SOLID: Determining the optimum biomarker strategies for the detection of advanced liver disease at the primary-secondary care interface

Undiagnosed advanced liver disease is common in the community due to high rates of harmful alcohol consumption and obesity, both of which can cause fatty liver disease. An estimated 1 in 4 individuals in the UK have non-alcoholic fatty liver disease (NAFLD) and rates of potentially harmful alcohol consumption are high in the community (15% females and 25% males in England). As a result, rates of cirrhosis (severe scarring of the liver) are increasing, which has led to rising liver-related deaths and increasing hospital admissions with liver failure. Liver disease is now in the top 3 leading causes of premature death (18-64 years) in the UK. Liver disease often goes unrecognised because it frequently has no symptoms until cirrhosis develops. GPs rely on liver blood tests to identify individuals with liver disease. However, only 50% of patients with advanced liver disease have raised liver blood tests, resulting in many being missed. Importantly, there is good evidence that up to 65% of individuals make significant lifestyle change when given a diagnosis of liver disease, which may help reduce their risk of developing more severe liver disease.

Most complications from liver disease occur in those with cirrhosis so identification and treatment before cirrhosis is important. Many individuals with liver disease have easily identifiable risk factors (alcohol and obesity) so could have a liver assessment to see if they have liver disease. There are some simple non-invasive blood tests for fibrosis available, such as the FIB-4 score that uses routine blood tests (age, liver enzymes and platelets), which can reliably exclude or identify advanced fibrosis in patients with fatty liver disease. We could therefore use this and other newer fibrosis tests to identify those with significant liver disease early and then treat them

We aim to establish a primary care pathway to identify patients with advanced liver disease in the community and use this to assess blood fibrosis biomarkers. Primary care offer 5 yearly health checks from 40 years and annual 'year of care' review looking at all a patient's chronic diseases in one appointment. These encounters offer an ideal place to conduct a liver assessment. In collaboration with partners from primary care and our local patient support group, LIVErNORTH, we aim to develop and integrate a 'liver assessment' in these annual reviews using a series of simple electronic care bundles. Care bundles serve as a checklist to help non-specialists manage medical conditions in a systematic way to ensure good care is provided. The pathway will use blood tests for fibrosis and an ultrasound-based test called transient elastography (TE), which measures the elasticity of the liver, to identify individuals with advanced liver disease. Elasticity of the liver is a very good indicator of the amount of scarring in the liver. Although TE is a good test for fibrosis, its disadvantage is that patients need to attend a hospital to have the tests done. Having a pathway that only uses blood tests to accurately diagnose advanced fibrosis would be simpler. The best pathway to identify advanced liver disease is not known. We aim to implement a pathway to identify patients with advanced liver disease using blood tests and TE and use it to test the performance of newer blood fibrosis biomarkers so we can design a new more efficient pathway. We plan to test simple, inexpensive fibrosis tests like FIB-4, and more complex blood fibrosis like enhanced liver fibrosis test (ELF) and Pro-C3, and will also store blood to look at future new tests. These fibrosis tests have been shown to be effective in liver biopsy studies of patients with NAFLD so we think they will perform well in this study. We will then aim to test the new pathway in a larger study multicentre study.

Aim: develop a primary care pathway as a biomarker evaluation platform to identify to individuals with advanced liver fibrosis

Patients: Patients with obesity, T2DM or harmful alcohol consumption attending annual reviews will be recruited. Searches in 2 GP practices indicate 2600 of 20,000 patients meet eligibility criteria.

Test biomarkers: FIB-4 is inexpensive with good negative predictive values and proven utility in 2-step fibrosis pathway with TE in NAFLD. ELF and PRO-C3 have good diagnostic accuracy alone or in combination with FIB-4 so we believe evaluating these biomarkers is warranted.

Transient elastography will be our standard to stage fibrosis because it is non-invasive and validated against liver biopsy. Although TE is imperfect, it is unethical to conduct liver biopsies in a case finding study. Liver stiffness (fibrosis) and controlled attenuation parameter (steatosis) will be measured using the M or XL probe. A valid scan will be defined as 10 valid elastography measurements with an IQR/median ratio <0.3. Only patients with valid TE readings will be used to assess biomarker performance. Our study has been powered to allow 5% failure and 10% non-attendance for TE rate.

Primary endpoint is correct diagnosis of advanced fibrosis (TE >10 kPa) using a 2-step pathway (FIB-4 and ELF or PRO-C3). In NAFLD, specificity for advanced fibrosis is 75% (71% sens) at 9.7 kPa and 90% at 14.1 kPa. >10 kPa has been chosen to maintain sensitivity. We recognise that there is a false positive rate for this cut-off so we will assess the final fibrosis stage after review in liver clinic with all test results including liver biopsy if performed. Given all 3 biomarkers have high sensitivity for advanced fibrosis, only patients with 1 or more elevated biomarker will have TE performed to rationalise resource.

Novel pathways will be developed using a per-protocol analysis and modelled to develop the most effective pathway on an 'intention to diagnose' basis.