Non-alcoholic steatohepatitis (NASH) is a disease where fat, inflammation and scar-tissue builds-up in the liver. If NASH worsens it can lead to severe complications such as liver failure, liver cancer or death. People with NASH often have obesity and type 2 diabetes (T2D), and many also get heart disease.
The scar-tissue in the liver is the most important predictor of the severe complications in NASH. Scar-tissue can only be measured by removing a small piece of the liver with a needle, a so-called liver biopsy. A liver biopsy is risky and cannot be used in all people with NASH. Several blood-based tests have been studied as measures of scar-tissue. These tests can predict scar-tissue, but it is unclear if they can predict the severe complications in NASH.
We will study if simple blood-based scar-tissue tests can predict severe liver disease, heart disease and death in people with obesity and/or T2D. To do this, we will use data from more than 1.5 million people examined in primary care in the United Kingdom (Clinical Practice Research Datalink). Using these data, 6 simple scar-tissue tests will be calculated and linked to occurrence of severe liver diseases, heart diseases and deaths found via hospital and death records.
We hope this study can help us to understand if simple tests can be used to predict the risk of severe complications in NASH. If the tests can predict the complications, it may decrease the need for liver biopsies and facilitate better treatment of people with NASH.
Biopsy-confirmed fibrosis predicts severe clinical outcomes in non-alcoholic steatohepatitis (NASH). Biopsies are, however, not usable in routine clinical practice and NASH is often undiagnosed/untreated. Simple non-invasive scores derived from standard measures (liver enzymes, body weight, type 2 diabetes (T2D), age) are associated with liver fibrosis. If such scores are associated with clinical outcomes, they could be used in clinical practice and help to address the significant unmet medical for better management of NASH.
The aim is to explore:
1. The prognostic potential of 6 non-invasive scores* on time to first NASH-related clinical outcome event in a population with obesity and/or T2D.
2. The prognostic potential of changes in 6 non-invasive scores* on time to first NASH-related clinical outcome event in a population with obesity and/or T2D.
Using a longitudinal cohort design, adults (≥18years) with obesity and/or T2D, at least one non-invasive score measurement in the Clinical Practice Research Datalink (CPRD) after 01 January, 2001, no alcohol-related disorders and/or other chronic liver diseases in the Hospital Episodes Statistics (HES) and/or no prescriptions of drugs inducing liver disease in CPRD are included. NASH-related clinical outcomes are liver events, cardiovascular events and all-cause mortality.
Aims are analysed using Cox proportional hazards models with age as time scale:
1. Associations between non-invasive scores at baseline and time to first event (liver, cardiovascular or death)
2. Associations between 6, 12, 36-months changes in non-invasive scores and time to first event (liver, cardiovascular or death)
Individuals are followed from date of inclusion until time of first event recorded in HES or Office for National Statistics Death Registration, migration from the databases, 10-years of follow-up or 01 January 2020, whichever comes first. Sensitivity analyses addressing obesity/T2D, alcohol, age, event type and reverse causality are made.
*Fibrosis-4 Index. AST-platelet ratio Index. Forns Index. BARD-score. NAFLD fibrosis-score. AST/ALT-ratio
The three primary outcomes of the study are listed below. Events in each endpoint are defined as ICD10 or OPCS4 codes from Hospital Episodes Statistics (HES) Outpatient data, HES Admitted Patient Care Data or Office for National Statistics (ONS) Death Registration Data.
Time to liver event - using the first report of any of the below events captured in HES or ONS:
• Liver mortality (ONS)
• Hospital contact for hepatocellular carcinoma (HES)
• Hospital contact for liver transplant (HES)
• Hospital contact for chronic liver failure (HES)
• Hospital contact for liver cirrhosis (HES)
• Hospital contact for decompensated liver events:
- Portal hypertension (HES)
- Ascites (HES)
- Transjugular intrahepatic portal shunt (HES)
- Hepatorenal syndrome (HES)
- Hepatic encephalopathy (HES)
- Gastro-oesophageal varices with/without bleeding (HES)
Time to CV event - using the first report of any of the below events captured in HES or ONS:
• CV mortality (ONS)
• Stroke (HES)
• AMI (HES)
• Hospital contact for unstable angina (HES)
• Hospital contact for heart failure (HES)
• Coronary revascularisation (HES)
Time to all-cause mortality – using a record in ONS Death Registration Data:
• Death record by any cause
Please see Tables 4 to 6 in Appendix 1 for the specific ICD10 and OPCS4 codes requested from HES and ONS used to define the events in each of the three endpoints. The defined liver and CV events occurring prior to baseline (index date) will be excluded in the time to liver and time to CV event analysis, respectively.
Tina Landsvig Berentzen - Chief Investigator - Novo Nordisk A/S
Tina Landsvig Berentzen - Corresponding Applicant - Novo Nordisk A/S
Anders Boeck Jensen - Collaborator - Novo Nordisk A/S
Jens Tarp - Collaborator - Novo Nordisk A/S
Kamal Kant Mangla - Collaborator - Novo Nordisk A/S
Kamlesh Khunti - Collaborator - University of Leicester
Katrine Grau - Collaborator - Novo Nordisk A/S
Louise Maymann Nitze - Collaborator - Novo Nordisk A/S
Maximilian Jara - Collaborator - Novo Nordisk A/S
Mette Skalshøi Kjær - Collaborator - Novo Nordisk A/S
Quentin Anstee - Collaborator - Newcastle University
HES Admitted Patient Care;HES Outpatient;ONS Death Registration Data