS Two hundred and fifty-two potentially relevant abstracts were identified. Only six publications were deemed to meet full eligibility criteria and one met most criteria. There is evidence for significant vertebral fracture relative risk reduction(RR) at 1 year for Risedronate (RR 81%; p<0.001), Teriparatide (RR 65%; p<0.05) and Strontium Ranelate (RR 59%; p=0.002) and 3 years for Risedronate (RR 44%; p=0.003), Alendronate (RR 38%; p<0.05) and Strontium Ranelate (RR 32%; p=0.013). There is evidence for significant non-vertebral fracture relative risk reduction at 1 year for Strontium Ranelate (RR 41%; p=0.027) but not Teriparatide (p=0.66) and 3 years for Strontium Ranelate (RR 31%; p=0.011) but not Risedronate (p=0.66). The only study to report a reduction in hip fracture at 3 years is the TROPOS study with Strontium Ranelate (RR 36%; p=0.046). DISCUSSION This review reinforces the irony that the least evidence is available for fragility fracture reduction in the group at greatest risk; the old old and those with non vertebral and hip fracture. Although there is good evidence for the benefit of the bisphosphonates (Alendronate and Risedronate), Teriparatide and Strontium Ranelate in vertebral fracture reduction, there are very limited data for non vertebral and hip fracture reduction. Strontium Ranelate is the only agent to date that has demonstrated a reduction in non vertebral and hip fracture events in this high risk elderly female population. Perhaps we need to adopt different strategies in managing older patients with osteoporosis as their fracture risks and treatment strategies may be quite different from younger populations.

Standard assessments of frailty are validated predictors of mortality in hospitalized patients with cirrhosis

The risk of morbidity and mortality for hospitalized patients with cirrhosis is high and incompletely captured by conventional indices. We sought to evaluate the predictive role of frailty in an observational cohort study of inpatients with decompensated cirrhosis between 2010 and 2013. The primary outcome was 90‐day mortality. Secondary outcomes included discharge to a rehabilitation hospital, 30‐day readmission, and length of stay. Frailty was assessed with three metrics: activities of daily living (ADL), the Braden Scale, and the Morse fall risk score. A predictive model was validated by randomly dividing the population into training and validation cohorts: 734 patients were admitted 1358 times in the study period. The overall 90‐day mortality was 18.3%. The 30‐day readmission rate was 26.6%, and the rate of discharge to a rehabilitation facility was 14.3%. Adjusting for sex, age, Model for End‐Stage Liver Disease, sodium, and Charlson index, the odds ratio for the effect of an ADL score of less than 12 of 15 on mortality is 1.83 (95% confidence interval [CI] 1.05‐3.20). A predictive model for 90‐day mortality including ADL and Braden Scale yielded C statistics of 0.83 (95% CI 0.80‐0.86) and 0.77 (95% CI 0.71‐0.83) in the derivation and validation cohorts, respectively. Discharge to a rehabilitation hospital is predicted by both the ADL (<12) and Braden Scale (<16), with respective adjusted odds ratios of 3.78 (95% CI 1.97‐7.29) and 6.23 (95% CI 2.53‐15.4). Length of stay was associated with the Braden Scale (<16) (hazard ratio = 0.63, 95% CI 0.44‐0.91). No frailty measure was associated with 30‐day readmission. Conclusions: Readily available, standardized measures of frailty predict 90‐day mortality, length of stay, and rehabilitation needs for hospitalized patients with cirrhosis. (Hepatology 2015;62:584–590

A Quality Improvement Initiative Reduces 30-Day Rate of Readmission for Patients With Cirrhosis.

BACKGROUND & AIMS Many hospitalized patients with cirrhosis are readmitted to the hospital within 30 days, particularly those with hepatic encephalopathy (HE). We performed a prospective study to assess the effects of a quality improvement protocol on readmission to a transplant centers liver unit within 30 days. METHODS We studied the effects of a quality improvement program in 824 unique patients with decompensated cirrhosis or receiving liver transplants (mean Model for End-Stage Liver Disease score, 17.7 ± 7.4) admitted to an inpatient hepatology unit from 2010 through 2013. The study had a year-long control period (626 admissions receiving usual care) and 2 intervention phases: a hand-held checklist phase (470 admissions) and an electronic phase that incorporated the checklist items into the electronic provider order entry system (624 admissions). The intervention phases included goal-directed lactulose therapy and rifaximin for overt HE, and prompts for antibiotic prophylaxis of spontaneous bacterial peritonitis. The primary endpoint was the difference in 30-day readmissions between the control and intervention phases. Trends in 30-day readmissions were compared with those of patients with decompensated cirrhosis admitted at another center. RESULTS During the electronic phase, study subjects had 40% lower adjusted odds of 30-day readmission than during the control period. The slope of the decline in readmissions over time was significantly greater than for patients at the other center (P < .0001). The proportion of patients with greater than grade 2 HE and 30-day readmission was 48.9% (66 of 135) in the control period versus 26.0% (27 of 104) in the electronic phase (P = .0003). Treatment of HE with rifaximin and secondary prophylaxis of spontaneous bacterial peritonitis with antibiotics (on discharge) were associated with lower adjusted odds of readmission (odds ratios, 0.39 and 0.40, respectively). The electronic phase was associated with 1.34 fewer hospital days for HE compared with the control period (P = .01). CONCLUSIONS In a prospective study, a quality improvement initiative that included electronic decision support reduced readmissions of patients with cirrhosis to the hospital within 30 days.

ChREBP regulates fructose-induced glucose production independently of insulin signaling

Obese, insulin-resistant states are characterized by a paradoxical pathogenic condition in which the liver appears to be selectively insulin resistant. Specifically, insulin fails to suppress glucose production, yet successfully stimulates de novo lipogenesis. The mechanisms underlying this dysregulation remain controversial. Here, we hypothesized that carbohydrate-responsive element-binding protein (ChREBP), a transcriptional activator of glycolytic and lipogenic genes, plays a central role in this paradox. Administration of fructose increased hepatic hexose-phosphate levels, activated ChREBP, and caused glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and hepatic steatosis in mice. Activation of ChREBP was required for the increased expression of glycolytic and lipogenic genes as well as glucose-6-phosphatase (G6pc) that was associated with the effects of fructose administration. We found that fructose-induced G6PC activity is a major determinant of hepatic glucose production and reduces hepatic glucose-6-phosphate levels to complete a homeostatic loop. Moreover, fructose activated ChREBP and induced G6pc in the absence of Foxo1a, indicating that carbohydrate-induced activation of ChREBP and G6PC dominates over the suppressive effects of insulin to enhance glucose production. This ChREBP/G6PC signaling axis is conserved in humans. Together, these findings support a carbohydrate-mediated, ChREBP-driven mechanism that contributes to hepatic insulin resistance.

Comparison of transient elastography, serum markers and clinical signs for the diagnosis of compensated cirrhosis.

Background and Aims:  Non‐invasive diagnosis of compensated cirrhosis is important. We therefore compared liver stiffness by transient elastography, APRI score, AST/ALT ratio, hyaluronic acid and clinical signs to determine which modality performed best at identifying compensated cirrhosis.

Cost-Effective Evaluation of Nonalcoholic Fatty Liver Disease With NAFLD Fibrosis Score and Vibration Controlled Transient Elastography.

OBJECTIVES:The risk of advanced fibrosis in nonalcoholic fatty liver disease (NAFLD) is traditionally assessed with a liver biopsy, which is both costly and associated with adverse events.METHODS:We sought to compare the cost-effectiveness of four different strategies to assess fibrosis risk in patients with NAFLD: vibration controlled transient elastography (VCTE), the NAFLD fibrosis score (NFS), combination testing with NFS and VCTE, and liver biopsy (usual care). We developed a probabilistic decision analytical microsimulation state-transition model wherein we simulated a cohort of 10,000 50-year-old Americans with NAFLD undergoing evaluation by a gastroenterologist. VCTE performance was obtained from a prospective cohort of 144 patients with NAFLD.RESULTS:Both the NFS alone and the NFS/VCTE strategies were cost effective at

Simple non-invasive biomarkers of advanced fibrosis in the evaluation of non-alcoholic fatty liver disease

5,795 and

Non-high-density lipoprotein cholesterol as a biomarker for nonalcoholic steatohepatitis.

5,768 per quality-adjusted life years (QALY), respectively. In the microsimulation, the NFS alone and NFS/VCTE strategies were the most cost-effective (dominant) in 66.8 and 33.2% of samples given a willingness-to-pay threshold of

Chronic Hepatitis B: Past, Present, and Future

100,000 per QALY. In a sensitivity analysis, the minimum cost per liver biopsy at which the NFS is cost saving is