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Time to focus chronic liver diseases back into the community: A review of primary care hepatology tools, pathways of care and reimbursement mechanisms

Open AccessPublished:October 22, 2022DOI:https://doi.org/10.1016/j.jhep.2022.10.010

      Abstract

      Addressing primary care’s low confidence in detecting and managing chronic liver disease (CLD) is becoming increasingly important due to escalating prevalence of its common lifestyle-related metabolic risk factors - obesity, physical inactivity, smoking and alcohol consumption. Whilst liver blood testing is frequently carried out for long term condition management, its interpretation is not typically focused on specific liver disease risk. Educational steps for primary care should outline how liver fibrosis is the flag of pathological concern, encourage use of pragmatic algorithms such as FIB-4 to differentiate between those requiring referral for further fibrosis risk assessment and those who can be managed in the community, and emphasise that isolated minor LFT abnormalities are unreliable in estimating risk of fibrosis progression. Measures to increase primary care’s interest and engagement should make use of existing frameworks for long term condition care, in order to embed liver disease consideration alongside other metabolic disorders, type 2 diabetes, cardiovascular disease, chronic kidney disease etc. Selling points when considering the required investment in developing local fibrosis assessment pathways include reduced reflex repeat testing of minor abnormalities and improved secondary care referrals, plus improvements in the patient’s journey through long term multimorbidity care. A focus on improving CLD is likely to have wide benefits across co-existing metabolic disorders, particularly when pathways are aligned with community lifestyle support services. The important message for primary care is to increase the value of existing monitoring rather than to generate more work.

      Keywords

      Authors contribution

      NG and RP have equally contributed to the drafting of the manuscript and editing of the final version.

      Conflicts of interest

      None of the authors have any conflict of interests.

      Financial support

      No funding was received for this specific work. NG has previously received investigator led research funding from Gilead Sciences for community liver disease. Gilead had no intellectual input into the drafting or editing of the manuscript. NG is supported by the Gastrointestinal and Liver Disorder theme of the NIHR Nottingham Biomedical Research Centre (Reference no: BRC-1215-20003).

      Introduction

      The development of chronic liver disease (CLD) as a distinct “specialism” based on tests (e.g. the liver biopsy) and expertise (e.g. liver transplantation) concentrated in hospital settings has advanced the care of patients over the last 50 years. A perhaps unintended consequence of this major success story is the perception that CLD is complex – beyond the capabilities or remit of primary care
      • Standing H.C.
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      • Exley C.
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      GPs' experiences and perceptions of early detection of liver disease: a qualitative study in primary care.
      . Of more concern, rating of prestige of hepatobiliary disease comes way down the list in disease hierarchy tables that demonstrate how doctors consider some diseases to be more worthy than others
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      • Album D.
      Legitimating the illegitimate: How doctors manage their knowledge of the prestige of diseases.
      . Compared to other metabolic diseases, the authors could find no published examples of primary care incentive mechanisms or nationally embedded management pathways for NAFLD in the UK or elsewhere. Indeed, liver disease could be seen as a Cinderella subject for primary care, such that few GPs - our ultimate intended audience - are likely to read this article. Thus the authors intentions are to highlight points where collaboration, guidance and training led by hepatologists can build stronger bridges across to primary care in future. With today’s changing mortality and morbidity away from infectious diseases towards long term conditions (LTCs) with shared lifestyle-related risk factors, current health priorities reflect increasing rates of multimorbidity and a need for integrated holistic care. The question for CLD is therefore how to evolve multidisciplinary team approaches that include primary care with this changing context: A critical component of this changing approach is to understand the challenges, barriers and facilitators that face primary care colleagues within a community setting. This paper will set out to explore these issues; setting out where solutions may lie, where uncertainties exists and where further work is needed.
      To achieve increased engagement of primary care in CLD the following essential factors should be addressed:
      • Consensus: A conceptual framework for a pathway which references points where initial indexes of suspicion arise, such as in response to LFT abnormalities; following incidental fatty liver finding on Ultrasound scan (USS), or case finding for high risk factors. The framework should also include the vision integrating community and specialist care of CLD.
      • Feasibility: The recommended tests or treatments should be locally available;
      • Funding: Relevant components of the care pathway are appropriately funded (such as Vibration controlled transient elastography (VCTE) capacity).
      • Training: Health professionals (HPs) involved in delivery of care can access appropriate training. Hepatologist and GP leadership is required to broadcast education on LD and lead local implementation.
      • Capacity: Adequate capacity of lifestyle services is available for signposting affected patients to.

      The need for simplifying and highlighting the important concepts of CLD for the primary care audience

      Tabled 1
      Does this liver abnormality indicate significant disease?
      What additional testing should I do in primary care?
      Should I be case finding individuals with high risk of liver disease?
      Should I refer?
      What should I tell my patient?
      In this article, we are focussed on common parenchymal liver disease driven by alcohol and metabolic risk factors over a prolonged period of time resulting in CLD. Fundamental to managing CLD is staging the severity of disease correctly to differentiate benign findings that can be managed with lifestyle prevention approaches within primary care from those that require hepatology referral. The key issue is to identify those with progressive disease with the highest risk of complications. Liver fibrosis represents the pathological entity synonymous with progression in the vast majority of cases but this is not widely understood outside of the hepatology community. Of course, there are certain rarer entities that will result in clinical outcomes and not progress through fibrosis. These conditions need specific consideration, with bespoke diagnostic approaches, which is beyond the remit of this review.
      Across different aetiologies, the development of hard clinical outcomes is independently associated with the presence of liver fibrosis at baseline
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      Enhanced liver fibrosis test can predict clinical outcomes in patients with chronic liver disease.
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      Serum fibrosis markers are associated with liver disease progression in non-responder patients with chronic hepatitis C.
      The progression to advanced fibrosis/compensated cirrhosis represents a landmark for two critical reasons. Firstly, this represents an increased risk of developing a liver related complication.
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      Decreased survival of subjects with elevated liver function tests during a 28-year follow-up.
      ,
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      • Diehl A.
      • Dasarathy S.
      • et al.
      Prospective Study of Outcomes in Adults with Nonalcoholic Fatty Liver Disease.
      . Secondly, it results in a specific change in evidence-based management strategies, including surveillance strategies for portal hypertension and liver cancer. These concepts are self evident for hepatology but they may need highlighting for primary care colleagues. The stratification of liver disease based on fibrosis also provides guidance on time frames for addressing lifestyle change. Early stage fibrosis does not mean that risk factors can be ignored without any consequence but as progression will occur over many years it provides primary care with realistic projections. Focusing on liver fibrosis will also help simplify the messages we provide to primary care doctors who are firstly overwhelmed with incidental findings of “fatty liver” on ultrasound, much of which represents benign steatosis but creates anxiety and additional workload for family doctors, and secondly who, without education, tend to over-rely on isolated LFTs to estimate seriousness of liver disease. There continues to be a search for accurate diagnostic tests for steatohepatitis, to identify those that will rapidly progress but these are currently not robust enough for implementation within the community. This represents an area of research uncertainty and is aligned to finding pharmacological treatments that have meaningful clinical efficacy.
      The first challenge for primary care is understanding testing regimes and the need to identify liver fibrosis. Liver function tests are commonly requested in primary care. A population study in Tayside, Scotland suggested that 25 % of the local population had liver enzyme tests measured over a 10 year period and 20 % of these tests will be abnormal at some point
      • Donnan P.T.
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      • Sullivan F.
      • et al.
      Development of a decision support tool for primary care management of patients with abnormal liver function tests without clinically apparent liver disease: a record-linkage population cohort study and decision analysis (ALFIE).
      . LFTs are tested frequently as part of long term conditions (LTC) and drug monitoring or for acute investigation of the ill patient; the Ballets study highlighted these reasons approximately accounted for 60 % of the origin of requests
      • Armstrong M.J.
      • Houlihan D.D.
      • Bentham L.
      • Shaw J.C.
      • Cramb R.
      • Olliff S.
      • et al.
      Presence and severity of non-alcoholic fatty liver disease in a large prospective primary care cohort.
      . The same study highlighted that investigation of abnormal liver tests found parenchymal disease, which was not either alcohol or metabolic related fatty liver disease, in 3 % of patients. Moreover, we know from community studies across Europe that the majority of individuals (> 70 %) with an index diagnosis of advanced liver disease have normal liver enzyme tests
      • Chalmers J.
      • Wilkes E.
      • Harris R.
      • Kent L.
      • Kinra S.
      • Aithal G.P.
      • et al.
      The Development and Implementation of a Commissioned Pathway for the Identification and Stratification of Liver Disease in the Community.
      • El-Gohary M.
      • Moore M.
      • Roderick P.
      • Watkins E.
      • Dash J.
      • Reinson T.
      • et al.
      Local care and treatment of liver disease (LOCATE) - A cluster-randomized feasibility study to discover, assess and manage early liver disease in primary care.
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      • Pera G.
      • Arteaga I.
      • Rodriguez L.
      • Aluma A.
      • Morillas R.M.
      • et al.
      High Prevalence of Liver Fibrosis Among European Adults With Unknown Liver Disease: A Population-Based Study.
      Thus, the message that liver enzyme tests are an inadequate surrogate of progressive disease needs to be crystal clear. In parallel the burden and relevance of minor abnormalities of LFTS has to be acknowledged. A clear framework of how to investigate these abnormalities, using pathways that integrate primary and secondary care must be rolled out. An important message is also that simply repeating LFTS, in the absence of an acute precipitant, is not a logical approach. The Ballets study highlighted that approx. 80 % of repeat tests remain abnormal
      • Armstrong M.J.
      • Houlihan D.D.
      • Bentham L.
      • Shaw J.C.
      • Cramb R.
      • Olliff S.
      • et al.
      Presence and severity of non-alcoholic fatty liver disease in a large prospective primary care cohort.
      and this is related to the underlying risk factors not changing. Reflex repetition of LFTS results in opportunity costs in both time and money.
      Developing models that focus on risk factors that drive CLD is attractive on a number of levels. From the primary care perspective, there has been a shift towards LTCs with shared lifestyle risk factors
      • Bezerra de Souza D.L.
      • Oliveras-Fabregas A.
      • Espelt A.
      • Bosque-Prous M.
      • de Camargo Cancela M.
      • Teixidó-Compañó E.
      • et al.
      Multimorbidity and its associated factors among adults aged 50 and over: A cross-sectional study in 17 European countries.
      , today’s health priorities reflect increasing rates of multimorbidity and a need for integrated holistic care. Embedding liver disease within the focus of multimorbidity is imperative if hepatology wants to cease to be seen as a “minority” sport in primary care. Whilst the association of diabetes and obesity and CLD are clearly recognised within hepatology; this is not necessarily the case in the community and CLD is not given the same prominence as cardiovascular or renal complications within the “metabolic” phenotype. In highlighting alignment with multimorbidity, there will be multiple benefits to CLD. Firstly, it will enable liver disease specific diagnostics and interventions to be integrated with evolving models of community LTC care. Secondly, stratifying for CLD may not only highlight those at greatest risk for liver related complications but also cardiovascular complications as highlighted by certain studies in NAFLD
      • Tada T.
      • Kumada T.
      • Toyoda H.
      • Mizuno K.
      • Sone Y.
      • Akita T.
      • et al.
      Progression of liver fibrosis is associated with non-liver-related mortality in patients with nonalcoholic fatty liver disease.
      ,
      • Golabi P.
      • Paik J.M.
      • Herring M.
      • Younossi E.
      • Kabbara K.
      • Younossi Z.M.
      Prevalence of High and Moderate Risk Nonalcoholic Fatty Liver Disease Among Adults in the United States, 1999-2016.
      . This in turn will promote broader understanding of how intensified treatments across the metabolic disease spectrum can generate wider health gains across multimorbidity clusters. The patient with multimorbidity’s journey through metabolic long term conditions should not be forgotten, with the need to understand which health concerns influence motivational engagement or disengagement. [“Would I feel more motivated if I improve my diet in order to help my diabetes or to help my liver disease?”]. Bringing CLD within the multimorbidity care architecture generates significant organisational challenges, considering how historical systems-based health care continues to create fixed silos of disease specialties.
      In parallel, we need to help primary care clarify and even “reduce” tests which may be mildly abnormal but in themselves provide little indication of severe liver disease. As mentioned, the request of many liver enzyme panel tests are part of other chronic disease management and medication monitoring. Methotrexate is an example of where different guidelines have been created by Dermatology and Rheumatology; historically there has been little input from hepatology. Liver enzyme tests are commonly used in statin monitoring but are often elevated as a result the underlying metabolic risk factors and not impending drug related liver injury. The benefit of statins outweigh the risks and a clear message needs to be made about initiating and/or continuing statins unless there is a doubling of liver enzyme tests over 3 months . The opportunity cost for primary care in investigating this “high volume to low yield” abnormalities is high but presents a leverage for hepatology. Of course, research uncertainties around how to rationalise drug monitoring for chronic disease management need to be addressed, - but such explorations may also open up collaborative multispecialty working opportunities.
      Whilst pragmatic answers to our five primary care questions can readily be provided, (box) and which is summarised as in a ‘Consider – Act- Manage’ Conceptual Framework (figure 1), educational approaches should also expand on the limitations of fibrosis algorithms plus understanding of the commonly benign nature of incidental fatty liver findings on ultrasound to avoid risks of over investigation and iatrogenic concern about abnormalities of little clinical relevance.

      Diagnostic tools and pathways for CLD in a community setting

      A recent systematic review by Abeysekera and colleagues
      • Abeysekera K.W.M.
      • Macpherson I.
      • Glyn-Owen K.
      • McPherson S.
      • Parker R.
      • Harris R.
      • et al.
      Community pathways for the early detection and risk stratification of chronic liver disease: a narrative systematic review.
      highlighted 12 studies in different international settings of community pathways for the early detection and stratification of CLD (Table 1). The findings are summarised in table 2below. There are currently three broadly described approaches; using abnormal liver enzyme tests, risk factors or a hybrid approach as the entry point into the pathway. The two-tier approach uses a “simple” test which can be calculated using tests collected routinely in primary care followed by a second specialist fibrosis test. Of the latter, VCTE and ELF were almost exclusively used and this presumably reflects their extensive validation in secondary care. In centres which incorporated a 2 step pathway, there appeared to be an improvement the detection rate of fibrosis e.g. from 3.4 % in a setting in Calgary, Canada to 43 % in Gateshead, UK
      • Mansour D.
      • Grapes A.
      • Herscovitz M.
      • Cassidy P.
      • Vernazza J.
      • Broad A.
      • et al.
      Embedding assessment of liver fibrosis into routine diabetic review in primary care.
      ,
      • Shaheen A.A.
      • Riazi K.
      • Medellin A.
      • Bhayana D.
      • Kaplan G.G.
      • Jiang J.
      • et al.
      Risk stratification of patients with nonalcoholic fatty liver disease using a case identification pathway in primary care: a cross-sectional study.
      . Where reported, the attended rates were excellent, many of the pathways reporting >90 % attendance rates. Finally, where economic modelling was performed all the proposed pathways were most cost effective than the standard of care (Table 3) (Table 4).
      Table 1Primary care uncertainty pointers
      Does this liver abnormality indicate significant disease?Review clinical history, metabolic risk factors and LFT trend. Remember LFTs do not reliably inform of progressive liver disease
      What additional testing should I do in primary care?Consider fibrosis algorithm – pragmatic choice – FIB-4 as baseline assessment
      Should I be screening people at high risk of liver disease?Consider liver risk within wider holistic metabolic risk for each individual
      Should I refer?Use local guideline to access second line fibrosis testing
      What should I tell my patient?Lifestyle referral support. Discuss review testing interval
      Table 2summary of SR findings ( adapted from Abeysekera et al)
      Entry point into pathwayFibrosis assessment (first test)Fibrosis assessment ( second test)Fibrosis detection rateTE attendance rate (where stated)
      Abnormal LFTS

      Number of Studies
      • Sanyal A.J.
      • Van Natta M.L.
      • Clark J.
      • Neuschwander-Tetri B.A.
      • Diehl A.
      • Dasarathy S.
      • et al.
      Prospective Study of Outcomes in Adults with Nonalcoholic Fatty Liver Disease.
      FIB-4

      NFS

      AST/ALT
      ELF and VCTE9 %- 26.6 %53 % to 97.2 %
      Risk factors

      Number of studies
      • Parkes J.
      • Roderick P.
      • Harris S.
      • Day C.
      • Mutimer D.
      • Collier J.
      • et al.
      Enhanced liver fibrosis test can predict clinical outcomes in patients with chronic liver disease.
      FIB-4

      Liver traffic light

      NFS
      VCTE9.2 % - 43 %93 % to 97.8 %
      Abnormal LFTS and risk factors Number of studies
      • Parkes J.
      • Roderick P.
      • Harris S.
      • Day C.
      • Mutimer D.
      • Collier J.
      • et al.
      Enhanced liver fibrosis test can predict clinical outcomes in patients with chronic liver disease.
      USS

      ELF

      AST/ALT

      FLI
      VCTE3.4 % -22 %71 %
      Table 3Factors affecting ‘buy-in’ to a fibrosis algorithm assessment pathway in primary care
      Target audiencePotential benefits/selling pointsObstacles
      Primary carePotential to reduce workload by reducing unnecessary repeat testing of insignificant LFT abnormalities

      Guidance on repeat testing intervals could reduce frequency of LTC recall

      Increased understanding/ confidence in a previously ‘complex’ specialty – could reduce inappropriate hepatology referral rates

      Increased confidence that low-fibrotic risk patients can be safely managed in primary care with lifestyle support.

      Widened perceived benefits of holistic lifestyle conversations/interventions when considering CLD within the metabolic basket of LTCs
      Perception of
      • increased testing and investigation
      • Treating ‘numbers not people’
      • Need for widespread training on new pathway
      • Funding needed to develop educational resources
      Access to fibrosis algorithm – not currently embedded in GP computer systems or included in standard LFT panel

      Inappropriate use of algorithm outside of its validated research limitations

      Limitations of VCTE capacity leading to long waits if/when referrals increase

      Coding difficulties – SNOMED codes not currently adequate to log data such as level of liver fibrosis risk or FIB-4 score

      Coding inadequacies result in lack of auditable data, which in turn limits evaluation of economic benefits, impact on workload or patient outcomes
      HepatologistsReduction in inappropriate referrals of insignificant minor LFT abnormalities

      Reduction in late presentation of advanced disease
      Increased referral rates for fibrosis stratification

      Pressure on capacity to follow up people with cirrhosis
      Pathology labsRole in guiding appropriate assessment of abnormal LFTsCosts and coordination needed across biochemistry and haematology labs to process FIB-4 and other algorithms
      Commissioners and public health teamsPotential to improve population health from cross-disciplinary focus on CLD and its risk factors

      Potential for investment in lifestyle services for CLD to benefit other health domains such as DM and CVD
      Continued investment may be hard to justify if financial savings from investment in CLD care do not deliver benefits over short-term funding cycles. Because primary and secondary care budgets are held separately, primary care commissioners may be disinclined to invest in a service where the clinical outcomes appear to benefit secondary care rather than primary care
      PatientsTypically people prefer community care to hospital based care.

      Earlier dx. Potential to understand how common risk factors have led to clustering of co-morbidities that may all respond to the same lifestyle changes.

      Patient satisfaction and reduced anxiety from avoiding unnecessary referral to secondary care
      Lead-time bias risk: Concern from being made aware of a slowly evolving condition that may always run a benign course and that has few therapeutic interventions [other than lifestyle change]

      Capacity issues creating delays in accessing second-line fibrosis testing resulting in increased anxiety
      Lifestyle servicesAwareness (and public demand) may trigger increased investment in obesity management services/alcohol servicesCapacity to provide lifestyle support may be further stretched from new indications of CLD
      Pharmaceutical industryGreater focus on CLD may promote more investment in treatmentsUnclear opportunities to recoup investment costs if pharmacological treatments prove unfeasible
      Table 4Box of research uncertainties
      Examples of area of uncertaintiesSpecific questions
      DiagnosisWhat is the optimal diagnostic strategy to identify liver fibrosis in a community setting?

      What risk factors or co-morbidity clusters should trigger NAFLD case-finding?

      Should proactive case-finding of NAFLD be undertaken in high risk groups? (eg T2DM and or CVD)

      How do we embrace techniques such as machine learning to enhance diagnosis ?

      How should GPs code and risk assess the determined drinker who also has a high BMI?

      Does a NAFLD diagnosis alter patient engagement with lifestyle improvement?

      In light of increased understanding of genetic causes of obesity, how much overlap is there with genetically driven obesity risk and risk of NAFLD/T2DM/CVD?
      MonitoringHow often should the assessment of fibrosis be made ?

      Is it more cost effective to do this in the community vs hospital setting ?
      Behavioural changeDoes aligning liver fibrosis stratification with behaviour change have benefit above and beyond usual lifestyle modification

      How and who should deliver “complex” interventions for CLD in the community?
      MultimorbidityWhat clusters of long term conditions should liver disease be aligned with and how should “holistic” care be delivered and managed in a community setting ?
      Long term outcomesWhat are the benefits of early and effective community diagnosis and intervention in terms of:

      Clinical outcomes – liver related and broader e.g. cardiovasacular and metabolic

      Patient reported outcomes

      Economic outcomes: For any money injection, where would maximal value be achieved between lifestyle services or more fibrosis pathway capacity investment?
      Novel treatmentsHow could R and D of pharmacological interventions be encouraged within community settings ?
      The systematic review highlights the breadth of tools that have the potential for deployment in a community setting. The first tool for fibrosis assessment should adhere to certain principles. The components should have evidence of diagnostic accuracy with clearly defined thresholds and be available as part of routine care. The limitations of some of the routine tests are succinctly highlighted in a recent EASL-Lancet document
      • Karlsen T.H.
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      The EASL–Lancet Liver Commission: protecting the next generation of Europeans against liver disease complications and premature mortality.
      . Of these tools many society guidelines
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      • Godfrey E.M.
      • et al.
      Guidelines on the management of abnormal liver blood tests.
      EASL.EASL-ALEH Clinical Practice
      Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis.
      have opted for use of FIB-4. Originally developed in the context of HIV/HCV co-infection
      • Sterling R.K.
      • Lissen E.
      • Clumeck N.
      • Sola R.
      • Correa M.C.
      • Montaner J.
      • et al.
      Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection.
      it has been extensively validated in secondary care
      • Mózes F.E.
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      • Selvaraj E.A.
      • Jayaswal A.N.A.
      • Trauner M.
      • Boursier J.
      • et al.
      Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis.
      and now a broader remit across the risk factors of alcohol and metabolic liver disease within the community is emerging
      • Rasmussen D.N.
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      • Johansen S.
      • Kjærgaard M.
      • Lindvig K.P.
      • Israelsen M.
      • et al.
      Prognostic performance of 7 biomarkers compared to liver biopsy in early alcohol-related liver disease.
      . Importantly, there is emerging evidence that FIB-4 has prognostic utility for clinical outcomes including liver related complications
      • Hagström H.
      • Talbäck M.
      • Andreasson A.
      • Walldius G.
      • Hammar N.
      Ability of Noninvasive Scoring Systems to Identify Individuals in the Population at Risk for Severe Liver Disease.
      ,
      • Lee J.
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      • Boursier J.
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      • Bossuyt P.M.
      • et al.
      Prognostic accuracy of FIB-4, NAFLD fibrosis score and APRI for NAFLD-related events: A systematic review.
      . Nonetheless, FIB-4 is not without its caveats. It has a relatively low positive predictive value and only a small proportion of those with a high threshold test will have significant disease. Thus, a further second line fibrosis test is needed to compliment FIB-4. Whilst the negative predictive value of FIB-4 is excellent for excluding significant disease ( data extrapolated from secondary care studies) care needs to be taken in reassurance especially in those with normal liver enzyme tests; some studies suggesting up to 40-50 % of patients with significant disease could be potentially missed by applying FIB-4 to those with an ALT in the normal range
      • Chalmers J.
      • Wilkes E.
      • Harris R.
      • Kent L.
      • Kinra S.
      • Aithal G.P.
      • et al.
      The Development and Implementation of a Commissioned Pathway for the Identification and Stratification of Liver Disease in the Community.
      ,
      • Graupera I.
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      • Roulot D.
      • Wong G.L.
      • et al.
      Low Accuracy of FIB-4 and NAFLD Fibrosis Scores for Screening for Liver Fibrosis in the Population.
      . There are additional issues about using age specific cut offs for FIB-4. It is unclear about which specific risk factors should be targeted or if case finding should occur on a general population basis. LiverScreen, a large prospective study, across 8 European countries and enrolling over 30,000 patients is currently underway to address this. A study in Germany suggests a structured population screening programme, using simple blood tests such as AST/ALT, could be feasible. The detection of advanced fibrosis/cirrhosis in the screening program was slightly higher than in controls (3.83 % vs. 3.36 %)
      • Labenz C.
      • Arslanow A.
      • Nguyen-Tat M.
      • Nagel M.
      • Wörns M.-A.
      • Reichert M.C.
      • et al.
      Structured Early detection of Asymptomatic Liver Cirrhosis: Results of the population-based liver screening program SEAL.
      . The effectiveness may be improved by refining the initial “screening “population and diagnostic tools. Uncertainty remains about the optimal choice of tools for liver fibrosis detection and the use of “hypothesis generating” strategies such as machine learning, using routinely collected data, are being explored presently
      • Bennett L.
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      • Morling J.R.
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      • et al.
      Health Technology Adoption in Liver Disease: Innovative Use of Data Science Solutions for Early Disease Detection.
      ,
      • Blanes-Vidal V.
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      • Nadimi E.S.
      • Krag A.
      Artificial intelligence outperforms standard blood-based scores in identifying liver fibrosis patients in primary care.
      This approach may also provide insights on how to ensure we do not miss rare causes of CLD.
      In figure 1, we have amalgamated the principal concepts of the leading society guidelines
      • Mansour D.
      • Grapes A.
      • Herscovitz M.
      • Cassidy P.
      • Vernazza J.
      • Broad A.
      • et al.
      Embedding assessment of liver fibrosis into routine diabetic review in primary care.
      ,17 and 20. Within this we would also suggest there is an important debate centred on where management occurs once initial risk stratification has occurred. We anticipate that depending on the country and local infrastructure this could occur in primary care, secondary care or hybrid systems that interface between primary/secondary care e.g. community liver hub centres serving populations of 50,000 to 100,000. Importantly, there should be a bi-directional travel of patients. As the risk factors for CLD are dynamic this means that risk stratification will need to be repeated after a certain time interval. Complex patients and those with high risk of reaching clinical outcomes would be monitored more carefully both in terms of tests, time interval and location. This model can be iterated with emerging diagnostics and treatments but critically will be proportionate to risk and not simply dependent on “referral bias”.
      A challenge remains about feasibility and implementation. This is highlighted by the experience of broadening the availability of second line fibrosis tests. The implementation of the 2016 NICE NAFLD guideline ( https://www.nice.org.uk/guidance/ng49) stalled in part because its recommendation “Consider using the enhanced liver fibrosis (ELF) test in people who have been diagnosed with NAFLD to test for advanced liver fibrosis” is not practically available in many health localities. This may have contributed to the finding of a recent nationwide UK survey recently suggested only 29 to 40 % of regions had a pathway in place to support community liver disease.
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      • Ryder S.
      Engagement with community liver disease management across the UK: a cross-sectional survey.
      Therefore, a key aspect is finding the balance between “optimal” diagnostic/prognostic performance of both first and second line fibrosis tests and their availability, cost, training needs and capacity of provision to understand the barriers for implementation. It is incumbent on hepatology to engage on these aspects in a unified approach with commissioners of health service, patients and primary care doctors.

      Selling the message: Factors to address for increased primary care engagement in liver disease

      Complex economic mechanisms, as well as the availability and quality of the evidence base, influence what primary care work is commissioned or is funded via insurance-based healthcare systems. Economic and clinical arguments for increasing investment in liver disease must compete with equally powerful arguments for investing in other diseases, which has been made increasingly challenging by the Covid-19 pandemic impact on health priorities. Initiatives to raise the profile of liver disease should not be promoted at the expense of other siloed clinical domains that failed in competitive funding allocation bids. Unfortunately, financially- and/or capacity- restricted health systems contribute to ‘disease hierarchies’ where some diseases out-compete for funding, publicity and research.
      Although liver disease is complex, improved engagement in liver disease management requires clear, practical instruction for non-specialists rather than high levels of expertise. GPs are ‘expert generalists’ carrying out huge amounts of filtering, risk assessments, case finding, signposting and management activities across all health domains, whilst some GPs also develop high levels of sub-specialist expertise in specific fields. Standards of care across many health domains have demonstrably improved when GPs have been given clear instruction, targets, funding/incentive mechanisms and/or relevant training. UK examples include the Quality and Outcomes Framework, where payments are attached to specific disease monitoring or management targets
      • Roland M.
      • Guthrie B.
      Quality and Outcomes Framework: what have we learnt?.
      and National Service Frameworks for mental health and for cardiovascular disease to benchmark standards of care
      • Swanton R.H.
      The National Service Framework: six years on.
      . National service frameworks were particularly effective when parallel health improvement systems were also adopted in secondary care, creating a cohesive unified sense of change
      • Schmidt H.
      • Gerber A.
      • Stock S.
      What can we learn from German health incentive schemes?.
      . Patient education campaigns in many countries have played important roles in driving forward standards of care, and now incentivisation examples of e-Health initiatives to improve digital health support are emerging across Europe. Evidence indicates that national smoking cessation policies were only strengthened and then mandated once public opinion – swayed by public information campaigns - demanded it.
      In addition, the patient’s journey through their healthcare needs should be considered, recognising that the majority of patients with CLD are likely to have co-morbidity clusters stemming from the same shared risk factors affecting diabetes, cardiovascular disease, renal disease and mental health problems, such as central obesity, excess alcohol consumption, inactivity and smoking
      • Akhavan Rezayat A.
      • Dadgar Moghadam M.
      • Ghasemi Nour M.
      • Shirazinia M.
      • Ghodsi H.
      • Rouhbakhsh Zahmatkesh M.R.
      • et al.
      Association between smoking and non-alcoholic fatty liver disease: A systematic review and meta-analysis.
      . This shared aetiology opens up fundamental opportunities and efficiencies when ‘pitching’ improvements to CLD care within an already over-burdened healthcare system. That LFT testing forms a fundamental component of most LTC monitoring - and that the same risk factor management conversations will apply regardless of the associated co-morbidity - open up economies within both testing and management approaches. Put simply: patients with CLD are already likely to be on the LTC radar undergoing regular liver blood monitoring. Much of the work is already being done – except that liver-relevant interpretation and onward referral commonly is not.
      From a patient perspective, a single appointment / blood testing regime that addresses all co-morbidities will feel more manageable than multiple parallel appointments for individual co-morbidities, particularly where the same lifestyle advice applies across them all. However, an organisational challenge when organising LTC reviews is that of nurse training, which impacts on nursing experience and pay: Not all primary care nurses are trained to give diabetes or asthma or COPD care, which involves both time and financial investment, but which will then influence a nurse’s pay scale. There may be difficulties in ensuring that the staff covering combined multimorbidity clinics are adequately trained to deal with all relevant co-morbidities. Equally, practices may not be able to afford the salaries of nurses who have accrued all the required training. Fortunately, proportionate training may provide a way of including CLD in LTC monitoring and there are already areas of synergy for example - lifestyle change. When added complexity is needed for behavioural change, psychological support and specific liver directed management this could occur in community liver hubs offering specific expertise across a population level but still delivered within a primary care context.

      Additional issues to explore in educational training on CLD in primary care

      Stigma is widespread, impacting on whether conversations about lifestyle are instigated and how support is conveyed. For example, misconceptions around reasons for raised gamma GT mean attribution to excess alcohol is the norm, adding to the perceived stigma of liver disease due to issues of self-blame, lack of trust and assumptions of denial in patients who deny drinking. The issue of stigma extends more broadly, for example, with regards to nomenclature of liver disorders and the questionable differentiation between alcohol-related and non-alcohol related liver disease.
      Stigma applies also to risk factors, particularly obesity which triggers often strongly held perceptions of personal responsibility despite the emerging strong evidence of both genetic and sociological basis of obesity
      • Flint S.W.
      Time to end weight stigma in healthcare.
      . Stigma arises within commissioners (lack of investment in alcohol / substance misuse services), HPs and patients themselves, who report feeling unworthy, guilt from self-blame, reluctance to seek help, and that the co-presence of mental health problems can make motivation difficult.
      Evaluation too is needed of the impact on patients of whether understanding the status of their liver health alters their engagement with lifestyle changes or uptake of support services. Currently perceptions persist among primary care staff that significant diagnoses such as diabetes or heart disease have little impact on adoption of lifestyle changes.
      • Aveyard P.
      • Lewis A.
      • Tearne S.
      • Hood K.
      • Christian-Brown A.
      • Adab P.
      • et al.
      Screening and brief intervention for obesity in primary care: a parallel, two-arm, randomised trial.
      This in turn impacts on how lifestyle advice is delivered. Using a ‘good news’ voice is a surprisingly effective modification to intervention delivery but requires belief of impact on the part of the intervention deliverer.
      The issue of coding is fundamental to achieving health improvements in any field. Unless data can be collected then intervention impact, costs, equality issues and degree of roll-out will remain hidden and lose its potential to influence future investment or research. Training should explain the benefits of audit as well as cover which diagnostic codes to use. However FIB-4 calculation is yet to be embedded in GP IT systems in the UK which inherently limits the ability to collect data or audit the impact of pathway adoption in any locality. Furthermore confusion persists as to whether accurately defining ALD or NAFLD in primary care is clinically relevant:- many people sometimes drink more than 14 units per week but on an irregular basis whilst also carrying excess weight – what code applies? The priority from a primary care perspective is to think beyond individual clinical specialties and to understand the interrelationships of each individual’s cluster of metabolic risks. This includes teaching the importance of evaluating liver fibrosis risk regardless of the cause of liver fat deposition, and for HPs to give tailored lifestyle support according to how the patient prioritises their health concerns relating to all their co-morbidities (https://cks.nice.org.uk/topics/multimorbidity/ )

      ‘Change-mongers’: How can a new standard of care be introduced?

      Even positive, beneficial change requires effort. Discovering how change can be driven requires understanding of the gains as well as barriers to adoption, and from an array of different perspectives in a multi-disciplinary health system. The following box explores benefits from and obstacles to adopting a fibrosis algorithm pathway in primary care from various clinical and patient viewpoints:

      Fibrosis pathway implementation learning points

      Lazarus et al illustrated
      • Lazarus J.V.
      • Palayew A.
      • Carrieri P.
      • Ekstedt M.
      • Marchesini G.
      • Novak K.
      • et al.
      European ‘NAFLD Preparedness Index’ — Is Europe ready to meet the challenge of fatty liver disease?.
      substantial international variation in readiness to develop national NAFLD pathways. They used four key criteria to create a NAFLD Preparedness Index: Policies/public health strategies; guidelines; epidemiological data collection; integrated NAFLD/multidisciplinary/ lifestyle care pathways. No country demonstrated high level preparedness.
      A UK example, the Scarred liver project, illustrates some important learning points: a major factor for success was co-creating a referral pathway between primary and secondary care. This has helped to overcome an initial barrier of the need to simply show short term cost savings, which is a challenge for a programme seeking long term health benefit. The persuasion and acceptance of commissioners to take a long term perspective was key. In parallel, hepatology made pragmatic choices based on focusing on what represented value on a “population health” basis and not simply choosing the lowest threshold that avoids missing any disease. GP engagement was driven not by any financial incentive but by the pathway forming an essential component if a hepatology opinion was being considered. As the pathway has become embedded within the community, capacity issues (based on availability of trained staff and capital equipment) have become apparent. The final aspect of the Scarred Liver project is that at the outset it was designed to be iterative and to dynamically incorporate emerging diagnostic strategies, behavioural change intervention and architectural change within the healthcare system. For example, the current iteration includes the introduction of social prescribers and health coaches working in the same clinic alongside the community VCTE service.
      Tabled 1
      Key points for establishing a liver fibrosis pathway:
      • Establish a multidisciplinary working group including key drivers of change
      • Agree fibrosis algorithm and pathway between primary and secondary care
      • Establish testing facility and capacity – eg lab provision of ELF, FIB-4 calculation etc and incorporate into request systems for liver blood test panel
      • Coordinate with local lifestyle services and local weight management pathways to ensure NAFLD is included within referral criteria for lifestyle services and Tier 3 weight management services
      • Broadcast new pathway to primary care through educational mechanisms, such as teaching sessions and by addendums to hepatology clinic correspondence

      Measuring the value of improving CLD care

      Evidence from introduction of fibrosis pathways suggests referral rates for VCTE will escalate rapidly, but impact on clinically meaningful outcomes (such as mortality from LD) will not be seen over the relatively short timescale of typical commissioning cycles, making arguments to commit scant funding to invest in scanning capacity in cash-strapped health systems a challenge. Comparing the increased costs of expanding community fibro-scanning capacity with potential reduced costs of reduced referrals to hepatology is further complicated by community care budgets being held separately from hospital service budgets. Financial gains for one department may be irrelevant to budgets held separately elsewhere in a disjointed health system. It is hoped that by positioning CLD within wider metabolic long term condition and multimorbidity management, wide benefits across the metabolic spectrum will be achieved through the efficiencies of more targeted testing, potential reductions in unnecessary investigation and referrals, plus greater confidence that lifestyle change can generate meaningful clinical health benefits.

      Summary

      The care of patients with chronic liver disease could usefully and efficiently be incorporated into wider long term condition care through adoption of local fibrosis pathways plus educational approaches to promote the structured ‘Consider- Act – Manage’ conceptual framework outlined in this article. Without aligning itself alongside the more common metabolic disorders that form the bulk of primary care workload, then CLD will continue to be side-lined by primary care due to persisting misconceptions that liver disease is too hard/rare/irrelevant/ or too much work.
      Aligning CLD with multimorbidity provides an opportunity for hepatology to integrate care across specialities, breaking down silos of care, leveraging finances and improving the overall care of patients.
      The messages for primary care are clear: better - not more - work.

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