Physical Activity, Inactivity and Sleep in Individuals with Hypertrophic Cardiomyopathy.

Physical activity presents an important cornerstone in the management and care of individuals with hypertrophic cardiomyopathy (HCM). Twenty-one individuals with HCM (age: 52±15 years old, body mass index (BMI): 30±7 kg/m2) completed 7-day monitoring using wrist-worn triaxial accelerometers (GENEActiv, ActivInsights Ltd, UK) and were compared to age and sex-matched healthy controls (age: 51±14 years old, BMI: 25±4 kg/m2). For individuals with HCM, clinical parameters (left atrial diameter and volume, peak oxygen consumption, NTproBNP and Minnesota Living with Heart Failure (MLHF)) were correlated with accelerometry. After adjusting for BMI, individuals with HCM spent less time in moderate-vigorous physical activity (MVPA) (86 (55-138) vs. 140 (121-149) minutes/day, p<0.05) compared to healthy controls. Individuals with HCM engaged in fewer MVPA-5 min (6 (2-15) vs. 27 (23-37) minutes/day, p<0.01) and MVPA-10 min bouts (9 (0-19) vs. 35 (17-54) minutes/day, p<0.01) versus healthy controls. For HCM only, peak oxygen consumption was correlated with MVPA (r=0.60, p<0.01) and MVPA-5 min bouts (r=0.47, p<0.05). MLHF score was correlated with sleep duration (r=0.45, p<0.05). Individuals with HCM should be encouraged to engage in moderate-intensity physical activity bouts and reduce prolonged periods of inactivity in order to potentially improve exercise tolerance and reduce disease burden.

Digital Intervention With Lifestyle Coach Support to Target Dietary and Physical Activity Behaviors of Adults With Nonalcoholic Fatty Liver Disease: Systematic Development Process of VITALISE Using Intervention Mapping.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is linked to excessive calorie consumption, physical inactivity, and being overweight. Patients with NAFLD can halt or decelerate progression and potentially reverse their condition by changing their lifestyle behavior. International guidelines recommend the use of lifestyle interventions; however, there remains a discordance between published guidelines and clinical practice. This is primarily due to a lack of NAFLD-specific interventions to support weight loss and improve liver function. OBJECTIVE: This study aims to use intervention mapping to systematically develop a digital intervention to support patients with NAFLD to initiate and maintain changes in their dietary and physical activity behavior to promote weight loss. METHODS: Intervention mapping consisted of 6 steps: step 1 involved a needs assessment with primary and secondary health care professionals (HCPs) and patients with NAFLD; step 2 involved identification of the social cognitive determinants of change and behavioral outcomes of the intervention; step 3 involved linking social cognitive determinants of behavioral outcomes with behavior change techniques to effectively target dietary and physical activity behavior; step 4 involved the development of a prototype digital intervention that integrated the strategies from step 3, and the information content was identified as important for improving knowledge and skills from steps 1 and 2; step 5 involved the development of an implementation plan with a digital provider of lifestyle behavior change programs to patients with NAFLD using their delivery platform and lifestyle coaches; and step 6 involved piloting the digital intervention with patients to obtain data on access, usability, and content. RESULTS: A digital intervention was developed, consisting of 8 modules; self-regulatory tools; and provision of telephone support by trained lifestyle coaches to help facilitate behavioral intention, enactment, and maintenance. A commercial provider of digital lifestyle behavior change programs enrolled 16 patients with NAFLD to the prototype intervention for 12 consecutive weeks. A total of 11 of the 16 participants successfully accessed the intervention and continued to engage with the content following initial log-in (on average 4 times over the piloting period). The most frequently accessed modules were welcome to the program, understanding NAFLD, and food and NAFLD. Goal setting and self-monitoring tools were accessed on 22 occasions (4 times per tool on average). A total of 3 out of 11 participants requested access to a lifestyle coach. CONCLUSIONS: Intervention mapping provided a systematic methodological framework to guide a theory- and evidence-informed co-design intervention development process for patients and HCPs. The digital intervention with remote support by a lifestyle coach was acceptable to patients with NAFLD and feasible to deliver. Issues with initial access, optimization of information content, and promoting the value of remote lifestyle coach support require further development ahead of future research to establish intervention effectiveness.

The degree of hepatic steatosis associates with impaired cardiac and autonomic function.

BACKGROUND & AIMS: Cardiovascular disease is the principle cause of death in patients with elevated liver fat unrelated to alcohol consumption, more so than liver-related morbidity and mortality. The aim of this study was to evaluate the relationship between liver fat and cardiac and autonomic function, as well as to assess how impairment in cardiac and autonomic function is influenced by metabolic risk factors. METHODS: Cardiovascular and autonomic function were assessed in 96 sedentary individuals: i) non-alcoholic fatty liver disease (NAFLD) (n = 46, hepatic steatosis >5% by magnetic resonance spectroscopy), ii) Hepatic steatosis and alcohol (dual aetiology fatty liver disease [DAFLD]) (n = 16, hepatic steatosis >5%, consuming >20 g/day of alcohol) and iii) CONTROL (n = 34, no cardiac, liver or metabolic disorders, <20 g/day of alcohol). RESULTS: Patients with NAFLD and DAFLD had significantly impaired cardiac and autonomic function when compared with controls. Diastolic variability and systolic variability (LF/HF-sBP [n/1]; 2.3 (1.7) and 2.3 (1.5) vs. 3.4 (1.5), p <0.01) were impaired in patients with NAFLD and DAFLD when compared to controls, with DAFLD individuals showing a decrease in diastolic variability relative to NAFLD patients. Hepatic steatosis and fasting glucose were negatively correlated with stroke volume index. Fibrosis stage was significantly negatively associated with mean blood pressure (r = -0.47, p = 0.02), diastolic variability (r = -0.58, p ≤0.01) and systolic variability (r = -0.42, p = 0.04). Hepatic steatosis was independently associated with cardiac function (p ≤0.01); TNF-α (p ≤0.05) and CK-18 (p ≤0.05) were independently associated with autonomic function. CONCLUSION: Cardiac and autonomic impairments appear to be dependent on level of liver fat, metabolic dysfunction, inflammation and fibrosis staging, and to a lesser extent alcohol intake. Interventions should be sought to moderate the excess cardiovascular risk in patients with NAFLD or DAFLD. LAY SUMMARY: Increased levels of fat in the liver impair the ability of the cardiovascular system to work properly. The amount of fat in the liver, metabolic control, inflammation and alcohol are all linked to the degree that the cardiovascular system is affected.

Barriers and Facilitators to Mediterranean Diet Adoption by Patients With Nonalcoholic Fatty Liver Disease in Northern Europe.

BACKGROUND & AIMS: Dietary interventions for weight loss are effective therapies for nonalcoholic fatty liver disease (NAFLD). The Mediterranean diet might benefit these patients, but it is not followed consistently in Northern European countries. We examined factors that determine Mediterranean diet adoption and maintenance in a northern European population. METHODS: We used a mixed-methods approach to investigate the effects of a 12-week Mediterranean diet intervention and perceived barriers and facilitators. Nineteen adults with NAFLD were recruited from a tertiary hepatology center in England. Participants were taught behavioral strategies through the provision of shopping lists, meal planners, and recipes; no advice was given on calorie allowances or physical activities. We used the 14-point Mediterranean diet assessment tool to assess dietary intake, based on a small number of foods in servings per day or servings per week, at baseline and after 12 weeks; participants were assigned scores of low (<5 points), moderate (6-9 points), or high (10-14 points). Semistructured interviews were audiorecorded, transcribed, and analyzed using the framework method. RESULTS: Twelve weeks after the dietary advice, Mediterranean diet adoption significantly increased from moderate to high (mean increase, 2.2 points; from 7.6 ± 2.5 at baseline to 9.8 ± 2.8 at 12 wk) (P = .006). This increase was associated with a mean reduction in body weight of 2.4 kg (from 99.2 ± 17.0 kg at baseline to 96.8 ± 17.5 kg at 12 wk) (P = .001) and increased serum concentrations of high-density lipoprotein cholesterol in 72% of participants (from 1.10 ± 0.8 at baseline to 1.20 ± 1.30 vs 1.00 ± 0.5 at 12 wk) (P = .009). Increased nutrition knowledge and skills, family support, Mediterranean diet promotion in media and clinical settings, and nutritional care facilitated diet changes. Barriers to Mediterranean diet uptake included an obesogenic environment, life stressors, and demand for convenience. Poor understanding of the causes and significance of NAFLD adversely affected readiness to change dietary habits. CONCLUSIONS: In an analysis of patients with NAFLD in the northern United Kingdom, we found a 12-week Mediterranean diet intervention was acceptable and associated with significant reductions in body weight and increased serum levels of high-density lipoprotein. We identified barriers and facilitators that could support appropriate treatment adaptations and guide personalized intervention approaches.

Health-related Quality of Life in Nonalcoholic Fatty Liver Disease Associates With Hepatic Inflammation.

BACKGROUND & AIMS: Chronic liver disease has negative effects on health-related quality of life (HRQL). We analyzed data from the European non-alcoholic fatty liver disease (NAFLD) registry to assess the effects of NAFLD on HRQL. METHODS: We collected data from 304 patients (mean age, 52.3 ± 12.9 years) with histologically defined NAFLD enrolled prospectively into the European NAFLD Registry in Germany, the United Kingdom, and Spain. The chronic liver disease questionnaire (CLDQ) was completed within 6 months of liver biopsy collection. RESULTS: The mean CLDQ overall score was 5.0 ± 1.2, with the lowest score in the category fatigue (4.3 ± 1.6) and the highest scores for activity (5.4 ± 1.4). Women had significantly lower CLDQ scores than men (4.6 ± 1.3 vs 5.3 ± 1.1; P < .001). We found negative correlations between CLDQ scores and presence of obesity (P < .001), type 2 diabetes (P < .001), and dyslipidaemia (P < .01). There was a negative correlation between level of aspartate aminotransferase, but not alanine aminotransferase, and HRQL. Higher histological score of steatosis (1 vs 3) resulted in lower mean CLDQ score (5.3 ± 1.1 vs 4.5 ± 1.4; P < .01); higher level of lobular inflammation (0 vs 3) also resulted in lower mean CLDQ score (5.3 ± 1.2 vs 3.9 ± 1.8; P <. 001). In contrast, advanced fibrosis (F3-4) compared to early or intermediate fibrosis (F0-2) had no significant effect on mean CLDQ score (4.9 ± 1.2 vs 5.1 ± 1.3; P = .072). In multivariate analysis, patients sex, age, presence of type 2 diabetes, and inflammation were independently associated with low HRQL. CONCLUSION: In an analysis of data from the European NAFLD registry, we observed a substantial burden of symptoms in patients. In addition to age, sex, and the presence of diabetes, detection of lobular inflammation in biopsies correlated with lower HRQL.

Effects of Exercise on Liver Fat and Metabolism in Alcohol Drinkers.

BACKGROUND & AIMS: Exercise is an important component of obesity-associated disorders and has been shown to reduce markers of nonalcoholic fatty liver disease (NAFLD). However, little is known about how these effects are influenced by alcohol intake. The authors performed a randomized controlled trial to investigate the effects of exercise on hepatic triglyceride content (HTGC) and metabolism in overweight or obese patients who consume alcohol. METHODS: The authors performed a prospective study of 27 patients (mean 54 ± 11 years of age, body mass index [BMI] 31 ± 4 kg/m2) with >5% HTGC in the United Kingdom, consuming alcohol (mean 221 ± 75 g/week). Anthropometry, body composition, HTGC, and abdominal fat were measured using plethysmography and magnetic resonance imaging. Subjects were assigned to groups that exercised (3 times/week on nonconsecutive days) for 12 weeks (n = 14) or continued standard care (control group, n = 13), maintaining baseline weight and alcohol consumption. The exercise program consisted of aerobic exercise (static cycling) and a circuit of resistance exercise (free weights and machines). Patients were examined at baseline and at 12 weeks; data collected on HTGC, body composition, metabolic control, circulating inflammatory, and fibrosis markers were assessed at baseline and at 12 weeks. Between-group differences were evaluated using an unpaired t test and within-group differences using a paired t test. The primary outcomes for this study were changes in HTGC between baseline and 12 weeks. RESULTS: After 12 weeks, there was no significant difference between the exercise and control groups in HTGC (reduction of 0.1% ± 2.1% in exercisers vs increase of 0.5 ± 2.1% in control group; P > .05). At week 12, the exercise group had significant reductions in subcutaneous fat (loss of 23 ± 28 cm2 in the exercisers vs increase of 12 ± 19 cm2 in the control group; P < .01), and whole body fat (loss of 2.1 ± 1.1 kg in the exercisers vs increase of 0.2 ± 2.1 kg; P < .01). The exercise group also had a significantly greater increase in lean body mass (increase of 1.9 ± 1.4 kg for the exercisers vs increase of 0.7 ± 1.5 kg for the control group; P < .01) and a significantly greater reduction in level of cytokeratin 18 (reduction of 49 ± 82 U/L in exercisers vs increase of 17 ± 38 U/L in control group; P < .05). There were no differences between groups in changes in metabolic factors or markers of inflammation. CONCLUSIONS: In a randomized controlled trial of obese individuals who consume alcohol, exercise significantly improved body composition and reduced hepatocyte apoptosis (cytokeratin 18), but did not reduce HTGC. This finding could indicate that alcohol consumption reduces the effects of exercise on NAFLD observed in previous studies. Clinical care teams should look to use exercise as part of the management strategy for people consuming alcohol, but optimal benefit may be as an adjunct to alcohol reduction and weight management strategies. (ISRCTN.com, Number: ISRCTN90597099).

Exercise Reduces Liver Lipids and Visceral Adiposity in Patients With Nonalcoholic Steatohepatitis in a Randomized Controlled Trial.

BACKGROUND & AIMS: Pharmacologic treatments for nonalcoholic steatohepatitis (NASH) are limited. Lifestyle interventions are believed to be effective in reducing features of NASH, although the effect of regular exercise, independent of dietary change, is unclear. We performed a randomized controlled trial to study the effect of exercise on hepatic triglyceride content (HTGC) and biomarkers of fibrosis in patients with NASH. METHODS: Twenty-four patients (mean age, 52 ± 14 y; body mass index, 33 ± 6 kg/m2) with sedentary lifestyles (<60 min/wk of moderate-vigorous activity) and biopsy-proven NASH were assigned randomly to groups that exercised (n = 12) or continued standard care (controls, n = 12) for 12 weeks while maintaining their weight. The exercise (cycling and resistance training) was supervised at an accredited sports center and supervised by a certified exercise specialist and recorded 3 times per week on nonconsecutive days. We measured HTGC, body composition, circulating markers of inflammation, fibrosis, and glucose tolerance at baseline and at 12 weeks. RESULTS: Compared with baseline, exercise significantly reduced HTGC (reduction of 16% ± 24% vs an increase of 9% ± 15% for controls; P < .05), visceral fat (reduction of 22 ± 33 cm2 vs an increase of 14 ± 48 cm2 for controls; P < .05), plasma triglycerides (reduction of 0.5 ± 1.0 mmol/L vs an increase of 0.3 ± 0.4 mmol/L for controls; P < .05), and γ-glutamyltransferase (reduction of 10 ± 28 U/L-1 vs a reduction of 17 ± 38 U/L-1 for controls; P < .05). There were no effects of exercise on liver enzyme levels, metabolic parameters, circulatory markers of inflammation (levels of interleukin 6, tumor necrosis factor-α, or C-reactive protein) and fibrosis. CONCLUSIONS: In a randomized controlled trial, 12 weeks of exercise significantly reduced HTGC, visceral fat, and plasma triglyceride levels in patients with NASH, but did not affect circulating markers of inflammation or fibrosis. Exercise without weight loss therefore affects some but not all factors associated with NASH. Clinical care teams should consider exercise as part of a management strategy of NASH, but weight management strategies should be included. Larger and longer-term studies are required to determine the effects of exercise in patients with NASH. ISRCTN registry.com: ISRCTN16070927.

High intensity intermittent exercise improves cardiac structure and function and reduces liver fat in patients with type 2 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: Cardiac disease remains the leading cause of mortality in type 2 diabetes, yet few strategies to target cardiac dysfunction have been developed. This randomised controlled trial aimed to investigate high intensity intermittent training (HIIT) as a potential therapy to improve cardiac structure and function in type 2 diabetes. The impact of HIIT on liver fat and metabolic control was also investigated. METHODS: Using an online random allocation sequence, 28 patients with type 2 diabetes (metformin and diet controlled) were randomised to 12 weeks of HIIT (n = 14) or standard care (n = 14). Cardiac structure and function were measured by 3.0 T MRI and tagging. Liver fat was determined by 1H-magnetic resonance spectroscopy and glucose control by an OGTT. MRI analysis was performed by an observer blinded to group allocation. All study procedures took place in Newcastle upon Tyne, UK. RESULTS: Five patients did not complete the study and were therefore excluded from analysis: this left 12 HIIT and 11 control patients for the intention-to-treat analysis. Compared with controls, HIIT improved cardiac structure (left ventricular wall mass 104 ± 17 g to 116 ± 20 g vs. 107 ± 25 g to 105 ± 25 g, p < 0.05) and systolic function (stroke volume 76 ± 16 ml to 87 ± 19 ml vs. 79 ± 14 ml to 75 ± 15 ml, p < 0.01). Early diastolic filling rates increased (241 ± 84 ml/s to 299 ± 89 ml/s vs. 250 ± 44 ml/s to 251 ± 47 ml/s, p < 0.05) and peak torsion decreased (8.1 ± 1.8° to 6.9 ± 1.6° vs. 7.1 ± 2.2° to 7.6 ± 1.9°, p < 0.05) in the treatment group. Following HIIT, there was a 39% relative reduction in liver fat (p < 0.05) and a reduction in HbA1c (7.1 ± 1.0% [54.5 mmol/mol] to 6.8 ± 0.9% [51.3 mmol/mol] vs. 7.2 ± 0.5% [54.9 mmol/mol] to 7.4 ± 0.7% [57.0 mmol/mol], p < 0.05). Changes in liver fat correlated with changes in HbA1c (r = 0.70, p < 0.000) and 2 h glucose (r = 0.57, p < 0.004). No adverse events were recorded. CONCLUSIONS/INTERPRETATION: This is the first study to demonstrate improvements in cardiac structure and function, along with the greatest reduction in liver fat, to be recorded following an exercise intervention in type 2 diabetes. HIIT should be considered by clinical care teams as a therapy to improve cardiometabolic risk in patients with type 2 diabetes. TRIAL REGISTRATION: www.isrctn.com 78698481 FUNDING: : Medical Research Council.

Targeting Lifestyle Behavior Change in Adults with NAFLD During a 20-min Consultation: Summary of the Dietary and Exercise Literature.

Non-alcoholic fatty liver disease (NAFLD) is largely linked to poor diet, lack of physical activity/exercise, and being overweight. In the absence of approved pharmaceutical agents, lifestyle modification, encompassing dietary change and increased physical activity/exercise to initiate weight loss, is the recommended therapy for NAFLD. Despite this, the use of lifestyle therapy within clinical settings is lacking with limited guidance available about what it should involve, how it should be delivered, and whether it can be feasibly delivered as part of standard care. This paper highlights the evidence for the use of lifestyle modification in NAFLD. While there is evidence to support use of behavioral strategies to support lifestyle behavior change in other clinical populations, these are yet to be assessed in people with NAFLD. However, there is sufficient evidence to suggest that behavioral intervention targeting diet and physical activity to promote weight loss in general is effective and a number of practical strategies are presented on how this could be achieved.

Cardiac structure and function are altered in type 2 diabetes and non-alcoholic fatty liver disease and associate with glycemic control.

BACKGROUND: Both non-alcoholic fatty liver disease (NAFLD) and Type 2 diabetes increase the risk of developing cardiovascular disease. The metabolic processes underlying NAFLD and Type 2 diabetes are part of an integrated mechanism but little is known about how these conditions may differentially affect the heart. We compared the impact of NAFLD and Type 2 diabetes on cardiac structure, function and metabolism. METHODS: 19 adults with Type 2 diabetes (62 ± 8 years), 19 adults with NAFLD (54 ± 15 years) and 19 healthy controls (56 ± 14 years) underwent assessment of cardiac structure, function and metabolism using high resolution magnetic resonance imaging, tagging and spectroscopy at 3.0 T. RESULTS: Adults with NAFLD and Type 2 diabetes demonstrate concentric remodelling with an elevated eccentricity ratio compared to controls (1.05 ± 0.3 vs. 1.12 ± 0.2 vs. 0.89 ± 0.2 g/ml; p < 0.05). Despite this, only the Type 2 diabetes group demonstrate significant systolic and diastolic dysfunction evidenced by a reduced stroke index (31 ± 7vs. controls, 38 ± 10, p < 0.05 ml/m2) and reduced E/A (0.9 ± 0.4 vs. controls, 1.9 ± 1.4, p < 0.05) respectively. The torsion to shortening ratio was higher in Type 2 diabetes compared to NAFLD (0.58 ± 0.16 vs. 0.44 ± 0.13; p < 0.05). Significant associations were observed between fasting blood glucose/HbA1c and diastolic parameters as well as the torsion to shortening ratio (all p < 0.05). Phosphocreatine/adenosine triphosphate ratio was not altered in NAFLD or Type 2 diabetes compared to controls. CONCLUSIONS: Changes in cardiac structure are evident in adults with Type 2 diabetes and NAFLD without overt cardiac disease and without changes in cardiac energy metabolism. Only the Type 2 diabetes group display diastolic and subendocardial dysfunction and glycemic control may be a key mediator of these cardiac changes. Therapies should be explored to target these preclinical cardiac changes to modify cardiovascular risk associated with Type 2 diabetes and NAFLD.

Modified high-intensity interval training reduces liver fat and improves cardiac function in non-alcoholic fatty liver disease: a randomized controlled trial.

Although lifestyle changes encompassing weight loss and exercise remain the cornerstone of non-alcoholic fatty liver disease (NAFLD) management, the effect of different types of exercise on NAFLD is unknown. This study defines the effect of modified high-intensity interval training (HIIT) on liver fat, cardiac function and metabolic control in adults with NAFLD. Twenty-three patients with NAFLD [age 54±10 years, body mass index (BMI) 31±4 kg/m(2), intra-hepatic lipid >5%) were assigned to either 12 weeks HIIT or standard care (controls). HIIT involved thrice weekly cycle ergometry for 30-40 min. MRI and spectroscopy were used to assess liver fat, abdominal fat and cardiac structure/function/energetics. Glucose control was assessed by oral glucose tolerance test and body composition by air displacement plethysmography. Relative to control, HIIT decreased liver fat (11±5% to 8±2% compared with 10±4% to 10±4% P=0.019), whole-body fat mass (35±7 kg to 33±8 kg compared with 31±9 kg to 32±9 kg, P=0.013), alanine (52±29 units/l to 42±20 units/l compared with 47±22 units/l to 51±24 units/l, P=0.016) and aspartate aminotransferase (AST; 36±18 units/l to 33±15 units/l compared with 31±8 units/l to 35±8 units/l, P=0.017) and increased early diastolic filling rate (244±84 ml/s to 302±107 ml/s compared with 255±82 ml/s to 251±82 ml/s, P=0.018). There were no between groups differences in glucose control. Modified HIIT reduces liver fat and improves body composition alongside benefits to cardiac function in patients with NAFLD and should be considered as part of the broader treatment regimen by clinical care teams. ISRCTN trial ID: ISRCTN78698481.

Is home-based, virtually delivered, group exercise feasible and acceptable for older patients with hepatocellular carcinoma? A non-randomised feasibility study (TELEX-Liver Cancer).

OBJECTIVES: The study aimed to assess the feasibility, acceptability and safety of delivering a home-based telehealth exercise intervention to older patients with hepatocellular carcinoma (HCC). DESIGN: Non-randomised feasibility study. SETTING: Patients were recruited from UK outpatient liver cancer clinics. PARTICIPANTS: Patients were aged ≥60 years with HCC, with post-treatment imaging reporting a complete response, partial response or stable disease. INTERVENTION AND DATA COLLECTION: Patients were invited to attend synchronous online exercise sessions, twice weekly for 10 weeks. Physical function and patient-reported outcomes were assessed pre-intervention and post-intervention. Qualitative data were collected via semistructured interviews after intervention completion. PRIMARY OUTCOME MEASURES: Recruitment, retention, exercise adherence and safety. RESULTS: 40 patients were invited to participate and 19 (mean age 74 years) provided consent (recruitment rate 48%). Patients completed 76% of planned exercise sessions and 79% returned to the clinic for follow-up. Hand grip strength (95% CI 1.0 to 5.6), Liver Frailty Index (95% CI -0.46 to -0.23) and time taken to perform five sit-to-stands (95% CI -3.2 to -1.2) improved from pre-intervention to post-intervention. Patients reported that concerns they had relating to their cancer had improved following the intervention (95% CI 0.30 to 5.85). No adverse events occurred during exercise sessions.Qualitative data highlighted the importance of an instructor in real time to ensure that the sessions were achievable, tailored and well balanced, which helped to foster motivation and commitment within the group. Patients reported enjoying the exercise intervention, including the benefits of peer support and highlighted perceived benefits to both their physical and mental health. Patients felt that the online sessions overcame some of the barriers to exercise participation and preferred attending virtual sessions over face-to-face classes. CONCLUSIONS: It is feasible, acceptable and safe to deliver supervised group exercise via videoconferencing to patients with HCC in their own homes. These findings will inform the design of a future, adequately powered randomised controlled trial to evaluate the efficacy of the intervention. TRIAL REGISTRATION NUMBER: ISRCTN14411809.

Cardiac structure and function are altered in adults with non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is associated with a twofold greater risk of developing cardiovascular disease. Despite this, little is known about the effect of NAFLD upon cardiac function, limiting our ability to identify therapeutic strategies. This study aimed to address this by defining the effect of NAFLD on cardiac function, structure, and metabolism. METHODS: Nineteen adults with NAFLD were age-, sex-, and BMI-matched to healthy controls without liver or metabolic disease. Cardiac structure and function were assessed using high-resolution cardiac MRI and tagging at 3.0 T. High-energy phosphate metabolism was assessed using (31)P-magnetic resonance spectroscopy to measure the PCr/ATP ratio. RESULTS: Adults with NAFLD had significantly thicker left ventricular walls at systole (14 ± 3 vs. 12 ± 2 mm; p <0.01) and diastole (8 ± 1 vs. 7 ± 1 mm; p <0.01) than those without fatty liver and showed decreased longitudinal shortening (14 ± 3 vs. 17 ± 3%; p <0.01). The eccentricity ratio was significantly higher in the NAFLD group (1.1 ± 0.2 vs. 0.9 ± 0.2 g/ml; p <0.01) indicating concentric remodelling. Peak whole wall strain was higher in the NAFLD group (19 ± 2 vs. 17 ± 3%; p <0.01), as was peak endocardial strain (28 ± 4 vs. 22 ± 5%; p <0.01). Cardiac metabolism, measured by PCr/ATP ratio, was not altered in NAFLD (1.8 ± 0.3 vs. 1.9 ± 0.3; p=0.36). CONCLUSIONS: Significant changes in cardiac structure and function are evident in adults with NAFLD in the apparent absence of metabolic changes or overt cardiac disease. Clinicians should continue to explore therapies to improve cardiac function as a means to modify the excess risk of cardiovascular disease associated with NAFLD.

Resistance exercise improves autonomic regulation at rest and haemodynamic response to exercise in non-alcoholic fatty liver disease.

Autonomic dysfunction has been reported in patients with NAFLD (non-alcoholic fatty liver disease) and is associated with clinical presentations. To date, there are no therapies to improve autonomic regulation in people with NAFLD. The present study defines the impact of a short-term exercise programme on cardiac autonomic and haemodynamic regulation in patients with NAFLD. A total of 17 patients with clinically defined NAFLD [age, 55±12 years; BMI (body mass index), 33±5 kg/m²; liver fat, 17±9%] were randomized to 8 weeks of resistance exercise or a control group to continue standard care. Resting and submaximal exercise (50% of peak oxygen consumption) autonomic and cardiac haemodynamic measures were assessed before and after the intervention. Resistance exercise resulted in a 14% reduction in HR (heart rate) and 7% lower SBP (systolic blood pressure) during submaximal exercise (16 beats/min, P=0.03 and 16 mmHg, P=0.22). Sympathovagal balance, expressed as LF/HF (low-frequency/high-frequency) ratio of the mean HR beat-to-beat (R-R) interval, was reduced by 37% (P=0.26). Similarly sympathovagal balance of DBP (diastolic blood pressure) and SBP variability decreased by 29% (P=0.33) and 19% (P=0.55), respectively in the exercise group only. BRS (baroreflex sensitivity) increased by 31% (P=0.08) following exercise. The mean R-R interval increased by 23% (159 ms, P=0.09). Parasympathetic regulation was decreased by 17% (P=0.05) and overall sympathovagal balance in BP regulation (LF/HF ratio) increased by 26% (P=0.02) following resistance exercise. Resting haemodynamic measures remained similar between groups. Resistance exercise therapy seems to improve autonomic and submaximal exercise haemodynamic regulation in NAFLD. Further studies are required to define its role in clinical management of the condition.

Feasibility and acceptability of an evidence-informed digital intervention to support self-management in people with non-alcoholic fatty liver disease: protocol for a non-randomised feasibility study (VITALISE).

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of disease ranging from simple fatty liver to non-alcoholic steatohepatitis, cirrhosis, liver cancer and liver failure. NAFLD affects up to 30-40% of adults in Western countries and is directly linked to overweight and obesity. There are no approved drugs to specifically target NAFLD, therefore weight loss achieved through changes in dietary and physical activity behaviours is the recommended management approach. However, achieving and sustaining weight loss is challenging for patients with NAFLD. We developed a NAFLD-specific digital lifestyle intervention (VITALISE) to target changes in dietary and physical activity behaviours of patients with NAFLD to initiate weight loss and weight loss maintenance. This study aims to evaluate the feasibility and acceptability of VITALISE in a secondary care clinical setting. METHODS: A single-centre, one-arm, prospective design will be used to assess the feasibility and acceptability of recruitment, uptake, engagement and completion of VITALISE. Health-related outcomes will be assessed at baseline and 6-months. An interim measure of self-reported weight, physical activity and self-efficacy will be recorded at 12-weeks. Qualitative semi-structured interviews conducted at 6 months follow up will further explore acceptability and feasibility and fidelity of receipt and enactment. The study aims to recruit 35 patients with newly diagnosed NAFLD over a 6-month time period. Eligible patients will have continuous access to VITALISE and monthly tele-coaching support for 6 months prior to follow-up with a hepatologist. DISCUSSION: VITALISE offers access to evidence and theory-informed tailored dietary and physical activity support for patients with NAFLD. The intervention is designed for use by patients in their own time, outside of the hospital setting to overcome well documented challenges including attending additional appointments, and lack of time during routine appointments to adequately address lifestyle behaviour change. This feasibility study will determine the feasibility of VITALISE to support clinical care delivery. TRIAL REGISTRATION: ISRCTN12893503.

Alignment of Physician-Stated vs Clinically Derived Reference Fibrosis Score in Patients with Non-Alcoholic Steatohepatitis: A Real-World European Survey.

Objective: Stratifying disease severity in patients with non-alcoholic steatohepatitis (NASH) is essential for appropriate treatment and long-term management. Liver biopsy is the reference standard for fibrosis severity in NASH, but less invasive methods are used, eg, Fibrosis-4 Index (FIB-4) and vibration-controlled transient elastography (VCTE), for which reference thresholds for no/early fibrosis and advanced fibrosis are available. We compared subjective physician assessment of NASH fibrosis versus reference thresholds to understand classification in a real-world setting. Methods: Data were drawn from Adelphi Real World NASH Disease Specific ProgrammeTM conducted in France, Germany, Italy, Spain and UK in 2018. Physicians (diabetologists, gastroenterologists, hepatologists) completed questionnaires for five consecutive NASH patients presenting for routine care. Physician-stated fibrosis score (PSFS) based on available information was compared with clinically defined reference fibrosis stage (CRFS) determined retrospectively using VCTE and FIB-4 data and eight reference thresholds. Results: One thousand two hundred and eleven patients had VCTE (n = 1115) and/or FIB-4 (n = 524). Depending on thresholds, physicians underestimated severity in 16-33% (FIB-4) and 27-50% of patients (VCTE). Using VCTE ≥12.2, diabetologists, gastroenterologists and hepatologists underestimated disease severity in 35%, 32%, and 27% of patients, respectively, and overestimated fibrosis in 3%, 4%, and 9%, respectively (p = 0.0083 across specialties). Hepatologists and gastroenterologists had higher liver biopsy rates than diabetologists (52%, 56%, 47%, respectively). Conclusion: PSFS did not consistently align with CRFS in this NASH real-world setting. Underestimation was more common than overestimation, potentially leading to undertreatment of patients with advanced fibrosis. More guidance on interpreting test results when classifying fibrosis is needed, thereby improving management of NASH.

The effect of preoperative behaviour change interventions on pre- and post-surgery health behaviours, health outcomes, and health inequalities in adults: A systematic review and meta-analyses.

BACKGROUND: Prehabilitation interventions are being delivered across surgical specialities to improve health risk behaviours leading to better surgical outcomes and potentially reduce length of hospital stay. Most previous research has focused on specific surgery specialities and has not considered the impact of interventions on health inequalities, nor whether prehabilitation improves health behaviour risk profiles beyond surgery. The aim of this review was to examine behavioural Prehabilitation interventions across surgeries to inform policy makers and commissioners of the best available evidence. METHODS AND FINDINGS: A systematic review and meta-analysis of randomised controlled trials (RCTs) was conducted to determine the effect of behavioural prehabilitation interventions targeting at least one of: smoking behaviour, alcohol use, physical activity, dietary intake (including weight loss interventions) on pre- and post-surgery health behaviours, health outcomes, and health inequalities. The comparator was usual care or no treatment. MEDLINE, PubMed, PsychINFO, CINAHL, Web of Science, Google Scholar, Clinical trials and Embase databases were searched from inception to May 2021, and the MEDLINE search was updated twice, most recently in March 2023. Two reviewers independently identified eligible studies, extracted data, and assessed risk of bias using the Cochrane risk of bias tool. Outcomes were length of stay, six-minute walk test, behaviours (smoking, diet, physical activity, weight change, and alcohol), and quality of life. Sixty-seven trials were included; 49 interventions targeted a single behaviour and 18 targeted multiple behaviours. No trials examined effects by equality measures. Length of stay in the intervention group was 1.5 days shorter than the comparator (n = 9 trials, 95% CI -2.6 to -0.4, p = 0.01, I2 83%), although in sensitivity analysis prehabilitation had the most impact in lung cancer patients (-3.5 days). Pre-surgery, there was a mean difference of 31.8 m in the six-minute walk test favouring the prehabilitation group (n = 19 trials, 95% CI 21.2 to 42.4m, I2 55%, P <0.001) and this was sustained to 4-weeks post-surgery (n = 9 trials, mean difference = 34.4m (95%CI 12.8 to 56.0, I2 72%, P = 0.002)). Smoking cessation was greater in the prehabilitation group before surgery (RR 2.9, 95% CI 1.7 to 4.8, I2 84%), and this was sustained at 12 months post-surgery (RR 1.74 (95% CI 1.20 to 2.55, I2 43%, Tau2 0.09, p = 0.004)There was no difference in pre-surgery quality of life (n = 12 trials) or BMI (n = 4 trials). CONCLUSIONS: Behavioural prehabilitation interventions reduced length of stay by 1.5 days, although in sensitivity analysis the difference was only found for Prehabilitation interventions for lung cancer. Prehabilitation can improve functional capacity and smoking outcomes just before surgery. That improvements in smoking outcomes were sustained at 12-months post-surgery suggests that the surgical encounter holds promise as a teachable moment for longer-term behavioural change. Given the paucity of data on the effects on other behavioural risk factors, more research grounded in behavioural science and with longer-term follow-up is needed to further investigate this potential.

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.

Stratification Of LIver Disease (SOLID): protocol for a prospective observational cohort study to determine the optimum biomarker strategies for the detection of advanced liver disease at the primary-secondary care interface.

INTRODUCTION: Undiagnosed fatty liver disease is prevalent in the community, due to high rates of harmful alcohol consumption and/or obesity. Fatty liver disease can progress to cirrhosis and its complications. Early identification of liver disease and treatment may prevent progression to cirrhosis. Biomarkers including FIB-4, enhanced liver fibrosis (ELF), PRO-C3 and vibration controlled transient elastography (VCTE) can stage liver fibrosis, but it is not known how well they perform in a primary care population. Moreover, no assessment of long-term prognostic ability of these biomarkers has been conducted in primary care. We aim to evaluate the performance of fibrosis biomarkers in primary care to develop a pathway to detect advanced fibrosis. METHODS AND ANALYSIS: This prospective, observational cohort study will recruit 3000 individuals with fatty liver disease risk factors (obesity, type 2 diabetes or hazardous alcohol consumption) at their primary care 'annual chronic disease review'. Participants will have a 'liver health check'. Two pathways will be evaluated: (1) all have FIB-4, ELF and VCTE performed, and (2) patients have an initial assessment with FIB-4 and ELF, followed by VCTE in only those with increased FIB-4 and/or ELF. Individuals with suspected significant/advanced liver fibrosis (liver stiffness measurement>8 kPa), will be reviewed in secondary care to confirm their fibrosis stage and institute treatment. The performance of FIB-4, ELF, PRO-C3, VCTE and novel biomarkers alone or in combination for advanced fibrosis/cirrhosis will be evaluated. Participants will be followed longitudinally via their electronic health records to assess long-term clinical outcomes. ETHICS AND DISSEMINATION: Ethical approval was obtained from the London-Chelsea Research Ethics Committee (22/PR/0535; 27 June 2022). Recruitment began on 31 October 2022. Outcomes of this study will be published in peer-reviewed journals and presented at scientific meetings. A lay summary of the results will be available for study participants and will be disseminated widely by LIVErNORTH.

Serum levels of fibrogenesis biomarkers reveal distinct endotypes predictive of response to weight loss in advanced nonalcoholic fatty liver disease.

BACKGROUND: NAFLD is associated with activation of fibroblasts and hepatic fibrosis. Substantial patient heterogeneity exists, so it remains challenging to risk-stratify patients. We hypothesized that the amount of fibroblast activity, as assessed by circulating biomarkers of collagen formation, can define a "high-risk, high-fibrogenesis" patient endotype that exhibits greater fibroblast activity and potentially more progressive disease, and this endotype may be more amendable to dietary intervention. METHODS: Patients with clinically confirmed advanced NAFLD were prescribed a very low-calorie diet (VLCD) intervention (∼800 kcal/d) to induce weight loss, achieved using total diet replacement. Serum markers of type III (PRO-C3) and IV collagen (PRO-C4) fibrogenesis were assessed at baseline every second week until the end of the VLCD, and 4 weeks post-VLCD and at 9 months follow-up. RESULTS: Twenty-six subjects had a mean weight loss of 9.7% with VLCD. This was associated with significant improvements in liver biochemistry. When stratified by baseline PRO-C3 and PRO-C4 into distinct fibrosis endotypes, these predicted substantial differences in collagen fibrogenesis marker dynamics in response to VLCD. Patients in the high activity group (PRO-C3 >11.4 ng/mL and/or PRO-C4 >236.5 ng/mL) exhibited a marked reduction of collagen fibrogenesis, ranging from a 40%-55% decrease in PRO-C3 and PRO-C4, while fibrogenesis remained unchanged in the low activity group. The biochemical response to weight loss was substantially greater in patients a priori exhibiting a high fibroblast activity endotype in contrast to patients with low activity. CONCLUSIONS: Thus, the likelihood of treatment response may be predicted at baseline by quantification of fibrogenesis biomarkers.