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23/101 Early detection of liver disease commissioning brief


Published: 27 July 2023

Version: 1.0 July 2023

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The aim of the Health Technology Assessment (HTA) Programme is to ensure that high quality research information on the clinical effectiveness, cost-effectiveness and broader impact of healthcare treatments and tests are produced in the most efficient way for those who plan, provide or receive care from NHS and social care services. The commissioned workstream invites applications in response to calls for research on specific questions which have been identified and prioritised for their importance to the NHS, patients and social care.

Research question

What is the most clinical and cost-effective method of selecting at risk people in primary care for referral to secondary care for management of chronic liver disease?

  • Intervention: Referral based on at risk phenotype (raised ALT; obesity; T2DM; alcohol excess) and then subjected to FIB-4, ELF and Fibroscan (transient elastography: TE) irrespective of ALT and referred if FIB-4 positive or FIB-4 indeterminate and either ELF or Fibroscan positive.
  • Patient group: Patients in primary care determined by the GP to be at risk of chronic liver disease due to their exposure to alcohol and/or overweight/obesity/type 2 diabetes.
    Applications are encouraged which include recruitment from geographic populations with high disease burden which have been historically underserved by research activity in this field.
  • Setting: Primary care.
  • Control: Standard care = opportunistic referral. GP’s judgement to refer to secondary care. All referred participants then have FIB-4 + ELF + Fibroscan. Non-referred patients remain in primary care. Subsequent analysis determines optimal combinations.
  • Study design: A randomised controlled trial with an internal pilot phase to test key trial processes such as recruitment and adherence. Clear stop/go criteria should be provided to inform progression from pilot to full trial. A schematic representation of potential study design as detailed in this PICO is available in the background document that provides further information to support applicants with this call. Please email to request this.
  • Important outcomes and outputs: Diagnosis of cirrhosis based on clinical consensus (a composite clinical outcome); proportion of referred patients with cirrhosis; proportion of patients referred judged not to have advanced liver fibrosis or cirrhosis; cost-effectiveness; user and participant acceptability.
    - Sub-group analysis of people in intervention arm with or without elevated ALT and different risk phenotypes.
    - Post hoc analysis of performance of FIB-4 and ELF v FIB-4 and Fibroscan v ELF and Fibroscan v all three.
    Other outcomes: Recommendations for potential future testing pathways for these patient groups.
    Existing Core Outcomes should be included amongst the list of outcomes unless a good rationale is provided to do otherwise. Applicants are encouraged to report recruitment and findings disaggregated by sex (and other demographic factors where relevant). 
  • Minimum duration of follow-up: Applicants to define and justify.
    Longer-term follow up: If appropriate, researchers should consider obtaining consent to allow potential future follow-up through efficient means (such as routine data) as part of a separately funded study.


Unlike most other major diseases which have seen a gradual reduction in mortality, deaths from liver disease have continued to rise considerably over the last 50 years. Liver disease is frequently silent, and ongoing liver injury might result in few overt symptoms and signs until end-stage liver disease has developed after which time it is often too late to intervene and noticeably impact upon morbidity and subsequent mortality.

The liver has remarkable powers of regeneration. While scar tissue may not disappear, if the underlying cause is removed liver function will often improve dramatically. If liver disease could be detected earlier there is the potential to intervene and limit subsequent disease development and before it manifests into chronic disease and its related sequelae.

Historically a blood test (the liver function test: LFT) has been used as a mechanism for referral of patients into secondary care for subsequent diagnosis of liver disease but this test can often be normal at various stages of disease while abnormal tests don’t necessarily correlate with disease. Alcohol, obesity and type 2 diabetes are significant risk factors for the development of liver disease and, with these morbidities increasing in a population that is also aging, this issue is only getting worse. Invasive biopsy of the liver is the gold standard method of liver disease diagnosis but is not without risk and it is impractical and would be unethical to offer this additional test very widely. It is therefore critical to find alternative means by which liver disease can be identified earlier in the disease’s progression in the hope that this can be slowed if not halted completely.

A number of alternative non-invasive tests (NITs) for liver disease are now being increasingly used in a variety of different populations and settings. There is now sufficient consensus within the liver community that the diagnostic performance of some combinations of these NITs are equivalent and adequate for stratification of patients in primary care.

Not only is there no need for further studies of diagnostic performance of these tests but also it would not be feasible to conduct a diagnostic performance evaluation of these tests in primary care using liver biopsy as reference test. It would not be methodologically sound to conduct a diagnostic performance study in which the NIT formed part of the composite clinical judgement (in place of liver histology) and waiting for clinical events would take too long. Utilising such a composite clinical consensus as the outcome for a comparison of referral pathways from primary care without having to wait for the long-term clinical events to occur would be possible and appropriate.

A randomised controlled trial to evaluate the effect and cost effectiveness of using NITs in primary care to improve detection of cirrhosis and reduce unnecessary referral of people without significant liver disease could change practice and provide an opportunity to intervene earlier in the course of the disease’s progression.

To support the ambitions of NIHR’s Best Research for Best Health: the next chapter, NIHR strongly encourages the inclusion of nurses, midwives and allied health professionals within well-developed research teams responding to this call, to increase the building of nurse, midwife and allied health professional-related research activity, capacity and capability across the professions. Depending on the level of experience, this could be through the role of lead applicant, as joint co-applicant (supported by detailed mentoring plans submitted with the application), or as a co-applicant member of the research team. Through this activity, NIHR aims to support nurses, midwives and allied health professionals to become future research leaders and release the potential to lead, use, deliver and participate in research as a part of their job.

Additional commissioning brief background information

A background document is available that provides further information to support applicants for this call. It is intended to summarise what prompted the call and the existing evidence base, including relevant work from the HTA and wider NIHR research portfolio. It was researched and written on the basis of information from a search of relevant sources and databases, and in consultation with a number of experts in the field. If you would like a copy please email

Making an application

If you wish to submit a Stage 1 application for this call, the online application form can be found on the funding opportunities page. To select this call, use the filters on the right of the screen or search using the call name and/or number.

Your application must be submitted online no later than 1pm on the 24 January 2024. Applications will be considered by the HTA Funding Committee at its meeting in March 2024.

Guidance notes and supporting information for HTA Programme applications are available.

Important: Shortlisted Stage 1 applicants will be given eight weeks to submit a Stage 2 application. The Stage 2 application will be considered at the Funding Committee in July 2024.

Applications received electronically after 1300 hours on the due date will not be considered.

For commissioned topics, the Programme strongly discourages the practice of the same co-applicant joining more than one competing team. There may be unusual circumstances where the same person could be included on more than on application eg a lead from a named charity or a unique national expert in a condition.

For such exceptions (i) each application needs to state the case as to why the same person is included (ii) the shared co-applicant should not divulge application details between teams and (iii) both teams should acknowledge in their application that they are aware that one of their co-applicants is part of a competing application and that study details have not been shared.

Should you have any queries please contact us by email at