Implementing the right care in the right place at the right time for non-alcoholic fatty liver disease (NAFLD-RRR study): a study protocol for a community care pathway for people with type 2 diabetes

Non-alcoholic fatty liver disease (NAFLD), the liver component of a group of conditions associated with metabolic dysfunction, is present in 47–64% of people with type 2 diabetes (T2D) [1]. NAFLD is a heterogeneous disorder with variable rates of liver disease progression and clinical outcomes [2‐4]. Although the leading causes of death are cardiovascular disease and extrahepatic malignancy, 5–10% of people with NAFLD develop complications of advanced liver disease over 10 to 20 years [5, 6]. Among people with T2D, up to one third (15–30%) are at risk of clinically significant fibrosis [7‐9] and there is a more than 2-fold increased risk of cirrhosis-related complications and liver disease mortality [10]. As a result, there is increasing recognition that an assessment of NAFLD and the severity of liver disease needs to be incorporated into the routine care of patients with T2D [7, 9, 11].

Several peak bodies recommend identifying people with T2D or metabolic syndrome at risk of advanced chronic liver disease (CLD) [12‐14]. In the absence of a structured approach to screening and risk stratification, the diagnosis of NAFLD in these high-risk people is inconsistent and often occurs incidentally, during investigation of other clinical concerns [15, 16]. These patients are more likely to have severe liver disease and hepatocellular carcinoma (HCC) at the time of diagnosis [17], which greatly limits available therapeutic options. In contrast, the majority of patients currently referred to hepatology clinics for evaluation of NAFLD do not have advanced fibrosis and could be appropriately managed in primary care with attention to cardiometabolic risk factors. At present there is limited data regarding how best to support the targeted detection of patients at highest risk of CLD among the immense number of people with T2D.

The most important prognostic marker for adverse liver outcomes and overall mortality is the presence of advanced fibrosis [5, 6, 18, 19], which can be assessed using combinations of non-invasive tests [19, 20]. Clinical judgement and liver enzymes are poor discriminators of NAFLD severity. In people with T2D, transient elastography can identify the subgroup of individuals with a high risk of advanced fibrosis. Screening studies in community [21] or hospital-based T2D clinics [22, 23] have shown that, using a liver stiffness measurement (LSM) threshold of ≥9.6 kPa, advanced fibrosis was confirmed in 40–50% of patients who received a liver biopsy [24, 25]. Using a 8.0 kPa cut-off to exclude advanced CLD has a sensitivity of 93% in NAFLD [26]. Transient elastography can be performed as a rapid point-of-care test and allows estimation of steatosis by controlled attenuation parameter (CAP) at the same time. Although clinical guidelines endorse the use of simple scores (NAFLD Fibrosis Score (NFS) and Fibrosis 4 Index (FIB-4)) for initial assessment of fibrosis, a substantial proportion (36–63%) of patients fall into an “indeterminate risk” category and require second-line assessment with transient elastography [8, 27].

To date, few studies have examined strategies to introduce routine assessment of fibrosis into T2D care pathways. We propose that implementation of a community-based NAFLD diagnosis, risk-stratification, and referral pathway for people with T2D is feasible, will provide earlier, targeted detection of advanced fibrosis, and reduce unnecessary referrals to hepatology outpatients for fibrosis risk assessment.

Our health system research study examines a community-based NAFLD diagnosis, risk-stratification, and referral pathway for people with T2D. Compared with the general population, people with T2D have a higher prevalence of NAFLD and are at increased risk of developing the more severe inflammatory disease NASH, progressive liver fibrosis, and HCC [10, 41]. Targeting this at-risk population and providing a clear pathway linking primary care and liver clinics will lead to earlier identification and appropriate management of people with a greater prospect of adverse liver-related outcomes.

Since advanced fibrosis (F3/F4) is the key prognostic factor in NAFLD [18], a noninvasive point of care test to reliably identify this subgroup is crucial. Previous studies suggest that simple fibrosis scores perform less well in people with diabetes and have a lower predictive value to detect NAFLD-related advanced fibrosis [42, 43]. In this study the direct use of liver FibroScan provides a well-validated real-time assessment of liver fibrosis as well as steatosis, and allows for timely delivery of the diagnosis and fibrosis risk category (low or increased risk) to the patient’s healthcare team.

An important component of this study is the provision of a letter to the patient’s GP and diabetes clinician that provides succinct guidance on the appropriate management and follow-up of their patient in primary care, as well as investigation of abnormal liver enzymes or referral to a liver clinic if required. This “case-based” learning approach supports primary care clinicians to manage NAFLD in their community practice, as primary care is where most of the healthcare in Australia is coordinated. The letters will be evaluated for their effectiveness in providing guidance to deliver evidence-based care for people with this chronic health condition. Additional objectives include improving the GP’s capacity to recognize, diagnose, risk stratify and manage other people with NAFLD in their practice population, and to foster collaboration and integrated care with colleagues to improve their patients’ metabolic health.

Strengths of this study include the in-depth phenotyping of patients which will enable a thorough analysis of health outcomes and confounding factors to be performed longitudinally. Key outcomes include major adverse cardiac events (inclusive of myocardial infarction, cerebrovascular accidents, or hospitalisation for heart failure), extrahepatic malignancy, development of chronic kidney disease (decrease in glomerular filtration rate < 60 mL/min/1.73m² for ≥3 months or markers of kidney damage) [44], hepatic-related events, and death. The predictive power of LSM and CAP for hepatic and extra-hepatic outcomes currently has sparse evidence, especially in the high-risk type 2 diabetes population.

Most studies have focused on clinical utility of FibroScan for the detection and risk stratification of NAFLD but there is limited real-world implementation research on the barriers to utilising current non-invasive tests (NITs) which will be assessed through focus groups and questionnaires. This knowledge gap was recognised in the consensus recommendations from the NAFLD public health agenda published this year [45]. There was unanimous agreement from the consensus group that there are “both economic and social arguments for taking action on NAFLD” and “early intervention could help reduce the burden of disease, associated health-care costs and economic losses” [45]. While there is data [46, 47] to support the economic burden of NAFLD with advanced chronic liver disease there is a lack of health economic data on implementing a screening program to detect early disease. In the NAFLD-RRR study we will be able to calculate the real-world costs of implementing a local screening program in a population at high-risk for advanced chronic liver disease.

This study does have limitations. The sole use of FibroScan for a diagnosis of advanced chronic liver disease is likely to overestimate the prevalence of advanced disease owing to its modest positive predictive value of 59% for advanced fibrosis [23]. However the diagnostic gold standard of liver biopsy carries an unjustifiable risk of adverse outcomes if implemented as a screening tool. FibroScan is a well validated NIT that can simultaneously assess hepatic steatosis and the risk of advanced fibrosis as a “point-of-care” test. It has one of the highest negative predictive values (84%) of all NITs currently available for clinical use in Australia to exclude advanced fibrosis/cirrhosis in people with type 2 diabetes [23]. Although the positive predictive value is lower at 59%, the reporting of outcome measures in this population will reduce the clinical significance of this overestimation [23]. Whilst allowing a rapid assessment for NAFLD, FibroScan requires a dedicated operator and is not currently widely available in the community. ShearWave elastography, available in many community radiology centres, has similar accuracy to FibroScan for the exclusion of advanced fibrosis although the test is not as well validated as FibroScan [48, 49].

Our study will provide important information about the feasibility of establishing a NAFLD pathway for people with T2D in primary care and the costs and health outcomes associated with the pathway compared to those experienced under usual care. The study represents a change to the current management model for chronic liver disease, in which people seek care to treat complications of progressive fibrosis, rather than maintaining health through illness prevention. As recently reported by the President of the American Academy of Family Physicians “ … we need to invest in a new model that would allow primary care clinicians and their teams to coordinate care locally, collaborate with community organizations and public health departments, maximize strengths of specialists, and address known social drivers of health … ” [50, 51].