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.

The effectiveness and acceptability of Mediterranean diet and calorie restriction in non-alcoholic fatty liver disease (NAFLD): A systematic review and meta-analysis.

BACKGROUND & AIMS: Lifestyle interventions that focus on reduced energy intake and improved dietary pattern are the mainstay of non-alcoholic fatty liver disease (NAFLD) management. However, it remains unclear which dietary approaches are most beneficial and promote greatest adherence. We aimed to synthesise data from randomised and clinical controlled trials, describing the effects of Mediterranean Diet and Calorie Restriction interventions on NAFLD surrogate markers, in adults. METHODS: We searched MEDLINE, Embase, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials (October 2021). Study quality was assessed using the Cochrane Collaboration's tools: risk of bias for randomised controlled trials, and risk of bias in non-randomised studies of interventions. Meta-analyses were performed using a random effects model, and the I2 statistic was used to assess heterogeneity. RESULTS: Of 4041 records identified, 26 articles with 3037 participants met the inclusion criteria, including studies on calorie-restricted interventions (CRI) (n 9), Mediterranean diet (MD) interventions (n 13) and MD component interventions (n 4). Studies were heterogeneous regarding intervention components, assessment of liver status and diet outcomes. 3 studies reported zero attrition and mean attrition rate for the remaining 23 studies was 14%. Post-intervention meta-analyses revealed that dietary interventions reduced alanine aminotransferase (ALT) (P < 0.001), aspartate aminotransferase (AST) (P = 0.004), Fatty Liver Index (FLI) (P < 0.001), hepatic steatosis (HS) (P = 0.02), and liver stiffness (P = 0.01). CRI had favourable effects on ALT (P < 0.001), HS (P < 0.001) and liver stiffness (P = 0.009). MD reduced ALT (P = 0.02), FLI (P < 0.001) and liver stiffness (P = 0.05). There was a dose-response relationship between degree of calorie restriction and beneficial effects on liver function and weight loss, suggesting that this approach should remain the cornerstone of NAFLD management. In addition, diet composition changes have potential for improving NAFLD and the limited data suggest that MD may be an effective diet therapy. CONCLUSION: These results support the current guidelines in NAFLD. However, further studies, which robustly evaluate the effects of interventions on dietary intake, acceptability and sustainability of the interventions, and quality of life and other patient-related outcomes are needed to support effective care delivery.

The effects of different parenteral nutrition lipid formulations on clinical and laboratory endpoints in patients receiving home parenteral nutrition: A systematic review.

BACKGROUND: Home parenteral nutrition (HPN) is a life-sustaining therapy for individuals with intestinal failure in a community setting. It refers to the intravenous infusion of macronutrients, micronutrients, fluids and electrolytes. Routinely used HPN solutions contain different quantities of these components. Consequently, each HPN solution may have different impacts on metabolism, inflammation and oxidative stress. Long-term use of HPN can lead to a number of adverse health outcomes including the development of metabolic bone disease, intestinal failure associated liver disease and poor quality of life but whether, and how, the composition of HPN solutions contributes to these health sequelae is poorly understood. The aim of this study is to systematically review and evaluate the evidence for the differential effects of HPN solutions and to understand what features are associated with differences in clinical endpoints. METHODS: A systematic literature search was conducted between September and December 2020, and updated in July 2021 using the MEDLINE (Ovid), EMBASE, Scopus, and Web of Science databases. Studies were selected according to the following criteria (a) adult participants (>18 years old) dependent on HPN; (b) randomised controlled trials, prospective cohort and cross-sectional study designs; (c) primary research comparing two or more HPN solutions and (d) published in English language. Data were extracted and study quality assessed using Cochrane Collaboration's tools: Risk of Bias for Randomised Controlled Trials (RCTs); Risk of Bias in Non-Randomised Studies of Interventions; and the Newcastle Ottawa Scale for cross-sectional studies. RESULTS: Of the 5148 articles identified, seven RCTs, two prospective cohort and one cross-sectional study were included with a total of 295 participants. Studies varied in terms of duration (one to 60 months) and sample size (n = 5 to 88). Ten studies compared lipid emulsions (LE) and one study also compared LE with lipid-free HPN. No studies were found that compared the amino acid, vitamin, trace element or electrolyte components of HPN. In general, LE were well tolerated with no significant adverse effects. LE containing olive +/or fish oil were associated with a lower ω-6:ω-3 fatty acid ratio, positive reductions in markers of liver function, and changes in blood and cell fatty acid profiles. CONCLUSIONS: Despite the increasing use of HPN, there is surprisingly little evidence available to guide the provision of macro and micronutrients in the adult population requiring this therapy. Although LE containing olive +/or fish oil show promise with regards to liver function and blood and cell fatty acid profiles, further studies are needed before drawing definitive conclusions on the clinical value of these emulsions. It is likely that one type of HPN solution alone cannot be uniformly applied to patient care, and each patient should be assessed on an individual basis.

Implementation of a care bundle improves the management of patients with non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is common and is associated with liver-related and cardiovascular-related morbidity. Our aims were: (1) to review the current management of patients with NAFLD attending hospital clinics in North East England (NEE) and assess the variability in care; (2) develop a NAFLD 'care bundle' to standardise care; (3) to assess the impact of implementation of the NAFLD care bundle. METHODS: A retrospective review was conducted to determine baseline management of patients with NAFLD attending seven hospitals in NEE. A care bundle for the management of NAFLD was developed including important recommendations from international guidelines. Impact of implementation of the bundle was evaluated prospectively in a single centre. RESULTS: Baseline management was assessed in 147 patients attending gastroenterology, hepatology and a specialist NAFLD clinic. Overall, there was significant variability in the lifestyle advice given and management of metabolic risk factors, with patients attending an NAFLD clinic significantly more likely to achieve >10% body weight loss and have metabolic risk factors addressed. Following introduction of the NAFLD bundle 50 patients were evaluated. Use of the bundle was associated with significantly better documentation and implementation of most aspects of patient management including management of metabolic risk factors, documented lifestyle advice and provision of NAFLD-specific patient advice booklets. CONCLUSION: The introduction of an outpatient 'care bundle' led to significant improvements in the assessment and management of patients with NAFLD in the NEE and could help improve and standardise care if used more widely.

Factors associated with engagement and adherence to a low-energy diet to promote 10% weight loss in patients with clinically significant non-alcoholic fatty liver disease.

OBJECTIVE: Clinical guidelines recommend weight loss to manage non-alcoholic fatty liver disease (NAFLD). However, the majority of patients find weight loss a significant challenge. We identified factors associated with engagement and adherence to a low-energy diet (LED) as a treatment option for NAFLD. DESIGN: 23 patients with NAFLD enrolled in a LED (~800 kcal/day) were individually interviewed. Transcripts were thematically analysed. RESULTS: 14/23 patients achieved ≥10% weight loss, 18/23 achieved ≥7% weight loss and 19/23 achieved ≥5% weight loss. Six themes were generated from the data. A desire to achieve rapid weight loss to improve liver health and prevent disease progression was the most salient facilitator to engagement. Early and significant weight loss, accountability to clinicians and regular appointments with personalised feedback were facilitators to engagement and adherence. The desire to receive positive reinforcement from a consultant was a frequently reported facilitator to adherence. Practical and emotional support from friends and family members was critically important outside of the clinical setting. Irregular working patterns preventing attendance at appointments was a barrier to adherence and completion of the intervention. CONCLUSIONS: Engagement and adherence to a LED in patients with NAFLD were encouraged by early and rapid weight loss, personalised feedback and positive reinforcement in the clinical setting combined with ongoing support from friends and family members. Findings support those identified in patients who completed a LED to achieve type 2 diabetes remission and highlight the importance of behaviour change support during the early stages of a LED to promote adherence.

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.

Feasibility of a Very Low Calorie Diet to Achieve a Sustainable 10% Weight Loss in Patients With Nonalcoholic Fatty Liver Disease.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is the most common liver condition worldwide. A weight loss goal of ≥10% is the recommended treatment for NAFLD; however, only a minority of patients achieve this level of weight reduction with standard dietary approaches. This study aimed to determine whether a very low calorie diet (VLCD) is an acceptable and feasible therapy to achieve and maintain a ≥10% weight loss in patients with clinically significant NAFLD. METHODS: Patients with clinically significant NAFLD were recruited to a VLCD (∼800 kcal/d) intervention using meal replacement products. Anthropometrics, blood tests (liver and metabolic), liver stiffness, and cardiovascular disease risk were measured at baseline, post-VLCD, and at 9-month follow-up. RESULTS: A total of 45 patients were approached of which 30 were enrolled 27 (90%) completed the VLCD intervention, and 20 (67%) were retained at 9-month follow-up. The VLCD was acceptable to patients and feasible to deliver. Intention-to-treat analysis found that 34% of patients achieved and sustained ≥10% weight loss, 51% achieved ≥7% weight loss, and 68% achieved ≥5% weight loss at 9-month follow-up. For those completing the VLCD, liver health (liver enzymes and liver stiffness), cardiovascular disease risk (blood pressure and QRISK2), metabolic health (fasting glucose, HbA1c, and insulin), and body composition significantly improved post-VLCD and was maintained at 9 months. DISCUSSION: VLCD offers a feasible treatment option for some patients with NAFLD to enable a sustainable ≥10%, weight loss, which can improve liver health, cardiovascular risk, and quality of life in those completing the intervention.

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.

Helmet Use Amongst Equestrians: Harnessing Social and Attitudinal Factors Revealed in Online Forums.

Equestrian activities pose significant head injury risks to participants. Yet, helmet use is not mandatory in Australia outside of selected competitions. Awareness of technical countermeasures and the dangers of equestrian activities has not resulted in widespread adoption of simple precautionary behaviors like helmet use. Until the use of helmets whilst riding horses is legislated in Australia, there is an urgent need to improve voluntary use. To design effective injury prevention interventions, the factors affecting helmet use must first be understood. To add to current understandings of these factors, we examined the ways horse riders discussed helmet use by analyzing 103 posts on two helmet use related threads from two different Australian equestrian forums. We found evidence of social influence on helmet use behaviors as well as three attitudes that contributed towards stated helmet use that we termed: "I Can Control Risk", "It Does Not Feel Right" and "Accidents Happen". Whilst we confirm barriers identified in previous literature, we also identify their ability to support helmet use. This suggests challenging but potentially useful complexity in the relationship between risk perception, protective knowledge, attitudes, decision-making and behavior. Whilst this complexity is largely due to the involvement of interspecies relationships through which safety, risk and trust are distributed; our findings about harnessing the potential of barriers could be extended to other high risk activities.