The paradigm shift from <scp>NAFLD</scp> to <scp>MAFLD</scp>: A global primary care viewpoint

Abstract

Half of the global overweight/obese adult population have metabolic-dysfunction-associated fatty liver disease (MAFLD),1 with prevalence rising, even among non-obese individuals.2, 3 This increase is observed globally and mostly in low- and low-middle-income countries of Africa, Asia and South America and represents a great worldwide burden on healthcare expenditures.4-7 Lifestyle changes and a healthy diet are still the cornerstone in the clinical management of these patients as approved medications are presently lacking.4, 8 In clinical settings, most patients with fatty liver disease are first identified and subsequently followed up in the community by primary care practitioners (PCPs).9 There is unequivocal evidence of the health-promoting influence of primary care and its role in the prevention of illness and death.10 In addition, in contrast to speciality care, primary care is characterized by a more equitable distribution as a healthcare service for all populations.10 In this context, primary care is central and may therefore help or hinder optimal chronic disease care. For PCPs, to provide effective and high-quality care, it is crucial to integrate novel knowledge, skills and favourable attitudes towards care that focuses on system reform and interactive patient and primary care team relationships.11 In 2020, a group of international experts reached a consensus to comprehensively revisit the current definition of fatty liver disease, including updating the nomenclature from non-alcoholic fatty liver disease (NAFLD) to metabolic-dysfunction-associated fatty liver disease (MAFLD), and more importantly introducing a simple set of ‘positive’ diagnostic criteria for both adults and children.12-15 The diagnosis of MAFLD is made if a patient has hepatic steatosis and is overweight or obese, has type 2 diabetes mellitus or two or more of the following: central obesity by ethnic-specific waist circumference cut-offs; blood pressure ≥ 135/85 mmHg or specific drug treatment; plasma triglycerides ≥150 mg/dL or specific drug treatment; plasma HDL-cholesterol <40 mg/dL for men and <50 mg/dL for women or specific drug treatment; fasting plasma glucose ≥100 mg/dL, 2-h post-load glucose ≥140 mg/dL or haemoglobin A1c ≥ 5.7%; homeostasis model assessment of insulin resistance ≥2.5 and plasma high-sensitivity C-reactive protein >2 mg/L. This call received substantial support from hepatologists across the globe, hepatology scientific societies, nursing and allied health leaders, pharma and regulatory science experts and patient associations.4, 5, 16-23 Nonetheless, the new nomenclature has also triggered controversy,24 suggesting the need for a consensus-driven redefinition of NAFLD.25 The high prevalence of fatty liver disease and its strong association with conditions traditionally managed in primary care such as obesity, diabetes mellitus, hypertension and hyperlipidaemia, positions general practitioners/family doctors to lead the charge of providing high-quality treatment at the scale that is needed to combat the fatty liver epidemic. Therefore, it is crucial to understand PCP perspectives regarding the proposed redefinition of fatty liver disease as well as the implications for the primary care of patients. In fact, the way PCPs envisage the utility of this change will play a significant role in global consensus building. Thus, the aim of this paper is for an international team of experts in primary care to provide perspective regarding the proposed redefinition of MAFLD. We think that the main role of PCPs is raising awareness, diagnosing cases, follow-up and detection of complications. The role of PCPs is essential in the detection and management of extra-hepatic associations as well as screening and surveillance of hepatocellular carcinoma. Currently, numerous systemic barriers exist for PCPs who are managing fatty liver disease. These include diagnosis and screening, efficient referral pathway, restrictive policies, disease awareness and continuum of care. We believe that the transformational change from NAFLD to MAFLD can help to overcome some of these barriers and promote widespread active case findings of MAFLD and improvement of care. NAFLD is woefully underdiagnosed in primary care, with multi-national and US studies demonstrating the prevalence of recorded NAFLD diagnoses at 2% and 5%, respectively, far below the estimated population prevalence of 25–30%.26, 27 Even in the presence of metabolic syndrome comorbidities and ultrasonographic or image testing reports of hepatic steatosis, NAFLD goes undiagnosed.28, 29 Reasons for these diagnostic errors are complex, with survey studies showing that NAFLD is not perceived as a priority in primary care, and there is a large knowledge deficit regarding NAFLD diagnosis and management. These phenomena result in a substantial disconnect between current guidelines and real-world clinical practice.30, 31 Alarmingly, a recent study demonstrated that 71% of primary care patients had a non-invasive fibrosis score (Fibrosis-4 Index [FIB-4] and NAFLD Fibrosis Score) in the indeterminate-risk or high-risk category for advanced fibrosis, reinforcing the clinical significance of knowledge deficits regarding diagnosis, although being the major determinant of complications.29 Primary care uptake might be hampered by the limited involvement of primary care physicians in the development of clinical practice guidelines. Apart from knowledge deficits, adherence to NAFLD clinical practice guidelines in routine primary care settings seems to be difficult for other reasons. These include (i) limited use or availability of complicated and expensive diagnostic tests required to diagnose NAFLD according to current guidelines; (ii) the time inconvenience of assessing alcohol consumption/dependence using different questionnaires with varying dimensions and (iii) the complexity of algorithms theoretically designed to facilitate the management of NAFLD. In this context, according to the American Association for the Study of Liver Diseases,32 the diagnosis of NAFLD requires an extensive set of laboratory tests (mostly negative) and an experienced specialist, to exclude other liver diseases that require high-level laboratory and clinical capabilities. It is clear that many of the investigations recommended in clinical practice guidelines are not attainable for most patients, even in commonly used international cohorts such as the National Health and Nutrition Examination Survey cohort.13 In addition, the economic costs for health systems and society for NAFLD, independent of its metabolic comorbidities, are to be considered.33 The complexity of the requirements for a diagnosis of NAFLD represents a substantial barrier for PCPs to begin screening or active case finding. Simplification of the diagnostic criteria for fatty liver disease suitable for a busy primary care environment is needed to enable treatment expansion into primary care at a larger scale.34 These criteria need to be both useful and practical, and their content should be guided by input from clinicians involved in the daily care of these patients, particularly PCPs. Another impediment is the amount of time required to obtain a detailed and accurate alcohol history, whereby patient management may be misdirected based on this dichotomization into alcoholic or non-alcoholic.13 In addition, the low availability and utilization of sensitive direct alcohol markers (e.g. phosphatidyl ethanol) in primary, secondary and tertiary care settings in different regions of the world make interviews or questionnaires the only tool for discriminating between alcoholic and non-alcoholic fatty liver disease. However, there is often a high variability in reported and measured levels of alcohol (especially between male and female). Notably, a recent study of 834 Portuguese adults demonstrated that while the fatty liver was detected in 37.8%, only 17.0% were diagnosed with NAFLD. Although these patients have some evidence of metabolic dysfunction, the threshold of alcohol intake falsely reduced the prevalence of NAFLD, thereby raising concerns about the utility of the current diagnostic approach in real-world healthcare.35 Additionally, the recommendations for the cut-off of alcohol consumption in NAFLD guidelines are based on the lowest-level evidence (primarily expert opinion) and on an arbitrary threshold. Notably, a recent study identified that alcohol consumption is associated with hepatic steatosis even in subjects with presumed NAFLD.36 In addition, alcohol intake within the current defined safe limits can still lead to NAFLD progression13, 37, 38 and increased risk of hepatocellular carcinoma.39, 40 To complicate the matter, the current cut-off of alcohol intake does not take into consideration the substantial inter-individual variability in response to alcohol consumption, based on a myriad of variables, including body mass index, alcohol-producing gut bacteria41 and the shared genetic basis between alcoholic and NAFLD.42, 43 To address these challenges, the removal of alcohol could simplify the diagnosis of NAFLD.12 Furthermore, it will facilitate the evaluation of the contribution of different alcohol intake levels to the risk and progression of the disease. Notably, although the amount of alcohol intake is not a prerequisite for the diagnosis or exclusion of MAFLD, it is still important to screen for harmful alcohol consumption in these patients.12 Similarly, testing for other causes of liver diseases such as viral hepatitis might be required based on clinical judgement. Speciality referrals are the intersection of care where patients, PCPs and speciality physicians work to address the patients' medical problems. The referral process begins with the patient and/or PCP's decision to involve specialized medical services and takes into account multiple aspects. An integrated healthcare referral pathway should improve the coordination of care. To achieve the goal of improving the quality of care delivered, we need to find the right balance between avoiding underdiagnosis as well as over-referral. Identifying those patients with advanced disease who might benefit from early specialist intervention remains a major clinical challenge in primary care because of the indolent asymptomatic nature of NAFLD and the varying presentations of the disease. Some patients with NAFLD are not identified until symptoms of decompensated cirrhosis necessitate hospitalization. On the other hand, it has been suggested that the vast majority of referrals of patients with NAFLD made to hepatologists could have been managed in primary care.44 A fundamental problem with the NAFLD model of care is that the approach to diagnosis is basically hospital-centred (i.e. concentrated in large urban hospitals and accredited laboratories) and before long will overwhelm these specialist-based services.45 Therefore, improving NAFLD diagnosis in primary care relies on harnessing a decentralized and demand-driven healthcare system, which itself focuses on efficient and effective healthcare delivery in primary care, especially in rural communities.46 As diagnostic accuracy improves, developing and disseminating accessible and reliable tools to PCPs for identifying patients most likely to develop liver-related complications (e.g. fibrosis, cirrhosis, hepatocellular carcinoma) will play a critical role in optimizing the speciality referral process.47 Reducing inappropriate referrals represents an opportunity to reduce unnecessary investigations, inconvenience and even harm for patients, pressure on secondary care services and costs for the healthcare system; which will only continue to worsen with the rising prevalence of the fatty liver disease. The notion of quality of care is complex, and quality improvement needs medical, contextual and policy consideration.48 Decisions to improve the quality of patient care must be made with a good knowledge of the disease (medical evidence), but at the same time, they must take into account patient-specific aspects of medical care (contextual evidence) and feasibility, equity and cost-effectiveness (policy evidence).48 At the policy level, issues of equity and cost-effectiveness must be addressed. The concept of health equity has been described as overcoming differences in healthcare that are unfair, unjust, unnecessary and avoidable.49 In low- and middle-income countries, evidence suggests that the cause of inequalities may be a reflection of the failure of healthcare services to reach the most deprived areas. These healthcare systems are suffering from underfunding and fragmentation of public and private systems and poor engagement of informal workers, which together affect equity.50 With rising income inequality, concerns have been raised that health inequalities are increasing and therefore may negatively impact the social stability of the community.51 In this context, according to the current guidelines,32 the ‘negative’ diagnosis of NAFLD requires an extensive set of negative laboratory tests (i.e. full aetiology screen), which are not feasible in limited-resource settings, thereby hampering extrapolation to regular patient care and aggravating health inequity.52 For example, there are substantial variations in available diagnostic capabilities when comparing rural health centres to urban ones. Diagnostic laboratories are often poorly resourced and sparsely distributed in rural regions.53, 54 In addition, in 2019, the World Health Organization estimated that out-of-pocket expenditure exceeded 40% of total health expenditure in low-income countries.55 Improved access may be achieved by using tests that do not require advanced laboratory support. In addition, in the context of finite healthcare resources, a goal of healthcare systems cannot be to maximize health gain without any consideration of cost. The cost-utility—including patient preferences and values, with special emphasis on equity—is a critical part of improving patient care. To realize the relevance of this, various studies have illustrated that the cost-effectiveness of a diagnostic test or criteria is the most important factor for healthcare utilization.56, 57 This difficulty implies that the adoption of less complex diagnostic criteria and approaches particularly for such highly prevalent disease as a fatty liver disease should consider all aspects of primary care delivery and expand capacity in low-income settings. A recent study suggested that one of the top five ordered laboratory tests by volume is the ‘basic metabolic panel’ including glucose and lipid profile, similar to that incorporated in the diagnostic criteria for MAFLD.58 Therefore, ensuring fatty liver disease care is equitable, sustainable and efficient on all counts is impossible if the status-quo is not significantly challenged to reduce the impact of inequalities on vulnerable populations. Simplification of diagnostic criteria, which can be incorporated into ‘usual care’ at low cost, is likely to be the first essential step towards the goal of reducing fatty liver disease-related morbidity and mortality, especially in low-income countries. The gaps in NAFLD identification in primary care likely reflect the gaps in PCP knowledge and awareness of relevant practice guidelines. A previous study found that nearly half (40%) of PCPs surveyed in this study were not familiar with clinical published guidelines for NAFLD management, which is translated into paradoxical screening practices.59 Similarly, multiple other studies again found substantially low rates of awareness and screening for NAFLD in their surveys of PCPs.60-62 Another study reported that 83% of PCPs wanted more education on the topic.63 There have been calls for greater awareness of the fatty liver disease among PCPs so that diagnosis is not delayed and patients can receive early and appropriate interventions, so we can bridge the gap between evidence and practice. Based on a transformational shift from NAFLD to MAFLD, the current MAFLD care model can be streamlined. Simplification of care will potentially have multiple benefits, including better allocation of resources to diagnose more patients (expanding access and coverage), improving identification of patients at risk of disease progression and acceleration of treatment initiation (linkage to care), reduction in complications among high-risk populations and lowering the long-term medical costs of complications, such as those associated with advanced liver disease, extra-hepatic complications of MAFLD or liver transplant (reducing burden), improvement in patient adherence and facilitation of task-shifting/patient management by PCPs (optimizing referral pathway). MAFLD criteria represent a pragmatic, real-world approach to identifing patients with fatty liver disease in primary care using simple tests. Compared with the standard NAFLD pathway of care involving specialist review and complicated laboratory-based testing, the MAFLD diagnostic model has the potential to offer a low-cost and easily accessible that can be in primary care and be for routine clinical use The of these criteria are to lead to significant in referral practice which will include a reduction in the of unnecessary referrals of fatty liver disease while at the same time improving early case identification and the detection of patients at high risk that may enable better use of effective management and a reduced disease In with this, numerous recent studies have demonstrated that MAFLD diagnostic criteria are practical, simple and the NAFLD criteria in identifying patients at high risk of hepatic fibrosis as well as extra-hepatic such as disease and chronic disease and findings were observed when MAFLD criteria were to patients with viral hepatitis and A similar simple care system based on simple diagnostic criteria and with support from clinicians for other has been and in various low- and middle-income countries. This approach has been to improve population health and reduce and is a for health and diagnosis need to reach larger of with fatty liver disease to combat the burden of the disease. Although metabolic is a of fatty liver disease screening for fatty liver disease among high-risk has been This is because among other the associated with the asymptomatic of the disease and the reflection of nomenclature on the of disease, the of awareness of active recommendations and low healthcare engagement of the most as current nomenclature does not any to other metabolic In MAFLD as a the disease in the with other metabolic such as chronic disease and markers of hepatic steatosis such as fatty liver based on body mass index, waist level, and could be to overcome the of of in primary care. A recent study of patients that fatty liver has diagnostic accuracy for the detection of hepatic steatosis in MAFLD. with even accuracy will be This change will facilitate the adoption of multiple health change for primary prevention by reducing to potentially harmful and risk and the for reducing the large and increasing burden of metabolic this of nomenclature may the that patients receive and risk reduction management With the to increase the awareness of NAFLD for a recent study demonstrated that from using NAFLD to MAFLD increased awareness of the disease among primary care and physicians in other other studies have patient awareness with the new This the of the MAFLD criteria in the context of routine clinical care adoption and suggests that the are on this with the more widespread use of the MAFLD criteria could result in even greater in the care of MAFLD the that NAFLD diagnostic criteria are based on the exclusion of other liver diseases a great barrier to consideration of and management of patients with liver diseases as well the between fatty liver disease and other liver This could result in and care of these patients, particularly with evidence that patients with MAFLD and other liver diseases including viral hepatitis and alcohol intake or hepatitis have more liver to those with disease In fact, an international expert group raised the of consideration of MAFLD in the hepatitis Notably, multiple recent studies demonstrated that in patients with or the MAFLD criteria are to the NAFLD criteria for identifying patients with more liver including steatosis, fibrosis and liver On the other hand, the shift to MAFLD will for a input from primary care, and for improving both liver-related and This the NAFLD definition represents a substantial barrier to full of the chronic care model at the primary care In fact, PCPs play a crucial role in the early detection of fatty liver disease and the prevention of clinical progression and potential complications, their appropriate evaluation of fatty liver disease is The in diagnosis and in which the MAFLD definition is we believe may facilitate the of effective fatty liver disease management, and in secondary and tertiary care but also reduce underdiagnosis in primary care by PCPs, a balance on of public This change will support PCPs to continue to to the health and of patients in the based on equity and for the of the We have that the change to the MAFLD definition has major and in (i) improvement in the capacity to and care for diseases (ii) clinical guidelines work in daily practice and (iii) policy to to equity on a worldwide The remains on to overcome the clinical and any A global consensus without that of and active of both clinicians (especially and more of the available scientific evidence is the The have to to the and of the

Topics & Concepts