Cost-comparison analysis of FIB-4, ELF and fibroscan in community pathways for non-alcoholic fatty liver disease

The health, societal and economic burden of chronic liver disease (CLD) is substantial and represents a public health priority [1, 2]. CLD is the 5th commonest cause of death in the United Kingdom, and the only one in the top five that is increasing [3]. With rising prevalence of risk factors for liver disease including obesity and alcohol, pressure on healthcare resources is likely to intensify. Better and earlier detection of CLD in primary care is key to improving health outcomes and associated costs [4].

Non alcoholic fatty liver disease (NAFLD) is the commonest cause of deranged liver function tests (LFTs) in primary care [5]. Only a minority (5%) of these cases progresses to clinically significant liver disease [6] whilst evidence highlights fibrosis severity as the key determinant of liver related morbidity and mortality [7, 8]. The identification of patients with significant liver disease is a primary care challenge, where accurate fibrosis assessment is limited by a reliance on LFTs, which are poor discriminators of liver fibrosis [9].

In the current ‘standard care’ (SC), primary care physicians (PCP) assess the severity of a patient’s liver disease and subsequent need for specialist referral based on history, examination, blood tests including LFTs and ultrasound.

Patients referred to secondary care deemed to have significant liver disease due to NAFLD may benefit from active management (including consideration for clinical trials of emerging therapies for NAFLD and fibrosis) [2, 10]. Patients with cirrhosis will be enrolled in pathways of care that improve outcomes through targeted screening and treatment for complications of cirrhosis including portal hypertension [11] and hepatocellular carcinoma (HCC) [12]. However, current primary care approaches result in the referral of many patients that do not have significant liver fibrosis, placing a burden on secondary care services, incurring unwarranted costs and generating unnecessary inconvenience and anxiety for patients [13]. Furthermore a significant number of patients with advanced liver fibrosis are missed and not referred to secondary care. These patients have been falsely reassured and will silently progress before presenting with end-stage liver disease or liver cancer.

The use of non-invasive liver fibrosis tests (NILT) [14] may improve PCP staging of disease [4, 15] and referral practice but there is a lack of health-economic evidence about the use of NILT in fatty liver disease to inform clinicians, commissioners and policy makers about the value of such strategies. In this study, we developed a probabilistic decision analytical model to investigate the clinical and cost impact of primary care risk stratification of patients with NAFLD.

A liver working group, comprising primary care physicians and secondary care liver specialists, commissioners, public health practitioners and patient representatives was formed in the London Boroughs of Camden and Islington to develop new pathways of care for patients with NAFLD. Part of the strategy was to establish current practice (standard care (SC)) (Fig. 1) and to establish pragmatic guidance on how to improve the identification of NAFLD cases with advanced liver disease for referral to secondary care. In the first instance, PCP favoured the selection of patients with deranged liver function tests (LFT) even though it was agreed that this would miss a minority of cases with liver fibrosis who have normal LFTs.

Our cost consequence analyses indicate that the use of NILT to stratify patients with NAFLD in primary care is clinically effective and cost saving. Utilizing fibroscan alone was most effective in detecting patients with advanced fibrosis, whilst employing FIB-4 and ELF delivered the greatest cost saving.

All of the scenarios using NILT in primary care permitted the earlier identification of advanced fibrosis/cirrhosis, creating opportunities to modify fibrosis progression [22, 51] and to start surveillance and treatment of varices and HCC. Modelling indicated that significant benefits could accrue from the detection of early stage curable HCC (stage 0/ A) and non-bleeding varices that can be treated with beta-blockers and band ligation that can avert emergency presentations with bleeding varices. A modest reduction in hospital admissions for other complications of CLD including jaundice, ascites and hepatic encephalopathy was demonstrated. The relatively limited impact of current care pathways on mortality, largely attributable to missed or late diagnosis of advanced fibrosis, highlights the need for new approaches to diagnosis and treatment to prevent NAFLD progression.

Of interest to commissioners, the implementation of NILT in primary care offers the potential to reduce the total number of referrals, and in particular the unnecessary referral of patients who have minimal fibrosis. Over a 1-year horizon, there was a reduction in total referrals of 70, 63, 56 and 29% in scenarios 2, 3, 4 and 5 respectively, with an 85, 78, 71 and 42% reduction in referrals of patients with non-advanced disease. Real-world data from a secondary care hepatology service found that 66% of referred patients had a baseline FIB-4 score < 1.30 indicating that these patients had a low risk of advanced fibrosis and could have avoided referral [13]. This group of patients represents an inefficient use of resources, adding pressure to overstretched outpatient specialist services and PCP healthcare budgets [52]. Introduction of the use of NILT in primary care would deliver immediate reductions in expenditure through avoidance of unnecessary referrals, unlike the cost-benefits associated with improved outcomes attributable to earlier diagnosis that accrue much later.

All scenarios were cost saving. The cost of detecting a case of advanced fibrosis using SC was £49,917.83 in scenario. This compared to £19,360.75 in scenario 2, £19,448.49 in scenario 3, £19,487.75 in scenario 4 and £20,451.35 in scenario 5. Healthcare budgets were reduced by 17, 15, 11 and 3% in scenarios 2, 3, 4 and 5 respectively, attributable to the reduction in costs associated with end stage liver disease and improved resource utilisation. The budget decrease in scenario 5 was modest as it was assumed all patients who failed fibroscan (5% of cohort) were referred to specialists.

In this analysis, we explored the impact of the use of FIB-4 and ELF to replicate a primary care pathway introduced in north London. This combination of tests was optimal for the stratification of patients in a hospital based population [53] and has subsequently been shown to be clinically effective [13] when applied in primary care where the proportion of cases of advanced fibrosis amongst cases of NAFLD is smaller.

There are limitations to the model. The model was populated with the best available published evidence. A lack of high quality data for some variables was remedied with expert opinion. The measures of performance for FIB-4, ELF and fibroscan were drawn from validations in hospital cohorts, but these estimates may be inappropriately high for primary care populations in which the prevalence of fibrosis is likely to be lower (spectrum bias) [54, 55]. The model assumes that use of ELF and fibroscan as second-tier tests has the same performance characteristics as a first-tier test. This may under-estimate the performance of the pathway. Additionally, the model was limited to FIB-4, ELF and fibroscan. Local PCP focus groups supported by consultants in Public Health, formed to aide Camden and Islington pathway development, outlined the practical need for simplicity, giving FIB-4 an advantage over the NAFLD-fibrosis score, which the PCP considered to be more challenging to obtain such as BMI, or associated with uncertainty about case definition such as diabetes. The model examines fibrosis, but not NASH, and so may underestimate disease progression. Other sources of error include analytical performance. We assumed a 5% failure rate for fibroscan but higher rates have been reported [47], whilst serum tests can be influenced by comorbidities. For the purposes of the model, liver biopsy was considered the reference test for liver fibrosis. Given the inherent inaccuracies associated with liver biopsy [56], this may have over-estimated the performance of liver biopsy. The cost estimate of liver biopsy incorporated procedural elements but not those associated with complications of the procedure. This approach may underestimate the true cost associated with liver biopsy. The clinical- and cost- efficiency of all scenarios are highly favourable, but may not reflect real-life outcomes. Not all patients with NAFLD consult their PCP, and pathway uptake by health professionals is variable. The base case is a 50-year-old man with abnormal transaminases, reflecting a screening strategy identified by the Camden and Islington steering committee as practical in real-life primary care practice. However this approach will miss cases of NAFLD with advanced fibrosis but normal LFTs. A screen-all strategy is likely to be clinically optimal, as patients with NAFLD and normal transaminases are at risk of significant fibrosis. The costing in the model is comprehensive, assuming full adherence to guidelines and protocols and thereby potentially overestimating the cost of care. We employed a probabilistic decision model as our main economic focus was on the payer perspective rather than a population health perspective, where alternative cost-effectiveness approaches using quality of life data and Markov simulations would be desirable. The lack of beta or triangular distributions and true probability sensitivity analysis limits the model. The model lacks cost/ QALY data and relies on descriptive measures including cost per case of advanced fibrosis detected. These outcome measures have no standard comparator limiting the current model. These shortcomings will be addressed in future work.

NAFLD should be considered as the hepatic manifestation of a multisystem disorder associated with widespread morbidity including cardiovascular disease, diabetes, hyperlipidaemia and cancer. While a fully comprehensive health economic model would need to take these morbidities into consideration we chose to focus on liver disease. Accommodating all NAFLD associated morbidities, their evaluation and management was beyond the scope of this study.

This study has several strengths. A comprehensive literature review was undertaken to identify estimates for clinical parameters, transition rates and costs. The study adds to the current body of evidence and our conclusions are similar to other health economic analyses [57]. A Health Technology Assessment undertaken for the National Institute for Health Research [19] concluded that use of NILT was more cost-effective than liver biopsy in detecting cases of advanced fibrosis. Tapper et al. [58] demonstrated that the use of the NAFLD fibrosis score and fibroscan in primary care yielded cost-effective results. Robust data are lacking regarding the performance of PCP’s in the identification of patients with advanced liver disease. Additionally, there is no published randomised controlled trial exploring the performance of NILT in primary care. Whilst limiting the model, the information provided by the analysis may be supplemented with the results from real-life pilot studies in due course. Harman et al. [59] have demonstrated the use of fibroscan in patients with risk factors for CLD, including diabetes, obesity and alcohol excess can increase detection of cirrhosis by 140%, similar to the modelling results in scenario 5 (132%). Our group has evaluated the pathway employing FIB-4 and ELF (Scenario 2) [13].

This study demonstrates that the introduction of NILT in primary care has the potential to increase the detection of cases of NAFLD with advanced fibrosis and cirrhosis, reduce unnecessary referrals to secondary care of patients at low risk of liver disease and to deliver immediate and sustained significant cost savings. The model provides compelling evidence for clinicians, commissioners and policy makers to consider the formal introduction of non-invasive liver fibrosis testing in primary care, in line with other central policy statements [4, 60, 61].