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.


Looking after your liver -reducing your risk of fatty liver disease
This booklet aims to give you some advice to help reduce your risk of developing liver disease in the future. Fatty liver disease is very common and affects 1 in 4 adults in the UK. This condition is caused by a build-up of fat within the liver and most often occurs in people who are overweight, have diabetes or who consume more than the recommended limit for alcohol. Fatty liver disease is one of the major causes of cirrhosis (severe scarring of the liver). Importantly, fatty liver disease can be reversible in many people if they make lifestyle changes. Healthy eating, weight loss, increasing physical activity and exercise as well as reducing or stopping alcohol consumption can all help reduce fat in the liver.

What is fatty liver disease?
Non-alcohol-related fatty liver disease (NAFLD) is caused by a build-up of fat within the liver and can occur in people who are overweight, have diabetes or have high cholesterol. In this condition, fat droplets develop within the liver cells causing damage, which can lead to liver inammation and scarring (brosis). Some people with NAFLD go on to develop cirrhosis. People with fatty liver might not know that they have the condition because it often doesn't cause any symptoms. Many people have undiagnosed NAFLD.
Ÿ 7 in 10 people with Type 2 diabetes have NAFLD Ÿ 8 in 10 people with obesity have NAFLD Ÿ 1 in 20 people with NAFLD develop progressive liver disease leading to cirrhosis Alcohol-related fatty liver disease: Drinking more than the recommended limits for alcohol can also lead to a build-up of fat in the liver leading to liver inammation, brosis and cirrhosis.
Ÿ Drinking more than14 units of alcohol a week increases the risk of liver disease and other alcohol-related complications such as cancer and dementia 2 Ÿ Over 90% of heavy alcohol drinkers (more than 50 units a week for males or more than 35 units a week for females) will develop fatty liver and 25% of heavy drinkers will develop cirrhosis.
People with obesity who also drink more than the recommended limit for alcohol have the highest risk of developing fatty liver disease and cirrhosis Why is it important to avoid developing fatty liver disease?
Ÿ One in 20 people with fatty liver will develop liver cirrhosis (severe scarring of the liver). People with cirrhosis are at risk of developing liver failure or liver cancer.
Ÿ Fatty liver disease increases the risk of developing diabetes, heart disease and stroke.

Can you reverse fatty liver disease?
Importantly, in many people fatty liver disease is reversible with lifestyle change, particularly with weight loss through healthy eating and increased physical activity: Ÿ Weight loss of more than 3% body weight can reduce liver fat.
Ÿ Weight loss of more than 5% body weight can reduce liver inammation.
Ÿ Weight loss of more than 10% body weight can reverse liver brosis.
Ÿ Exercise can reduce liver fat.
Reducing or stopping alcohol consumption can improve fatty liver disease, particularly in people who drink more than the recommended limits for alcohol. Alcohol also contains a lot of calories so reducing alcohol intake can help with weight loss as well.
BMJ Publishing Group Limited (BMJ) disclaims all liability and r Supplemental material placed on this supplemental material which has been supplied BMJ Open Gastro doi: 10.1136/bmjgast-2022-001092 :e001092.
Given that cirrhosis can cause life threatening complications, it is important that fatty liver disease is identied and treated at an early stage before cirrhosis develops.

Eating a healthy diet
A well-balanced and healthy diet is essential to avoid damage to your liver. The following advice can help: Ÿ Try to eat regular meals and avoid snacking in between.
Ÿ Control your calorie intake through eating smaller portions.
Ÿ Avoid foods that are high in sugar or saturated fat (avoid the red trafc light labelled food).
Ÿ Eat at least 5 portions of fruit and vegetables per day.
Ÿ Eat some beans, pulses, sh, eggs and lean meat or vegetarian protein.
Ÿ Avoid eating large amounts of carbohydratebased foods such as potatoes, bread, rice or pasta -carbohydrate should only be about a third of what you eat each day.
Ÿ Drink 6-8 glasses of water per day -try to avoid sugar-sweetened drinks.
For more detailed dietary advice then look at the 'Eat well -NHS' website ( ) or www.nhs.uk/live-well/eat-well/ ask your GP, practice nurse or dietitian for some information.
Please note -if you are diabetic it is important you discuss this with your diabetes support team and dietitian. Control of your diabetes and blood sugars is essential in helping reversal of fatty liver disease.

Work out your body mass index (BMI)
Your BMI is a measure of your weight relative to your height and gives an indication of whether you have a healthy weight. You can calculate your BMI by putting If you have a BMI in the overweight or obese category this increases the risk of developing fatty liver, diabetes and heart disease. In most cases weight loss would improve your health and reduce your risk of developing these weight-related conditions.

Some tips for successful weight loss
Ÿ Monitor and record your weight weekly to assess your progress.
Ÿ Set short-term realistic goals as well as having a longer-term goal.
Ÿ Monitor what you are eating.
Ÿ Plan your meals to avoid being tempted by unhealthy foods or drinks in the shops.
Ÿ Increase the amount of physical activity you do each day.

Physical activity, exercise and your liver
Being more physically active can help reduce liver fat and improve your fatty liver disease. The more physically active you are, the better.
Ÿ Exercise has been shown to decrease liver fat independent of weight loss Ÿ Increasing daily physical activity can help you to lose weight alongside changes in your diet Ÿ Importantly: physical activity and exercise can help you to maintain weight loss in the long term  There are lots of other health benets of increasing physical activity and exercise if you have fatty liver disease.
These include:

What type and how much physical activity/exercise do I need to do?
The NHS recommends doing two different types of activity -moderate aerobic exercise ('cardio'; walking, running, swimming or cycling) and strengthening exercises (lifting, pulling or pushing exercises). Both of these can help prevent or treat fatty liver disease.
Aim for at least 30 minutes of moderate intensity exercise a day on at least 5 days each week. This can be broken down into 10-minute bouts, if this is more manageable. If you can't do the recommended amount at the moment, don't worry. Make a start by doing what you can. As your body gets used to being more active, build up your activity levels by pushing yourself a bit harder or keeping going for longer. You should feel a bit out of breath and warm. Do strengthening exercises that work all your major muscle groups (legs, hips, back, abdomen, chest, shoulders and arms) on 2 days a week.

Improve mood
Reduce anxiety and depression Increase energy levels Improve sleep patterns Improve self-esteem Improve muscle strength and muscle bulk Increase bone density Improve flexibility Improve heart health Improve blood pressure It is important to set yourself an achievable goal and try to gradually build up to this -the more physical activity/exercise you can do, the better! For more detailed physical activity advice/ideas then visit the NHS 'How t today' website ( ) or www.howttoday.co.uk Sport England's 'We are undefeatable' website (https://weareundefeatable.co.uk/). You can also get information from you GP or practice nurse.

Safer drinking
Alcohol consumption can contribute to the development of fatty liver if you drink more than the recommended limits for alcohol. It is therefore important to stay within the current guidelines for health.

Useful Contacts
For further information, you can contact LIVErNORTH -details overleaf and on the back cover.