The health care experience of adults with metabolic dysfunction-associated steatohepatitis and influence of PNPLA3: A qualitative study.

BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive form of metabolic dysfunction-associated steatotic liver disease, for which there is limited information about patient experience, including the patient journey. METHODS: In this study, we conducted interviews with patients with MASH to qualitatively evaluate the patient journey and help elucidate the experiences of this patient population. We also investigated if the patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M variant (non-Hispanic) or being of Hispanic ethnicity may influence patient experiences because these 2 subgroups develop advanced liver disease more frequently than other patient groups. RESULTS: One-to-one interviews were conducted with 28 adults (with PNPLA3 I148M genetic variant, n = 10; Hispanic, n = 8) living in the United States who had been diagnosed with MASH with liver fibrosis. Patients were asked open-ended questions about their experiences before, at, and after their diagnosis. The data collected found that patients experienced a long process of misdiagnoses before their diagnosis of MASH, a lack of clear information provided by clinicians, and limited accessibility to support groups. Hispanic patients reported "impact on family/friends" (75%) and "fear of disease progression" (75%) more frequently than the other patient cohorts interviewed. This is the first report of "fear of progression" in patients with MASH. No patients who were White and had the PNPLA3 I148M variant reported nausea/vomiting, in contrast to other patient cohorts. CONCLUSIONS: This qualitative study identified key aspects of the patient journey that are important for clinical providers and medical teams to recognize. We also propose a new algorithm that could be developed to help screen relatives of patients who are found to carry the PNPLA3 I148M variant.

Comparing preferences to evaluations of barrier self-efficacy for two strength training programs in US older adults.

BACKGROUND/OBJECTIVES: Engagement in regular physical activity is one of the best strategies for older adults to remain healthy. Unfortunately, only 35% of older adults meet guidelines for muscle strengthening activities. Eliciting participant preferences is one possible way to improve physical activity engagement. However, other sources of participant input to improve uptake and maintenance remain uninvestigated. This study compared preferences to self-efficacy ratings for two strength training programs. METHODS: We conducted a national cross-sectional survey of 611 US adults over age 65. We compared two participant evaluations (the preferred program and the program for which they had higher barrier self-efficacy) of two hypothetical strength training programs (45 minutes performed three times per week (traditional) and 5 minutes performed daily (brief)). RESULTS: Most participants (68%) preferred the brief strength training program. The difference in self-efficacy ratings was an average of 1.2 (SD = 0.92). One in five participants preferred a strength training program for which they had less self-efficacy; nearly all of these participants (92%) preferred the traditional strength training program but had more self-efficacy for the brief strength training program. CONCLUSION: Older adults reported preferring and having more self-efficacy for a brief compared to a traditional strength training program. Differences in self-efficacy ratings between the two strength training programs were large. Preferences were often not congruent with ratings of self-efficacy. SIGNIFICANCE/IMPLICATIONS: Preferences for strength training programming may not always reflect the program most likely to be maintained. Future investigations should evaluate differences in behavioral uptake, maintenance, and outcomes from two comparative strength training interventions using preferences and self-efficacy.

Exercise training improves serum biomarkers of liver fibroinflammation in patients with metabolic dysfunction-associated steatohepatitis.

BACKGROUND AND AIMS: Exercise training is recommended for all patients with metabolic dysfunction-associated steatotic liver disease and may reverse liver fibrosis. Whether exercise training improves liver fibrosis without body weight loss remains controversial. We further investigated this relationship using serum biomarkers of liver fibroinflammation in a post hoc analysis of an exercise trial where patients did not lose significant body weight. METHODS: In the NASHFit trial, patients with metabolic dysfunction-associated steatohepatitis were randomized to receive either moderate-intensity aerobic exercise training or standard clinical care for 20 weeks. Mediterranean-informed dietary counselling was provided to each group. Change in serum biomarkers was measured and compared between the two groups. RESULTS: Exercise training led to improvement in serum biomarkers of liver fibroinflammation, including (1) ≥17 IU/L reduction in alanine aminotransferase (ALT) in 53% of individuals in the exercise training group compared to 13% in the standard clinical care group (p < 0.001; mean reduction 24% vs. 10% respectively) and (2) improvement in CK18 (-61 vs. +71 ng/mL, p = 0.040). ALT improvement ≥17 IU/L was correlated with ≥30% relative reduction in magnetic resonance imaging-measured liver fat and PNPLA3 genotype. CONCLUSION: Exercise training improves multiple serum biomarkers of liver fibroinflammation at clinically significant thresholds of response without body weight loss. This study provides further evidence that exercise training should be viewed as a weight-neutral intervention for which response to intervention can be readily monitored with widely available non-invasive biomarkers that can be applied at the population level.

Liver Transplant Outcomes in Young Adults with Cirrhosis Related to Nonalcoholic Fatty Liver Disease.

BACKGROUND: The prevalence of nonalcoholic fatty liver disease (NASH) and cryptogenic cirrhosis (CC) is constantly increasing in adolescents and young adults (AYAs). METHODS: In a retrospective UNOS database evaluation, we analyzed postoperative outcomes of AYAs with nonalcoholic NASH/CC undergoing LT between January 1st, 2003 and March 5th, 2021. After exclusions, 85,970 LT recipients, 393 (47.1%) AYAs with NASH/CC and 441 (52.9%) AYAs with other metabolic conditions, were analyzed. RESULTS: During the study period, the number of LTs performed for AYAs with NASH/CC increased from 4%-7% but decreased from 6.6%-5.3% compared to LTs performed for NASH/CC in all ages. In comparison to AYAs with other metabolic conditions, AYA LT recipients with NASH/CC had a higher prevalence of metabolic syndrome (MetS) components, including diabetes and increased body mass index (P < .0001 for both). Patient and graft survival in AYAs with NASH/CC were significantly lower in comparison to AYAs transplanted for other metabolic conditions (P < .0001) (Hazard Ratio = 1.93, P < .001). Patient survival in AYAs with NASH/CC was significantly better in comparison to older (40-65-year-old) patients with the same diagnosis (P = .01). CONCLUSIONS: Our study found that the overall number of LTs in AYAs with NASH increased significantly, but to a lesser degree compared to the older population with the same diagnosis. Outcomes after LT in AYAs with NASH/CC were worse compared to LT for other metabolic conditions, but significantly better in comparison to older patients. The prevalence of LT for NASH/CC in AYAs is growing. MetS may contribute to worse outcomes in AYAs.

Exercise in the Management of Metabolic-Associated Fatty Liver Disease (MAFLD) in Adults: A Position Statement from Exercise and Sport Science Australia.

Metabolic-associated fatty liver disease (MAFLD) is the most prevalent chronic liver disease worldwide, affecting 25% of people globally and up to 80% of people with obesity. MAFLD is characterised by fat accumulation in the liver (hepatic steatosis) with varying degrees of inflammation and fibrosis. MAFLD is strongly linked with cardiometabolic disease and lifestyle-related cancers, in addition to heightened liver-related morbidity and mortality. This position statement examines evidence for exercise in the management of MAFLD and describes the role of the exercise professional in the context of the multi-disciplinary care team. The purpose of these guidelines is to equip the exercise professional with a broad understanding of the pathophysiological underpinnings of MAFLD, how it is diagnosed and managed in clinical practice, and to provide evidence- and consensus-based recommendations for exercise therapy in MAFLD management. The majority of research evidence indicates that 150-240 min per week of at least moderate-intensity aerobic exercise can reduce hepatic steatosis by ~ 2-4% (absolute reduction), but as little as 135 min/week has been shown to be effective. While emerging evidence shows that high-intensity interval training (HIIT) approaches may provide comparable benefit on hepatic steatosis, there does not appear to be an intensity-dependent benefit, as long as the recommended exercise volume is achieved. This dose of exercise is likely to also reduce central adiposity, increase cardiorespiratory fitness and improve cardiometabolic health, irrespective of weight loss. Resistance training should be considered in addition to, and not instead of, aerobic exercise targets. The information in this statement is relevant and appropriate for people living with the condition historically termed non-alcoholic fatty liver disease (NAFLD), regardless of terminology.

Use of a Mobile-Assisted Telehealth Regimen to Increase Exercise in Transplant Candidates: A Home-Based Prehabilitation Pilot and Feasibility Trial.

INTRODUCTION: Physical fitness assessed by the Liver Frailty Index (LFI) and 6-minute walk test (6MWT) informs the prognosis of liver transplant candidates, although there are limited data on its reversibility after prehabilitation. On a home-based exercise trial, we aimed to improve LFI and 6MWT and to investigate trial feasibility and intervention adherence. METHODS: Liver transplant candidates with cirrhosis wore a personal activity tracker and used Exercise and Liver FITness app for 14 weeks, including a 2-week technology acclimation run-in. The 12-week intervention consisted of Exercise and Liver FITness app plus personal activity tracker and 15-/30-minute weekly calls with a physical activity coach aiming to complete ≥2 video-training sessions/week, or ≥500 step/d baseline increase for ≥8 weeks. We defined feasibility as ≥66% of subjects engaging in the intervention phase and adherence as ≥50% subjects meeting training end point. RESULTS: Thirty-one patients (61 ± 7 years, 71% female, model for end-stage liver disease 17 ± 5, ∼33% frail) consented and 21 (68%) started the intervention. In the 15 subjects who completed the study, LFI improved from 3.84 ± 0.71 to 3.47 ± 0.90 ( P = 0.03) and 6MWT from 318 ± 73 to 358 ± 64 m ( P = 0.005). Attrition reasons included death (n = 4) and surgery (n = 2). There was 57% adherence, better for videos than for walking, although daily steps significantly increased (3,508 vs baseline: 1,260) during best performance week. One adverse event was attributed to the intervention. DISCUSSION: Our clinical trial meaningfully improved LFI by 0.4 and 6MWT by 41 m and met feasibility/adherence goals. In-training daily step increase supported physical self-efficacy and intervention uptake, but maintenance remained a challenge despite counseling.

Exercise Is Medicine for Nonalcoholic Fatty Liver Disease: Exploration of Putative Mechanisms.

Exercise remains a key component of nonalcoholic fatty liver disease (NAFLD) treatment. The mechanisms that underpin improvements in NAFLD remain the focus of much exploration in our attempt to better understand how exercise benefits patients with NAFLD. In this review, we summarize the available scientific literature in terms of mechanistic studies which explore the role of exercise training in modulating fatty acid metabolism, reducing hepatic inflammation, and improving liver fibrosis. This review highlights that beyond simple energy expenditure, the activation of key receptors and pathways may influence the degree of NAFLD-related improvements with some pathways being sensitive to exercise type, intensity, and volume. Importantly, each therapeutic target of exercise training in this review is also the focus of previous or ongoing drug development studies in patients with nonalcoholic steatohepatitis (NASH), and even when a regulatory-agency-approved drug comes to market, exercise will likely remain an integral component in the clinical management of patients with NAFLD and NASH.

Procedural-Related Bleeding in Hospitalized Patients With Liver Disease (PROC-BLeeD): An International, Prospective, Multicenter Observational Study.

BACKGROUND & AIMS: Hospitalized patients with cirrhosis frequently undergo multiple procedures. The risk of procedural-related bleeding remains unclear, and management is not standardized. We conducted an international, prospective, multicenter study of hospitalized patients with cirrhosis undergoing nonsurgical procedures to establish the incidence of procedural-related bleeding and to identify bleeding risk factors. METHODS: Hospitalized patients were prospectively enrolled and monitored until surgery, transplantation, death, or 28 days from admission. The study enrolled 1187 patients undergoing 3006 nonsurgical procedures from 20 centers. RESULTS: A total of 93 procedural-related bleeding events were identified. Bleeding was reported in 6.9% of patient admissions and in 3.0% of the procedures. Major bleeding was reported in 2.3% of patient admissions and in 0.9% of the procedures. Patients with bleeding were more likely to have nonalcoholic steatohepatitis (43.9% vs 30%) and higher body mass index (BMI; 31.2 vs 29.5). Patients with bleeding had a higher Model for End-Stage Liver Disease score at admission (24.5 vs 18.5). A multivariable analysis controlling for center variation found that high-risk procedures (odds ratio [OR], 4.64; 95% confidence interval [CI], 2.44-8.84), Model for End-Stage Liver Disease score (OR, 2.37; 95% CI, 1.46-3.86), and higher BMI (OR, 1.40; 95% CI, 1.10-1.80) independently predicted bleeding. Preprocedure international normalized ratio, platelet level, and antithrombotic use were not predictive of bleeding. Bleeding prophylaxis was used more routinely in patients with bleeding (19.4% vs 7.4%). Patients with bleeding had a significantly higher 28-day risk of death (hazard ratio, 6.91; 95% CI, 4.22-11.31). CONCLUSIONS: Procedural-related bleeding occurs rarely in hospitalized patients with cirrhosis. Patients with elevated BMI and decompensated liver disease who undergo high-risk procedures may be at risk to bleed. Bleeding is not associated with conventional hemostasis tests, preprocedure prophylaxis, or recent antithrombotic therapy.

Physical Activity and Nonalcoholic Fatty Liver Disease: A Roundtable Statement from the American College of Sports Medicine.

ABSTRACT: Although physical activity (PA) is crucial in the prevention and clinical management of nonalcoholic fatty liver disease, most individuals with this chronic disease are inactive and do not achieve recommended amounts of PA. There is a robust and consistent body of evidence highlighting the benefit of participating in regular PA, including a reduction in liver fat and improvement in body composition, cardiorespiratory fitness, vascular biology, and health-related quality of life. Importantly, the benefits of regular PA can be seen without clinically significant weight loss. At least 150 min of moderate or 75 min of vigorous intensity PA are recommended weekly for all patients with nonalcoholic fatty liver disease, including those with compensated cirrhosis. If a formal exercise training program is prescribed, aerobic exercise with the addition of resistance training is preferred. In this roundtable document, the benefits of PA are discussed, along with recommendations for 1) PA assessment and screening; 2) how best to advise, counsel, and prescribe regular PA; and 3) when to refer to an exercise specialist.

Mobile health lifestyle intervention program leads to clinically significant loss of body weight in patients with NASH.

BACKGROUND AIMS: Lifestyle intervention remains the foundation of clinical care for patients with NASH; however, most patients are unsuccessful in enacting sustained behavioral change. There remains a clear unmet need to develop lifestyle intervention programs to support weight loss. Mobile health (mHealth) programs offer promise to address this need, yet their efficacy remains unexplored. APPROACH RESULTS: We conducted a 16-week randomized controlled clinical trial involving adults with NASH. Patients were randomly assigned (1:1 ratio) to receive Noom Weight (NW), a mHealth lifestyle intervention program, or standard clinical care. The primary end point was a change in body weight. Secondary end points included feasibility (weekly app engagement), acceptability (>50% approached enrolled), and safety. Of 51 patients approached, 40 (78%) were randomly assigned (20 NW and 20 standard clinical care). NW significantly decreased body weight when compared to standard clinical care (-5.5 kg vs. -0.3 kg, p = 0.008; -5.4% vs. -0.4%, p = 0.004). More NW subjects achieved a clinically significant weight loss of ≥5% body weight (45% vs. 15%, p = 0.038). No adverse events occurred, and the majority (70%) of subjects in the NW arm met the feasibility criteria. CONCLUSIONS: This clinical trial demonstrated that NW is not only feasible, acceptable, and safe but also highly efficacious because this mHealth lifestyle intervention program led to significantly greater body weight loss than standard clinical care. Future large-scale studies are required to validate these findings with more representative samples and to determine if mHealth lifestyle intervention programs can lead to sustained, long-term weight loss in patients with NASH.

American College of Sports Medicine (ACSM) International Multidisciplinary Roundtable report on physical activity and nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: We present findings from the inaugural American College of Sports Medicine (ACSM) International Multidisciplinary Roundtable, which was convened to evaluate the evidence for physical activity as a means of preventing or modifying the course of NAFLD. APPROACH AND RESULTS: A scoping review was conducted to map the scientific literature and identify key concepts, research gaps, and evidence available to inform clinical practice, policymaking, and research. The scientific evidence demonstrated regular physical activity is associated with decreased risk of NAFLD development. Low physical activity is associated with a greater risk for disease progression and extrahepatic cancer. During routine health care visits, all patients with NAFLD should be screened for and counseled about physical activity benefits, including reduction in liver fat and improvement in body composition, fitness, and quality of life. While most physical activity benefits occur without clinically significant weight loss, evidence remains limited regarding the association between physical activity and liver fibrosis. At least 150 min/wk of moderate or 75 min/wk of vigorous-intensity physical activity are recommended for all patients with NAFLD. If a formal exercise training program is prescribed, aerobic exercise with the addition of resistance training is preferred. CONCLUSIONS: The panel found consistent and compelling evidence that regular physical activity plays an important role in preventing NAFLD and improving intermediate clinical outcomes. Health care, fitness, and public health professionals are strongly encouraged to disseminate the information in this report. Future research should prioritize determining optimal strategies for promoting physical activity among individuals at risk and in those already diagnosed with NAFLD.

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.

Patients with Nonalcoholic Steatohepatitis and Advanced Liver Disease Have the Lowest Cardiorespiratory Fitness.

BACKGROUND & AIMS: Cardiorespiratory fitness and liver fibrosis are independently associated with poor outcomes in patients with nonalcoholic steatohepatitis (NASH), however, conflicting reports exist about their relationship. We aimed to better characterize the relationship between cardiorespiratory fitness and liver histology in a cross-sectional study of patients with biopsy-proven NASH. METHODS: Participants aged 18-75 years completed VO2peak fitness assessment using symptom-limited graded exercise testing. Participants were compared by liver fibrosis stage and NAFLD Activity Score (NAS). Multivariable models were constructed to assess factors related to relative VO2peak, including liver fibrosis and NAS. RESULTS: Thirty-five participants with mean age 48 ± 12 years and body mass index 33.5 ± 7.6 kg/m2 were enrolled. Seventy-four percent of participants were female and 49% had diabetes. A dose-dependent relationship was found between relative VO2peak and liver fibrosis. Relative VO2peak was significantly lower in participants with advanced fibrosis (F3 disease- 15.7 ± 5.3 vs. ≤ F2 disease- 20.7 ± 5.9 mL/kg/min, p = 0.027). NAS > 5 was also associated with lower relative VO2peak (22.6 ± 5.7 vs. 16.5 ± 5.1 mL/kg/min, p = 0.012) compared to NAS ≤ 5. With multivariable modeling, advanced fibrosis remained independently predictive of relative VO2peak while NAS trended towards significance. DISCUSSION AND CONCLUSIONS: Advanced liver fibrosis is independently associated with cardiorespiratory fitness in patients with NASH. This may explain the incremental increase in mortality as liver fibrosis stage increases. Further research is needed to determine if exercise training can improve cardiorespiratory fitness across multiple stages of liver fibrosis and directly reduce morbidity and mortality in patients with NASH.

Exercise Training Is Associated With Treatment Response in Liver Fat Content by Magnetic Resonance Imaging Independent of Clinically Significant Body Weight Loss in Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

INTRODUCTION: Exercise training is crucial in the management of nonalcoholic fatty liver disease (NAFLD); however, whether it can achieve clinically meaningful improvement in liver fat is unclear. We investigated the association between exercise training and the achievement of validated thresholds of MRI-measured treatment response. METHODS: Randomized controlled trials in adults with NAFLD were identified through March 2022. Exercise training was compared with no exercise training. The primary outcome was ≥30% relative reduction in MRI-measured liver fat (threshold required for histologic improvement in nonalcoholic steatohepatitis activity, nonalcoholic steatohepatitis resolution, and liver fibrosis stage). Different exercise doses were compared. RESULTS: Fourteen studies (551 subjects) met inclusion criteria (mean age 53.3 yrs; body mass index 31.1 kg/m 2 ). Exercise training subjects were more likely to achieve ≥30% relative reduction in MRI-measured liver fat (odds ratio 3.51, 95% confidence interval 1.49-8.23, P = 0.004) than those in the control condition. An exercise dose of ≥750 metabolic equivalents of task min/wk (e.g., 150 min/wk of brisk walking) resulted in significant treatment response (MRI response odds ratio 3.73, 95% confidence interval 1.34-10.41, P = 0.010), but lesser doses of exercise did not. Treatment response was independent of clinically significant body weight loss (>5%). DISCUSSION: Independent of weight loss, exercise training is 3 and a half times more likely to achieve clinically meaningful treatment response in MRI-measured liver fat compared with standard clinical care. An exercise dose of at least 750 metabolic equivalents of task-min/wk seems required to achieve treatment response. These results further support the weight-neutral benefit of exercise in all patients with NAFLD.

Physical Activity and Risk of Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Physical activity offers promise to protect against multiple non-hepatic primary cancers. We performed a systematic review to quantify the association between physical activity and hepatocellular carcinoma (HCC) risk. METHODS: We searched the Cochrane Library, Embase, Medline and trial registries through December 2020 for studies that measured physical activity levels in adults at risk for HCC. The primary outcome was HCC. Subgroup analysis was performed limiting to vigorous physical activity. Proportions and random-effects odds ratios (OR) with corresponding 95% confidence intervals (CI) were calculated. RESULTS: Seven studies met inclusion criteria, comprising 777,662 subjects (median age 55 years; 55% female). Greater amounts of physical activity were associated with less HCC (OR 0.65, 95% CI 0.45-0.95, p = 0.03) compared to lower amounts. Vigorous physical activity was associated with even less HCC (OR 0.62, 95% CI 0.49-0.79, p < 0.01). CONCLUSIONS: This meta-analysis demonstrates that greater amounts of physical activity are associated with lower odds of HCC. These results support the use of regular physical activity as an effective way to prevent HCC and provide helpful data to support a for future exercise-based interventional study to better define the optimal exercise prescription for patients at risk for primary liver cancer.

Bile acids and the gut microbiota: metabolic interactions and impacts on disease.

Despite decades of bile acid research, diverse biological roles for bile acids have been discovered recently due to developments in understanding the human microbiota. As additional bacterial enzymes are characterized, and the tools used for identifying new bile acids become increasingly more sensitive, the repertoire of bile acids metabolized and/or synthesized by bacteria continues to grow. Additionally, bile acids impact microbiome community structure and function. In this Review, we highlight how the bile acid pool is manipulated by the gut microbiota, how it is dependent on the metabolic capacity of the bacterial community and how external factors, such as antibiotics and diet, shape bile acid composition. It is increasingly important to understand how bile acid signalling networks are affected in distinct organs where the bile acid composition differs, and how these networks impact infectious, metabolic and neoplastic diseases. These advances have enabled the development of therapeutics that target imbalances in microbiota-associated bile acid profiles.