Title: Improving Nutritional Status in Patients with Liver Cirrhosis Through More Accurate and Individualised Nutritional Treatment.
Funder: Health Education England

Abstract: Background Sarcopenia, muscle wasting accompanied by reduced muscle function is the most common complication of cirrhosis and is associated with reduced survival and increased morbidity. Despite differences in nutritional status, currently all patients with advanced cirrhosis are recommended to follow a high-energy, high-protein diet. Patients frequently have problems meeting these recommendations due to poor appetite and early satiety. Oral nutritional supplements or tube feeding in addition to food are often required. Research using indirect calorimetry (IC) to measure resting energy expenditure (REE) shows that only 15-34% of patients are hypermetabolic. In clinical practice REE is currently estimated using predictive equations, but could be measured using a new handheld indirect calorimeter (HHC). The mechanisms involved in the loss of appetite in cirrhosis are not fully understood. In this study the factors affecting patients' appetite and intake will be evaluated, specifically patients' perspectives, satiety and gut hormone response, to determine how nutritional treatment can be individualised. Research Questions Is a HHC more accurate than predictive equations in determining REE in patients with cirrhosis? Does satiety and gut hormone response to eating differ between patients with cirrhosis and healthy volunteers? What factors affect patients' capacity to eat and meet their energy requirements? Specific Aims To compare values for REE measured by a HHC and clinical predictive equations with a research-standard IC in patients with cirrhosis. To compare the satiety and gut hormone response to eating in patients with cirrhosis to that in healthy volunteers. To explore the perspectives of patients with cirrhosis regarding eating and following energy intake recommendations. Plan of Investigation The research aims will be addressed by three sub-studies: Sub-study 1:A Comparison of Measured and Predicted Resting Energy Expenditure 25 patients with advanced cirrhosis will be admitted overnight to a clinical research facility. Their body composition will be assessed by densitometry, dual-energy x-ray absorptiometry and deuterium dilution to allow REE to be expressed relative to fat-free mass. After an overnight fast REE will be measured by research-standard IC, HHC and predicted by equations. Analysis will establish if the HHC is more accurate than currently used predictive equations. Sub-study 2:A Correlational Evaluation of Intake, Satiety and Gut Hormones During Eating The same 25 patients, plus 25 healthy volunteers will have energy and nutrient intake assessed by 3-day food diary, satiety assessed by visual analogue scales (VAS) whilst eating a standardised meal and serum levels of total and active glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) measured before and after an oral nutritional supplement. Analysis will establish if there is a difference in energy intake, nutrient intake, amount and rate of food consumed, VAS scores and total and active GLP-1 and PYY serum levels between patients and healthy volunteers. Sub-study 3:A Qualitative Study of Patient Perspectives on Eating and Meeting Energy Recommendations Following sub-studies 1 and 2 the same 25 patients will be invited to one-to-one interviews. Semi-structured interviews will be used to explore patients' perspectives on eating, meeting current energy recommendations and having energy requirements measured rather than predicted. A descriptive thematic analysis using the framework approach will establish themes important to patients. Summary of potential benefits to patients and the NHS The data from the three sub-studies will be synthesised for the following potential benefits: Updated guidance on nutritional treatment of patients with advanced cirrhosis. Improved nutritional status. Targeted nutritional support if HHC is more accurate. Better-nourished patients are likely to have reduced incidence of infection, complications of cirrhosis, hospital admissions and lengths of stay, with associated cost-savings. Reduced overfeeding and unnecessary oral nutritional supplement prescription could be cost-saving. Future research topics important to patients maybe generated.

Lay abstract: Aim The aim of this research is to help patients with liver cirrhosis to become better nourished by individualising the nutritional treatment they receive. Background In England and Wales up to 60,000 people have cirrhosis and there has been a 40% increase in cirrhosis in the last 10 years. Patients with end-stage liver cirrhosis frequently experience muscle wasting, which increases their likelihood of medical complications and reduces overall survival. Muscle wasting may be combined with decreased or increased fat stores. Despite this all patients are recommended to have a high-energy, high-protein diet. For individual patients to meet these dietary recommendations, oral nutritional supplements or feeding with the help of a tube are often required in addition to food. Research using indirect calorimeters (energy measuring machines), shows that only 15-34% of patients with cirrhosis have high-energy needs. These machines are not available on wards and in clinics, therefore dietitians use a simple calculation to estimate energy needs but these are often inaccurate. Alternative portable machines have been developed to measure energy needs but, so far, little work has been done to explore their value. This research will compare results from a portable machine to a standard machine used in a research department to check that the portable machine is accurate. The portable machines results will also be compared to dietitian's calculations. Poor appetite and feeling full quickly are common issues for people with cirrhosis and make following the recommended high-energy, high-protein diet difficult. The reasons why patients experience poor appetite are not fully understood. This research will measure the patient's rate of food intake and level of fullness whilst eating and compare the results to those of healthy volunteers. Additionally levels of gut hormones that suppress appetite will be measured before and after drinking an oral nutritional supplement. To date there is little research on what is important to patients with cirrhosis from their point of view and no research has focused on their experience of eating or their opinions of nutritional treatment. In this research patients will be interviewed about their views on these issues. Research design and methods There will be three parts to the research. The same patients will take part in 1 and 2 and may also take part in 3. Healthy volunteers will take part in 2 only. Parts 1 and 2 will be during the same overnight admission to the NIHR/Wellcome Trust Clinical Research Facility at Cambridge University Hospitals NHS Foundation Trust. Part 3 will take place later at a location convenient to the patient: Part 1: Measurement of energy needs by both research-standard and portable energy measuring machines and dietitian's calculation. Part 2: Measurement of food intake, appetite and gut hormones. Part 3: Interviews with patients with cirrhosis to explore their experiences of eating, nutritional treatment and having energy needs measured in part 1. The findings from this research will be used to improve and individualise guidelines for the nutritional treatment of patients with cirrhosis. This has the potential to help patients become better nourished and stronger to cope with future treatments or complications. Consequently there is potential to save the NHS money through fewer hospital admissions and shorter stays. The findings will also generate new information that will provide the basis for future research. Patient and public involvement Patients have been actively involved in developing this research project. There was support for the research. The following comment regarding current nutritional treatment clearly summarised why the research is needed: One size fits all at the moment Patients have contributed to the project design, wording and raised issues that the researcher had not considered. A patient and public involvement advisory group will have an important role in managing the research when it starts. Dissemination The research findings will be shared in traditional ways such as in scientific journals and at academic conferences. People who have taken part in the research will be invited to an event at the end of the project where the research findings will be presented. All the findings from the research will be published for patients in an information leaflet. The patient and public involvement advisory group will have a central role in the design of this leaflet and making sure it is disseminated to those who it is most relevant to.

Research activity codes: 6.7 PHYSICAL;7.1 INDIVIDUAL CARE NEEDS
Health categories: CANCER AND NEOPLASMS;CARDIOVASCULAR;METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL;STROKE