Serum Fibroblast Growth Factor 21 Is Markedly Decreased following Exercise Training in Patients with Biopsy-Proven Nonalcoholic Steatohepatitis.

BACKGROUND AND AIMS: Exercise remains a key component of nonalcoholic fatty liver disease (NAFLD) treatment. However, mechanisms underpinning the improvements in NAFLD seen with exercise are unclear. Exercise improved liver fat and serum biomarkers of liver fibrosis in the NASHFit trial. We investigated exercise's mechanism of benefit by conducting a post hoc analysis of these data to determine the relationship between serum fibroblast growth factor (FGF) 21, which is implicated in NAFLD development, and exercise. METHODS: In the 20 wk NASHFit trial, patients with nonalcoholic steatohepatitis (NASH) were randomized to receive moderate-intensity aerobic exercise training or standard clinical care. Mediterranean-informed dietary counseling was provided to each group. Change in serum FGF21 was measured after an overnight fast. RESULTS: There was a significant improvement in serum FGF21 with exercise training compared to standard clinical care (p = 0.037) with serum FGF21 reducing by 22% (-243.4 +/-349 ng/mL) with exercise vs. a 34% increase (+88.4 ng/mL +/-350.3 ng/mL) with standard clinical care. There was a large inverse association between change in serum FGF21 and change in cardiorespiratory fitness (VO2peak) (r = -0.62, 95% CI -0.88 to -0.05, p = 0.031), and on multivariable analysis, change in VO2peak remained independently associated with change in FGF21 (ß = -44.5, 95% CI -83.8 to -5.11, p = 0.031). CONCLUSIONS: Serum FGF21 is markedly decreased in response to aerobic exercise training, offering a novel mechanism to explain the observed reduction in liver fat and improvement in serum biomarkers of liver fibrosis in patients with NASH who do exercise.

NASHFit: A randomized controlled trial of an exercise training program to reduce clotting risk in patients with NASH.

BACKGROUND AND AIMS: NASH is a common disease associated with increased rates of thromboembolism (TE). Although exercise training can lessen thrombotic risk in patients with vascular disease, whether similar findings are observed in patients with NASH is open for study. APPROACH AND RESULTS: We conducted a 20-week randomized controlled clinical trial involving patients with biopsy-confirmed NASH. Patients were randomly assigned (2:1 ratio) to receive either an exercise training program or standard clinical care. The primary endpoint was change in plasminogen activator inhibitor 1 (PAI-1) level, an established thrombotic biomarker. Twenty-eight patients were randomly assigned (18 exercise training and 10 standard clinical care). PAI-1 level was significantly decreased by exercise training when compared to standard clinical care (-40 ± 100 vs. +70 ± 63 ng/ml; p = 0.02). Exercise training decreased MRI proton density fat fraction (MRI-PDFF; -4.7 ± 5.6 vs. 1.2 ± 2.8% absolute liver fat; p = 0.01); 40% of exercise subjects had a ≥30% relative reduction in MRI-PDFF (histological response threshold) compared to 13% for standard of care (p < 0.01). Exercise training improved fitness (VO2 peak, +3.0 ± 5.6 vs. -1.8 ± 5.1 ml/kg/min; p = 0.05) in comparison to standard clinical care. CONCLUSIONS: This clinical trial showed that, independent of weight loss or dietary change, exercise training resulted in a significantly greater decrease in thrombotic risk than standard clinical care in patients with NASH, in parallel with MRI-PDFF reduction and improvement in fitness. Future studies are required to determine whether exercise training can directly impact patient outcomes and lower rates of TE.

Utilization of a Directly Supervised Telehealth-Based Exercise Training Program in Patients With Nonalcoholic Steatohepatitis: Feasibility Study.

BACKGROUND: Most patients with nonalcoholic fatty liver disease (NAFLD) are physically inactive despite the well-known benefits of physical activity. Telehealth offers promise as a novel way to deliver an exercise training program and increase physical activity. However, the feasibility, safety, and efficacy of telehealth-based exercise programs is unknown in patients with NAFLD. OBJECTIVE: The aim of this study was to determine the feasibility of a directly supervised exercise training program delivered exclusively with telehealth to patients with nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD. METHODS: In response to COVID-19 research restrictions, we adapted an existing clinical trial and delivered 20 weeks of moderate-intensity aerobic training 5 days a week under real-time direct supervision using an audio-visual telehealth platform. Aerobic training was completed by walking outdoors or using a home treadmill. Fitness activity trackers with heart rate monitors ensured exercise was completed at the prescribed intensity with real-time feedback from an exercise physiologist. RESULTS: Three female patients with biopsy-proven NASH were enrolled with a mean age of 52 (SD 14) years. The mean body mass index was 31.9 (SD 5.1) kg/m2. All patients had metabolic syndrome. All patients completed over 80% of exercise sessions (mean 84% [SD 3%]) and no adverse events occurred. Body weight (mean -5.1% [SD 3.7%]), body fat (mean -4.4% [SD 2.3%]), and waist circumference (mean -1.3 in. [SD 1.6 in.]) all improved with exercise. The mean relative reduction in magnetic resonance imaging-proton density fat fraction (MRI-PDFF) was 35.1% (SD 8.8%). Mean reductions in hemoglobin A1c and Homeostatic Model Assessment for Insulin Resistance were also observed (-0.5% [SD 0.2%] and -4.0 [SD 1.2], respectively). The mean peak oxygen consumption (VO2peak) improved by 9.9 (SD 6.6) mL/kg/min. CONCLUSIONS: This proof-of-concept study found that supervised exercise training delivered via telehealth is feasible and safe in patients with NASH. Telehealth-based exercise training also appears to be highly efficacious in patients with NASH, but this will need to be confirmed by future large-scale trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT03518294; https://clinicaltrials.gov/ct2/show/NCT03518294.

An Electronic Questionnaire to Survey Colorectal Cancer Screening Status and Identify High-Risk Cohorts in Large Health Care Organizations.

Though improved screening practices have reduced the incidence and mortality of colorectal cancer (CRC), screening rates continue to be suboptimal. This is especially true of high-risk individuals, who are difficult for clinicians to identify during a typical health care encounter. The authors developed an electronic patient questionnaire that determined an individual's CRC screening status and identified high-risk individuals. The questionnaire was administered to employees through the Department of Human Resources. The response rate was 44.7%; 81.2% of respondents aged ≥50 years were up-to-date on CRC screening; 878 high-risk individuals were identified, 77.7% of whom were up-to-date on CRC screening. However, among high-risk individuals aged 40 to 49 years, only 45.8% reported up-to-date CRC screening. The questionnaire was effective in measuring CRC screening rates and identifying high-risk individuals. Dissemination by the Department of Human Resources was novel, effective, and was not dependent on a health care encounter to assess screening or high-risk status.

Breaking Down Barriers to Physical Activity in Patients with Nonalcoholic Fatty Liver Disease.

BACKGROUND: Lifestyle changes, including physical activity, are the cornerstones of the treatment of nonalcoholic fatty liver disease (NAFLD). For unclear reasons, most NAFLD patients do not achieve the recommended amount of weekly activity. AIMS: Our aim was to measure perceived barriers to physical activity and enablers to exercise intervention. METHODS: Consecutive subjects aged 18-70 with NAFLD were prospectively enrolled. An exercise motivation questionnaire was administered to assess current behaviors and perceived barriers. RESULTS: Eighty-seven subjects (60% female) were enrolled with mean age 52 years and mean body mass index (BMI) 34.5 kg/m2. Metabolic comorbidities were common: 49% had hyperlipidemia, 42% hypertension, and 40% diabetes. The majority (75%) did not achieve ≥ 150 min/week of physical activity. Ninety-one percent agreed that activity was important in improving NAFLD; 88% desired to be more active. Lack of exercise resources and education from treating provider (47%), physical discomfort during exercise (44%), and time constraints (32%) were the most common barriers. Rates of fitness tracker (34%), gym (33%), exercise program (33%), and personal trainer (17%) use were low. CONCLUSIONS: While nearly all subjects with NAFLD identify physical activity to be important and desire to be more active, only a few meet activity recommendations. This discordance is due to a perceived lack of resources and education, physical discomfort, and time constraints. Better understanding of these barriers and behaviors are important to improve morbidity and mortality in NAFLD. Future behavioral research removing the identified barriers is of great importance to global public health and should be prioritized.

Abdominal Pain and Anxious or Depressed State Are Independently Associated With Weight Loss in Inflammatory Bowel Disease.

BACKGROUND: Many factors impact nutritional status in inflammatory bowel disease (IBD). We undertook this study to evaluate the potential role that abdominal pain has on weight loss and dietary behavior in IBD. METHODS: This is a retrospective cohort study utilizing data from an IBD registry at our institution between January 1, 2015 and August 31, 2018. Pain scores and nutritional outcomes were derived from validated questionnaires while key associated clinical data were derived from the medical record. RESULTS: Three hundred and three patients (154 females; 206 Crohn's disease) were included in this study. Ninety-six patients (31.7%) had experienced a 6-lb or greater weight loss in the prior month. On multivariate analysis, abdominal pain and anxious/depressed state were independently associated with weight loss, while female gender and NSAID use were inversely associated with weight loss (P < 0.05). IBD patients with abdominal pain also reported significantly poorer dietary behavior than those without this symptom. CONCLUSIONS: Abdominal pain is more likely to result in negative dietary outcomes and independently associated with weight loss in IBD. IBD providers should screen for malnutrition when patients report abdominal pain.

Nonalcoholic steatohepatitis Fitness Intervention in Thrombosis (NASHFit): Study protocol for a randomized controlled trial of a supervised aerobic exercise program to reduce elevated clotting risk in patients with NASH.

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide affecting upwards of one third the global population. For reasons not fully understood, individuals with NAFLD and its more severe variant, nonalcoholic steatohepatitis (NASH), are at increased risk for venous thromboembolism which significantly increases morbidity and mortality. Lifestyle changes centering around exercise training are the mainstay of treatment for NAFLD/NASH. While exercise training can lessen venous thromboembolic risk in healthy persons and those with cardiovascular disease, whether or not this benefit is seen in patients with NAFLD/NASH remains unknown. In order to better understand how exercise training impacts thrombosis risk in NAFLD, we present the design of a thirty-two week randomized controlled clinical trial of 42 sedentary subjects age 18-69 with biopsy proven NASH. The main aim is to determine the impact of an aerobic exercise training program on the abnormal hemostatic system unique to NAFLD/NASH. The main outcome is change in plasminogen activator inhibitor one level, an established marker for venous thromboembolism. Secondary outcomes include body composition, cardiorespiratory fitness, control of comorbid metabolic conditions (e.g., obesity, hypertension, hyperlipidemia, diabetes), dietary composition, health related quality of life, liver enzymes and histology, NAFLD/NASH disease activity (e.g., biomarkers, clinical decision aids), microbiome, other markers of hemostasis, and PNPLA3 gene expression. The study represents the first clinical trial of an exercise training program to reduce elevated clotting risk in subjects with NAFLD/NASH.

Gastrointestinal hypoalgesia in inflammatory bowel disease.

BACKGROUND: Pain perception is critical for detection of noxious bodily insults. Gastrointestinal hypoalgesia in inflammatory bowel disease (IBD) is a poorly understood phenomenon previously linked to poor patient outcomes. We aimed to evaluate the risk factors associated with this condition and to discern characteristics that might differentiate these patients from pain-free quiescent counterparts. METHODS: We performed a retrospective analysis using an IBD natural history registry based in a single tertiary care referral center. We compared demographic and clinical features in 3 patient cohorts defined using data from simultaneous pain surveys and ileocolonoscopy: a) active IBD without pain (hypoalgesic IBD); b) active IBD with pain; and c) inactive IBD without pain. RESULTS: One hundred fifty-three IBD patients had active disease and 43 (28.1%) exhibited hypoalgesia. Hypoalgesic IBD patients were more likely to develop non-perianal fistulae (P=0.03). On logistic regression analysis, hypoalgesic IBD was independently associated with male sex, advancing age and mesalamine use, and inversely associated with anxious/depressed state and opiate use. Hypoalgesic IBD patients were demographically and clinically similar to the pain-free quiescent IBD cohort (n=59). Platelet count and C-reactive protein were more likely to be pathologically elevated in hypoalgesic IBD (P=0.03), though >25% did not exhibit elevated inflammatory markers. CONCLUSIONS: Hypoalgesia is common in IBD, particularly in male and older individuals, and is associated with an increased incidence of fistulae and corticosteroid use. Novel noninvasive diagnostic tools are needed to screen for this population, as inflammatory markers are not always elevated.