Understanding NAFLD Referral Pathways in the UK and Ireland Phase 1 Report Findings Hannah Pheasant 9th June 2019

1.  Background and introduction 2.  What is the current need and demand? 3.  What are the current guidelines? 4.  What is currently happening?

–  Current service provision –  Examples of good practice

5.  How does current supply compare to guidelines 6.  Summary/discussion

–  What’s working well –  What’s not working so well

7.  Next steps and phase 2

Contents

Introduction

•  Aim: To support the Gilead UK and Ireland NASH team to understand the current state of play of NAFLD referral pathways in the UK and Ireland

•  Phase 1 objectives: –  To estimate need, demand and supply for NAFLD

services across the UK and Ireland (based on best available data)

–  To rapidly review the published guidelines and evidence-base on NAFLD care pathways

–  To map, compare and contrast current NAFLD care pathways in the UK and Ireland

Definition and spectrum of disease

Primary NAFLD is: •  an excess of fat in the liver (hepatic

steatosis) •  that is not a result of excessive

alcohol consumption •  or other secondary causes

Secondary causes include side effects of certain medications, hepatitis C virus (HCV) infection and particular endocrine conditions (NICE, 2016)

Estimate of need and demand for NAFLD services across the UK and Ireland

The current prevalence of NAFLD and NASH in general population

•  Estimated prevalence of NAFLD and NASH in adults is approximately 20-30% and 3-5% respectively

Source: NICE, 2016; Younossi, 2016; Alexander, 2018; Adelphi Values, 2018

Nearly 14 million adults have NAFLD and nearly 2.23 million adults have NASH in the UK and Ireland

Source: Office for National Statistics, Population Estimates for UK, England and Wales, Scotland and NI: Mid-2018; Republic of Ireland Central Statistics Office

Only approximately 83,500 people diagnosed with NAFLD

Prevalence of NAFLD in high risk groups •  NAFLD is more common in people with central obesity,

insulin resistance or T2DM, hypertension and dyslipidaemia (NICE, 2016)

•  More than 50% of patients with T2DM (53%)/MetS (54%) will have NAFLD (NICE, 2016a)

•  More than 45% of patients with high BMI (46%) will have NAFLD (NICE, 2016) and up to 90% among patients with morbid obesity who are undergoing bariatric surgery will have NAFLD (Tanajewski, 2017; Alexander, 2018)

•  Those who are obese or have T2DM are associated with at increased risk of progressive NAFLD (NASH and fibrosis) and adverse liver related outcomes

Prevalence of childhood obesity in England

Source: NCMP, 2017/18

Prevalence studies have shown that up to 38% of obese children have evidence of NAFLD (NICE, 2016)

Percentage of patients receiving a liver transplant due to NASH is progressively increasing in Europe

Source: The European Liver Transplant Registry (Belli, 2018)

Review of the published guidelines and evidence-base on NAFLD care pathways

Current guidelines on NAFLD

NICE obesity (2014), weight management (2014), preventing excess weight gain (2015), T2DM in adults (2015), cirrhosis (2016)

Comparative analysis of NICE, EASL and AASLD: Assessment and Diagnosis

Similarities Differences Characteristic points for defining and initially diagnosing NAFLD

Screening strategies in high-risk populations (eg T2DM, MetS and obesity) recommended by EASL but not NICE or AASLD

Systematic screening is not recommended

Initial evaluation for NAFLD patients incidentally identified through abnormal LFTs or USS (EASL and AASLD)

LFTs not a sensitive screening or diagnostic tool

Use of non-invasive tests for diagnosis in suspected NAFLD patients: USS for 1st line examination to identify liver steatosis (EASL and AASLD); NICE high priority research question

Need for further research on preferred non-invasive tests for accurately identifying NASH in people with NAFLD

Use of prognostic scores for predicting presence of steatohepatitis (EASL)

Liver biopsy is the ‘gold standard’ for diagnosing NAFLD, NASH and staging liver fibrosis

Preferred non-invasive tools for assessment of advanced fibrosis (ELF versus NFS and FIB-4) and imaging tools (eg TE)

When to use a liver biopsy to confirm a diagnosis

Comparative analysis of NICE, EASL and AASLD: Management and Treatment

Similarities Differences 1st line treatment of NAFLD patients should involve weight loss including maintenance

FU of NAFLD patients ranges from 2-3 years for low risk and 6 months to 2 years for high risk (≥F3/F4) (EASL and NICE)

Similar dietary deficit amounts (500-1000kcal/day)

Management of metabolic disorders and links to associated services (EASL only)

No drugs have currently been approved for treatment of NASH

Target weight loss ranges from 3-10%

Statin use is safe for NAFLD patients being treated for dyslipidaemia to reduce cardiovascular risk

Different dietary macronutrient composition and exclusion of NAFLD promoting foods

Bariatric surgery for NAFLD patients who are obese and meet eligibility criteria although criteria differs by guideline

Type, duration and intensity of physical activity differs

Use of liver transplants for NAFLD patients (EASL and AASLD) although not discussed in NICE

Who to treat with pharmacotherapy (eg NASH with/without fibrosis and stage of fibrosis or high risk of disease progression)

Use of off label pharmacological treatment

FU and monitoring the effectiveness of pharmacotherapy

NICE Algorithm: assessment and monitoring of NAFLD (2016)

EASL algorithm for non-invasive assessment of NAFLD (2016)

Sample of key publications…

Actively screen high risk patients

GPs should be incentivised to identify patients with liver disease through the QOF scheme

Targeted identification: incorporate a liver health check into existing routine practices

Improved collection of NAFLD data in both 1 and 2 care, and through death certification

Identify the 15-20% of NAFLD cases likely to progress to severe liver disease when screening for other obesity-related diseases

NHS England should introduce a series of CQUIN schemes relating to liver services that are commissioned at a specialized level

Current service service provision and comparative analysis of current NAFLD care pathways in the UK and Ireland

Patient pathway of current practice

Use of simple assessment tools for NAFLD Clinical assessment tool % completed

in 1 care % completed in 2 care

Body mass index 26% 82%

Waist circumference Not routinely performed in either 1 or 2 care

Alcohol history No data 79%

Overall liver aetiology screen •  Ferritin •  Hepatitis B and C serology •  Liver autoantibodies

32% 86% 88% 86% 91%

Liver ultrasound 37% 81%

Fatty Liver Index Score 89% not performed in either 1 or 2 care

Source: UK NAFLD survey data (Sheridan et al, 2017)

Non-invasive fibrosis risk stratification tool Non-­‐invasive  fibrosis  risk  stra0fica0on  tool % routinely used in 2 care AST/ALT ratio* 53% Fibroscan (Transient Elastrography) 50% NAFLD Fibrosis Score* (NFS) 41% FIB-4 Score* 16% AST to Platelet Ratio Index (APRI)* 6% Enhanced Liver Fibrosis (ELF) or other serum fibrosis markers

5%

Source: UK NAFLD survey data (Sheridan et al, 2017)

* requires AST measurement; AST is often not routinely recorded

Recommended by NICE, 2016

Summary of current service provision •  Pool of undiagnosed NAFLD patients in 1 and 2 care especially in high risk

groups •  Over-reliance on and over-use of abnormal LFTs; gateway to 2 care •  Inappropriate use of 2 care expertise to assess and diagnosis patients •  Unnecessary demand for 2 care leads to bottle neck: delays in assessment

for those who with highest need and over medicalisation for those with low need

•  Inappropriate use of limited NHS resources •  Simple assessment tools not being routinely conducted in 1 care •  Various non-invasive diagnostic risk assessment tools for fibrosis used (but

only in 2 care) •  Unclear use of liver biopsy in 2 care •  Uncertain management of patients in 1 and 2 care (ie no universal

provision of weight loss and lifestyle advice) •  No or poor interconnection with associated services (eg weight

management/obesity, T2DM)

Examples of good practice

Sample of good practice examples

Comparative analysis of example pathways: identification, diagnosis, stratification

Comparative analysis of example pathways: identification, diagnosis, stratification (continued)

Comparative analysis of example pathways: management, evidence, funding

Comparative analysis of example pathways: management, evidence, funding (continued)

Similarities and differences across the example pathways

Similarities Differences Increased and faster identification and diagnosis

Type of pathway (eg CLD, NAFLD, Abnormal LFTs/ALT, target risk factors)

Earlier diagnosis of patients (provides opportunity for lifestyle changes)

Choice of non-invasive fibrosis risk stratification tool (eg FIB4, NFS, STL, ELF, TE, AST/ALT)

Identification of asymptomatic patients with advanced fibrosis/cirrhosis

Use of TE in primary care eg Nottingham and Southampton

Shift diagnosis and risk stratification to 1 care

1 or 2 tier risk stratification (eg C&I, Nottingham and Southampton 2 step)

Decreased referrals to 2 care and reserved for medium/high risk of advanced fibrosis

Use of technology and electronic databases (eg Dundee, ICE; Hull & East Yorkshire ERS & Choose and Book; Others, EMIS/SystmOne)

Piloting use of 2 care tools in 1 care setting (eg FIB4, NFS, ELF, Fibroscan)

Joint physical or virtual 1 and 2 care clinics (GP and Hepatologist) (eg Nottingham, Southampton, Hull & East Yorkshire)

Decreased costs in short term (and predict long term savings) eg Dundee, Nottingham, Hull, C&I, Southampton

Alignment with different guidelines (eg NICE x 4 or EASL x 4)

Gaps and duplications across the example pathways

Gaps Duplications Examples on effective management and follow up are lacking; pathways primarily focus on identification and diagnosis (except Nottingham, ? Newcastle)

Patients overlap across pathways eg can be both T2DM and excess alcohol consumption (ie NAFLD and ALD pathway)

On going uncertainty about the most validated fibrosis risk assessment tool (and optimal thresholds) for use in 1 care

Diagnostic tools duplicated in 1 and 2 care ?

Interaction and links to related pathways and services (eg obesity, T2DM)

Information on demand management across whole of pathway (bottle neck from increased diagnosis)

Information on cost effectiveness of example care pathways especially LT clinical outcomes

Sustainable sources of funding although main source is CCGs

Lack of generalisability (eg Nottingham)

Follow up and monitoring in 1 and 2 care

Comparative analysis of current supply and NAFLD pathway guidelines

Comparative of analysis of national guidance and current practice

Comparative of analysis of national guidance and current practice

Comparative of analysis of national guidance and current practice

Summary of what’s working well and what’s not working as well

Working well

Not working so well

Conclusion •  NAFLD is an important public health problem •  Extent of the disease burden is severely under-recognised; large numbers

of asymptomatic undiagnosed patients •  National NICE NAFLD guidelines exist but local implementation is absent,

ad hoc and limited to pockets of good practice •  Current practice inappropriately relies on abnormal LFTs as marker for

detecting NAFLD and referral on to 2 care •  Good practice examples all aim to shift diagnosis from 2 or 3 care to 1

care, and pilot use of diagnostic tools in 1 care. Building evidence of effectiveness

•  But, example care pathways have significant differences, gaps in service provision and struggle with LT commissioning and sustainability

•  Vital starting point but currently no standardised pathway that could be adopted by whole of UK and Ireland

•  No national performance management/incentivisation schemes •  Integration of NAFLD diagnosis and management with associated

comorbidities is lacking (national and local level) •  Significant gaps and uncertainties in the evidence base – await further

published research •  Inadequate and inequitable service provision across UK and Ireland •  Overall, clearer guidance needed for NAFLD patients across whole care

pathway

References

References •  Adephi Values. Structured literature review: The epidemiology and burden of disease of NASH. Internal Report for

Gilead, 2018. •  Alexander M, Loomis AK, Fairburn-Beech J, van der Lei J, Duarte-Salles Y, Prieto-Alhambra D, Ansell D, Pasqua A, Lapi

F, Rijnbeek3 P, Mosseveld M, Avillach P, Egger P, Kendrick S, Waterworth DM, Sattar N and Alazawi W. Real-world data reveal a diagnostic gap in non-alcoholic fatty liver disease. BMC Medicine 2018; 16:130

•  All-Party Parliamentary Hepatology Group (APPHG). APPHG Inquiry into improving outcomes in liver disease. March 2014.

•  Baker C. House of Commons Briefing Paper Obesity Statistics. 2018; No 3336. •  Belli L et al. Impact of DAAs on liver transplantation: Major effects on the evolution of indicators and results. An ELITA

study based on the ELTR register. Journal of Hepatology 2018 vol. 69; 810-817 •  Burke L, Williams B, Mann V, Wong LL, Corless L, Abouda G. The COMMANDS study: improving community-based

diagnosis and management of non-alcoholic fatty liver disease. Journal of Hepatology Poster Presentation 2017; 66: S333- S542

•  Burke L, Williams B, Abouda G, Corless L. The Community based management of NAFLD Study (COMMANDS): Improved diagnosis and referral using a novel integrated care pathway. Journal of Hepatology Poster Presentation 2018: 68: S365-S604

•  Carruthers JE, Bottle A, Laverty AA, Khan SA, Millett C, Vamos EP. Nationwide trends in non-alcoholic steatohepatitis (NASH) in patients with and without diabetes between 2004–05 and 2014–15 in England. Diabetes Res Clin Pract 2017; 132: 102–07.

•  Collins B. Adoption and spread of innovation in the NHS. The King’s Fund 2018. Available from URL: https://www.kingsfund.org.uk/publications/innovation-nhs

•  Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases (AASLD). Hepatology 2018; 67: 328-357

•  Dandamudi N. Non-alcoholic steatohepatitis (NASH) Epidemiology. Datamonitor Healthcare. 2018 •  Davies SC. Annual Report of the Chief Medical Officer, Surveillance Volume, 2012: On the State of the Public’s Health.

London: Department of Health (2014) •  Donnan PT, McLernon D, Dillon JF, 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). Health Technology Assessment 2009;13:1–134.

References •  Dyson JK, et al. Non-alcoholic fatty liver disease: a practical approach to treatment. Frontline Gastroenterology 2014;

5:277-286 •  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. PLoS ONE 2018; 13(12): e0208798

•  European Association for the Study of the Liver (EASL). European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016; 64: 1388-1402

•  Foundation for Liver Research. Financial case for action on liver disease: escalating costs of alcohol misuse, obesity and viral hepatitis. July, 2017. Available from URL: http://www.liver-research.org.uk/liverresearch-assets/financialcaseforactiononliverdiseasepaper2017.pdf

•  Fracanzani AL, Valenti L, Bugianesi E, et al. Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: a role for insulin resistance and diabetes. Hepatology 2008; 48: 792–98.

•  Harman DJ, Ryder SD, James MW, et al. Direct targeting of risk factors significantly increases the detection of liver cirrhosis in primary care: a cross- sectional diagnostic study utilising transient elastography. BMJ Open 2015; 5:e007516.

•  Harman DJ, Ryder SD, James MW, et al. Obesity and type 2 diabetes are important risk factors underlying previously undiagnosed cirrhosis in general practice: a cross-sectional study using transient elastography. Pharmacol Ther. 2017; 00:1–12. https://doi.org/ 10.1111/apt.14463

•  Harris R, Harman DJ, Card TR, Aithal GP, Guha IN. Prevalence of clinically significant liver disease within the general population, as defined by non-invasive markers of liver fibrosis: a systematic review. Lancet 2017; 2(4): 288-297

•  Rezael Hemami M, Boyd KA, Inglis SK, Dow E, Dillon JF. Cost-effectiveness of intelligent liver function test (iLFT) for investigation of patients with abnormal liver function tests. University of Glasgow Poster Presentation.

•  Leoni S, Tovoli F, Napoli L, Serio I, Ferri S, Bolondi L. Current guidelines for the management of non-alcoholic fatty liver disease: A systematic review with comparative analysis. World J Gastroenterology 2018; 24(30): 3361-3373

•  Liver Wellness and Diabetes Ireland. Media Release – Results of Irish Liver Screen Initiative. 2018. Available from URL: https://www.diabetes.ie/recent-irish-liver-screening-results/

•  Majumdar et al. Referral pathways for patients with non-alcoholic fatty liver disease based on non-invasive fibrosis tests: diagnostic accuracy and cost analysis of a two-tier approach. Journal of Hepatology 2017; 66: S51

•  Mariot T, Sbardella E, Moolla A, Hazlehurst JM, Tan GD, Ainsworth M, Cobbold JFL, Tomlinson JW. Prevalence and severity of non-alcoholic fatty liver disease are underestimated in clinical practice: impact of a dedicated screening approach at a large university teaching hospital. Diabetes Med 2018; 35(1):89-98

•  Miller MH, Fraser A, Leggett G, et al. Development and validation of diagnostic triage criteria for liver disease from a minimum data set enabling the ‘intelligent LFT’ pathway for the automated assessment of deranged liver enzymes. Frontline Gastroenterology 2018; 9:175–182

References •  National Institute for Health and Care Excellence (NICEa). Non- Alcoholic Fatty Liver Disease (NAFLD): Assessment and

Management (2016). Available from URL: http//www.niceorg.uk\guidance\ng49 •  National Institute for Health and Care Excellence (NICEb). Obesity: identification, assessment and management (2014).

Available from URL: https://www.nice.org.uk/guidance/cg189 •  National Institute for Health and Care Excellence (NICEb). Weight Management: lifestyle services for overweight or

obese adults (2014). Available from URL: https://www.nice.org.uk/guidance/ph53 •  National Institute for Health and Care Excellence (NICEd). Preventing excess weight gain (2015). Available from URL:

https://www.nice.org.uk/guidance/ng7 •  National Institute for Health and Care Excellence (NICEe). Type 2 Diabetes Mellitus in adults: management (2015).

Available from URL: https://www.nice.org.uk/guidance/ng28 •  National Institute for Health and Care Excellence (NICEf). Cirrhosis in over 16s: assessment and management (2016).

Available from URL: https://www.nice.org.uk/guidance/ng50 •  Newsome PN, Cramb R, Davison SM, et al. Guidelines on the management of abnormal liver blood tests. Gut 2018;

67:6–19 •  NHS Wales. National Clinical Priority E: Liver Disease. GMS Contract 2017-18. Available from URL:

http://www.wales.nhs.uk/sites3/docmetadata.cfm?orgid=480&id=307392 •  NHS Wales. Annual statement of progress. Liver Disease Delivery Plan May 2017. Available from URL:

https://gov.wales/topics/health/nhswales/plans/liver-disease/?lang=en •  Norris S. The hidden dangers of a fatty liver. Diabetes and Cardiology Review 2017. Available from URL:

https://liverwellness.ie/articles/ •  Public Health England. Public Health Outcomes Framework. Available from URL:

https://fingertips.phe.org.uk/profile/public-health-outcomes-framework •  Robinson E, Miller M, Brennan P, Dillon J, Dow E, Donnan P, Bartlett B, Mcintyre P, Neville R, Boyd K. Intelligent liver

function diagnostic pathway – Relevance of alanine transaminase normal values. Journal of Hepatology 2018; 68: S605-S842

•  Royal College of General Practitioners. Liver Disease Toolkit. Available from URL: https://www.rcgp.org.uk/clinical-and-research/resources/toolkits/liver-disease-toolkit.aspx

•  Sheridan DA, et al. Care standards for non-alcoholic fatty liver disease in the United Kingdom 2016: a cross-sectional survey. Frontline Gastroenterology 2017; 8:252–259

•  Sheron N, Moore M, Ansett S, Parsons C, Bateman A. Developing a ‘traffic light’ test with potential for rational early diagnosis of liver fibrosis and cirrhosis in the community. Br J Gen Pract 2012; 62: e616–24

•  Srivastava et al. Primary care sequential use of FIB-4 and the enhanced liver fibrosis test to stratify patients with non-alcoholic fatty liver disease increases cirrhosis detection and reduces referrals of patients with mild disease – 2 year study analysis. Journal of Hepatology 2017; 66: S68

•  Standing HC, Jarvis H, Orr J, Exley C, Hudson M, Kaner E, Hanratty B. GPs’ experiences and perceptions of early detection of liver disease: a qualitative study in primary care. Br J Gen Pract 2018; 68 (676): e743-e749

References •  Tanajewski L, Harris R, Harman DJ, et al. Economic evaluation of a community- based diagnostic pathway to

stratify adults for non- alcoholic fatty liver disease: a Markov model informed by a feasibility study. BMJ Open 2017;7: e015659

•  Terrault N, Pageaux GP. A changing landscape of liver transplantation: King HCV is dethroned, ALF and NAFLD take over! Journal of Hepatology 2018 vol. 69; 767–768

•  Tsochatzis EA, Newsome PN. Non-alcoholic fatty liver disease and interface between primary and secondary care. Lancet 2018; 3:509-17

•  The Health Foundation. Innovating for Improvement. Implementation of an Innovative e-consult Integrated Care Pathway to Improve Community- based Management of Non-Alcoholic Fatty Liver Disease in East Yorkshire. Hull and East Yorkshire Hospitals NHS Trust.

•  Williams R et al. Gathering momentum for the way ahead: fifth report of the Lancet Standing Commission on Liver Disease in the UK. Lancet 2018; 392:2398-412

•  Wilson JMG, Jungner G. Principles and practices of screening for disease. Geneva, Switzerland: World Health Organization; 1968. Report No.: Public Health Papers No. 34. Available from URL: http://whqlibdoc.who.int/php/WHO_PHP_34.pdf.

•  Wong YC, McPherson K, Marsh T, Gortmaker SL, Brown M. Health and economic burden of the project obesity trends in the USA and the UK. Lancet 2011; 378; 815-25

•  York Health Economics Consortium. Economic Impact Evaluation Case Study: Liver Disease Diagnostic Pathway 2018. Available at URL: https://nhsaccelerator.com/wp-content/uploads/2018/03/Scarred-Liver-Pathway-Economic-Case-Study.pdf

•  Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64:73–84.

Any questions?

Next steps and phase 2

Phase 2: Stakeholder mapping, engagement and consultation

•  Conduct semi-structured telephone interviews with key stakeholders (n=30) from across UK and Ireland –  Examples of key stakeholders (policy makers, providers,

commissioners, patient organisations): representatives from case studies, NHS England, PHE, CCGs, PH LAs, HWBs, RCGPs, clinicians across 1, 2 and 3 care, patient organisations

–  Examples of questions to include: clarify information, further information and views on existing pathways and services; type of pathway (CLD, NAFLD, abnormal LFTS), referral routes and interaction between 1,2 and 3 care; commissioning and funding routes; barriers to and opportunities for implementing a pathway; recommendations for improvements in service provision/referral pathways; staff training needs etc

•  Analyse qualitative data and identify key themes •  Review and revise phase 1 desktop report based on phase

2 findings