Healthcare and Socioeconomic Costs of NAFLD: a Global Framework to Navigate the Uncertainties

Abstract

Left unaddressed, NAFLD will continue to have substantial health, economic and social implications. To address the challenge, a paradigm shift is needed in the way NAFLD is conceptualised. Concerted, collaborative action across medical specialities, industry sectors and governments will be vital to tackling this public health threat. To drive this change, in this review, we present current global healthcare and socioeconomic costs for NAFLD and highlight priority actions to take. The estimated healthcare costs of patients with NAFLD are nearly twice as high as their age-matched counterparts without the disease and are highest in advanced fibrosis and end-stage liver disease. NAFLD is accountable for the highest increase in disability-adjusted life years (DALYs) among all liver diseases globally. NAFLD and NASH-specific drug therapies are not available and there is considerable uncertainty regarding the cost, optimal length of treatment, impact on liver-related outcome and mortality. Among the currently available bariatric procedures, sleeve gastrectomy is reported to be the most cost-effective for NASH resolution. Gastric bypass remains very expensive, while data on bariatric endoscopy are limited. Lastly, we propose a global NAFLD/NASH investment framework to guide the development of achievable yet ambitious country-specific targets and strategic actions to optimise resource allocation and reduce the prevalence of NAFLD and NASH. Its focus on high-level inputs will be critical to enabling a political and financial environment that supports clinical-level implementation of NAFLD prevention, treatment and care efforts, across all settings.

Introduction

Non-alcoholic fatty liver disease (NAFLD), which is characterised by excess fat in the liver, is an increasingly prevalent chronic liver disease, often as a result of obesity¹. Non-alcoholic steatohepatitis (NASH) is the histologic phenotype of NAFLD characterised by liver injury (inflammation and ballooning) in addition to steatosis. In contrast to simple steatosis, NASH is more rapidly progressive to cirrhosis and complications². NASH is the second most common indication for liver transplantation in the United Kingdom and the USA^{3, 4} and an important cause of liver cancer⁵. A multisystem disease, NAFLD is an independent risk factor for several comorbidities, such as type 2 diabetes (T2D)⁶, hypertension and dyslipidemia^{7, 8}. In the USA, the life expectancy of people with NAFLD is four years lower than their age-matched counterparts^{8, 9}. The most common causes of death include cardiovascular events, extrahepatic cancers and cirrhosis-related complications^{10, 11}.

Consequent to increasing prevalence and associated diseases, the healthcare and economic burden of NAFLD is substantial¹². The cost of care for NAFLD patients is nearly twice as high as those without the disease, likely due to multiple factors including testing, monitoring and hospitalisation¹³. Additionally, there is an indirect societal impact subsequent to early mortality, absenteeism, caregiver burden, as well as reduced health-related quality of life¹⁴. The lack of effective and sustainable therapeutic interventions to halt disease progression, reduce comorbidities and mortality make this a major healthcare problem worldwide.

While NAFLD is closely related to obesity, diabetes and cardiovascular disease, the public health and health systems responses to the issue have been weak and fragmented. In this review, we summarise the healthcare and economic burden of NAFLD and discuss the challenges posed by the increasing prevalence worldwide. We highlight the gaps in research, uncertainties related to the future management and treatment, and the need for a global framework and national action plans in tackling this condition to decrease the global burden of disease on health systems and the economy.

Healthcare Costs of NAFLD

The global NAFLD prevalence over the last 4 decades is estimated to be 30%, with rates between 44% in Latin America and 28% in Asia Pacific (Figure 1). The prevalence has increased from 24% in 1991–2006 to 38% in 2021 and is projected to continue to rise^15–22(Figure 2). Type 2 diabetes and obesity are closely associated with a higher risk of NAFLD. Globally, it is estimated that 55–70% of people with T2D have NAFLD, 30–60% have NASH and 12–20% have clinically significant fibrosis (stage ≥2)^{16, 23}. Likewise, approximately 75–80% of patients undergoing bariatric surgery for weight loss have NAFLD proven by imaging and liver biopsy^{24, 25}. Healthcare cost estimates available in literature differ by region, country, disease phenotype (NAFLD vs NASH), database and methodology, but they are uniformly high when compared to individuals without the disease or with T2DM and unclear NAFLD status. In the US, the lifetime cost of care for all patients with NASH was estimated around US $222 billion in 2017¹⁴.

Figure 1.

Global NAFLD prevalence (1998–2022)

Figure 2.

Increasing NAFLD prevalence over time

A recent model developed by Younossi et al, investigated the economic costs of NASH in the U.S. by obesity status²⁶. Using a discrete-time Markov model which involved patients with NASH who were allowed to move through 9 health states and 3 absorbing death states (liver, cardiac, and other deaths) with 1-year cycles and 20-year horizon in which the transition probabilities were estimated from literature and population-based data, the investigators found that for the U.S, NASH cases were forecasted to increase by 82.6%, from 11.61 million (2020) to 19.53 million (2039). During the same period, they also found that cases of advanced liver disease will increase by 77.9%, from 1.51 million to 2.67 million. However, overall, the proportion of NASH cases within the NAFLD population will remain approximately the same at 13% indicating that the rate of NASH is not accelerating over time but growing in proportion to NAFLD cases. The projected cumulative estimated direct healthcare costs were reported as 1,208.47 billion USD for those patients who were obese and had NASH while for those with NASH but who were not obese, the costs were reported to be 453.88 billion USD. By 2039, the projected NASH attributable healthcare cost per patient was reported to increase from 3,636 USD to 6,968 USD, with the increase most likely driven by the growing number of patients with NASH and advanced fibrosis.

In Europe the total NASH-related costs ranged between €8548-19 546M in 2018²⁷. Of these, health system costs were €619–1292M, while wellbeing costs (which measure costs associated with DALYs) were €41 536–90 379M. Other studies estimate an annual cost of about €35 billion (from €354 to €1,163 per patient) in Europe and $103 billion ($1,613 per patient) in the US¹². In a more recent study from Europe and US from 2018, the mean total annual per patient cost of NASH was €2,763, €4,917, and €5,509 for direct medical, direct non-medical, and indirect costs, respectively²⁸. Per patient cost was estimated to be the highest in the US and the lowest in France.

Another modeling study assessing cost of NASH was conducted in Hong Kong²⁹. This study suggested the total costs of NASH to be $1.32 billion (USD) with an average per person cost of $257. In addition, the study suggested that the costs of NASH in 2017–2018 accounted for 0.41% of Hong Kong’s total health expenditures.

In an analysis of a large US-based insurance claims database, the annual cost of longitudinal care per NAFLD patient is significantly higher than controls matched by age, sex, presence of diabetes, hypertension, dyslipidemia, cardiovascular disease and length of follow-up ($3,789 versus $2,298)¹³. Importantly, the cost is even higher around first NAFLD diagnosis ($7,804). The largest increases in healthcare utilisation which may account for the increased costs were represented by imaging, hospitalisations, liver biopsies, laboratory tests and outpatient office visits. Hospitalisations of patients with NAFLD have tripled in the US between 2007–2014³⁰, especially among men, Hispanics and government insured patients. Similarly, healthcare costs were nearly twice as high in patients with NAFLD than matched controls in cohorts from Sweden³¹, Italy³², Germany³³, France³⁴ and Spain³⁵. It is important to note that the independent impact of NAFLD on healthcare costs was not consistently analysed in all studies and the contribution of metabolic comorbidities could contribute to an overestimation of the economic burden of the disease. This potential confounding is an important limitation to be considered in the design of future studies.

Moreover, there are substantial discrepancies between the cost estimates in the European versus US studies. Whereas some regional variations are expected, the large inconsistencies are more likely a result of differences in assumptions used in the models. We call for standardisation of transition rates between disease stages, utility scores, resource utilisation estimates, and their consistent use in different models to eliminate uncertainty.

A common finding of all studies is that the care is more expensive in advanced stages, likely due to the evaluation and management of complications related to end-stage-liver disease, including hospitalisations. Early detection is crucial for timely intervention to prevent disease progression and could ultimately have an impact on decreasing socioeconomic costs. Therefore, rational utilisation of healthcare resources to detect the small proportion of those who are at risk for fibrosis in the general population is critical, and this will require the implementation of clinical care pathways that are not only feasible, efficient and accessible but also cost-effective. Several strategies for proactive case finding have been recommended, most of which include sequential testing with blood-based biomarkers followed by elastography^36,37. However, there is considerable heterogeneity in these approaches between regions, countries and even practice settings³⁸. Several models have demonstrated that a sequential approach using FIB-4 or the NAFLD fibrosis score, followed by elastography (vibration-controlled transient elastography or magnetic resonance elastography), are cost-effective, especially when used in high-risk populations such as those with T2DM or obesity, and could avert a significant number of liver biopsies, resulting in systemic cost-savings and QALYs gain^39–45. The development of optimal screening strategies for NAFLD with fibrosis in primary care and community settings remains a critical research focus^{48, 49}. In the absence of effective medications leading to NASH resolution or fibrosis improvement, early detection strategies for NASH fibrosis will have to evidence that they improve long term outcomes through the facilitation early weight loss intervention and the management of metabolic risk factors. Nevertheless, given the high disease prevalence, it is becoming increasingly clear that NAFLD identification and management requires multidisciplinary efforts and implementation of models of care that combine primary care physicians, hepatologists, endocrinologists, weight management specialists, dieticians and others.

Socioeconomic costs indirectly associated with NAFLD

In addition to the direct health care costs, the total economic costs include the indirect effect of premature mortality and disability resulting from NAFLD and related complications, commonly assessed through disability-adjusted life years (DALYs). In an analysis of the Global Burden of Disease data from 2007–2017, NAFLD was the most rapidly growing contributor to liver mortality and morbidity¹. NAFLD was responsible for 6–17% of liver-cancer related death globally (with a 26% increase), 9% of the global cases of cirrhosis (with a 15% increase) and the highest increase in DALYs. Among the world regions, Asia accounted for 48% of the global incidence in liver-related complications from NAFLD and 46% of NAFLD-related death, with a 2% annual percent change increase in DALYs⁴⁸. Similar trends were seen in the United States, where the highest increase in death rates and years of life lost from cirrhosis and HCC were due to alcohol-related liver disease, followed by NAFLD⁹. It remains unclear whether the impact on DALYs is solely attributable to NAFLD, especially in early stages, as most studies which have not focused on cirrhosis and HCC have not adjusted for all possible associated confounders beyond age. It is likely that metabolic comorbidities can contribute to the disability estimation, and these should be considered in future study designs.

In addition, patients with NASH experience worse health-related quality of life (HRQL), lower productivity and increased healthcare utilization when compared to the general population and individuals with T2DM after matching for confounders⁴⁹. The indirect economic impact of NAFLD related to impairment of HRQL and work productivity can add to the direct economic burden of NAFLD, leading to substantial societal costs.

Socioeconomic inequalities and NAFLD

Globally, low socioeconomic status (SES) is associated with greater mortality^50–52. An individual’s sociocultural and economic context directly influences their lifestyle, environment and access to health systems, which in turn impact the risk of morbidity, which in turn negatively affects the socioeconomic system at the individual and population levels⁵³.

Studies of SES in NAFLD are scarce but the topic has received increasing attention in recent years. Socially disadvantaged populations have a higher risk of NAFLD and related complications^54–57. In a recent analysis of US the National Health and Nutrition Examination Survey (NHANES) database in 2017–2018, high-quality diet, increased physical activity and college education were associated with a lower risk of hepatic steatosis by VCTE⁵⁴. Food insecurity may be an independent predictor of NAFLD and advanced fibrosis among low-income adults^58–60. Processed meat consumption⁶¹ and inadequate physical activity⁶² are independent predictors of NAFLD. In children, community socioeconomic deprivation was associated with younger age at NALFD diagnosis, but not with NAFLD severity⁶³. Children in low SES have a higher prevalence of obesity, higher added sugar intake, such as sweets and soft drinks, and lower fruit and vegetable intake⁶⁴. In the US, lack of health insurance is associated with higher risk of death in those hospitalised with NAFLD³⁰.

Elements of SES are intertwined, and the distinction between their level of contribution can be difficult. For example, higher income allows for a healthier diet, more physical activity, increased self-care, and access to high-quality healthcare. Given this relationship between SES and health, health strategies to decrease NAFLD burden should target these inequalities⁶⁵. Current international efforts such as the Sustainable Development Goals (SDGs) and the WHO European Action Plan 25×25 health plan (25% decrease in mortality from major noncommunicable diseases (NCDs) by 2025)⁶⁶ promote these components at the population level, such as universal access to a nutritious diet, education, walkable environments, and high quality healthcare. As NAFLD is not included in the aforementioned initiatives, a NAFLD-specific framework, using 16 SDG targets and 7 indicators, has been developed to place NAFLD in the global, multisectoral context, similar to other NCDs⁶⁷. These include health, agriculture, education, the economy and the environment (Figure 3). This framework can be used to prioritise strategies and identify context-specific policies and intervention to decrease healthcare and socioeconomic costs.

Figure 3.

Proposal for a global NAFLD/NASH investment framework

Treatment costs

Treatment of NAFLD remains a major challenge in the absence of approved therapies to date. Current methods vary in effectiveness, invasiveness and cost. Life-style changes in dietary choices and physical activity are effective interventions for NASH resolution, fibrosis regression⁶⁸, portal hypertension⁶⁹ and the likelihood of needing a liver transplant⁷⁰, which can likely be adopted at lower cost than invasive interventions. However, they are unlikely to have a large impact on the burden of NAFLD, because less than 10% of individuals achieve and maintain sufficient weight loss⁶⁸. The most effective intervention to date is bariatric surgery, which is more expensive, but can lead to sustainable NASH resolution in 84%, and fibrosis regression in 70% of patients at five years^{71, 72} and reduce liver-related and major cardiovascular events⁷³. An economic evaluation using a Markov-based state-transition model to simulate the impact of sleeve gastrectomy, Roux-en-Y gastric bypass, and intensive lifestyle intervention in patients with NASH and compensated cirrhosis suggests that bariatric surgery could be highly cost-effective compared to usual care. While sleeve gastrectomy is cost-effective across all classes of obesity, with an incremental cost-effectiveness ratio (ICER) raging between $18716 (for mild obesity) and $6563 (for severe obesity) per quality-adjusted life year (QALY). However, the cost of gastric bypass would have to decrease by $2289 (for mild obesity) to $4489 (for severe obesity) to meet the cost-effectiveness threshold of $100 000 per QALY⁷⁴. Both gastric bypass and sleeve gastrectomy can lead to an increase in QALYs in patients with NASH and cirrhosis when compared to standard of care⁷⁴. It is important to note that in patients with cirrhosis the choice for surgical weight loss approaches should be made after careful evaluation of risks based on hepatic function and presence of portal hypertension, irrespective of BMI.

Endoscopic interventions for weight loss, such as endoscopic sleeve gastroplasty, are safe and effective novel interventions that can complement lifestyle modifications for management of class 1 and 2 obesity, but their role in NASH treatment remains to be demonstrated⁷⁵. Other methods, such as intragastric balloon placement show promising results for NASH resolution and fibrosis improvement in 50% of patients⁷⁶. Cost-effectiveness studies with long-term follow-up to assess for sustainability of results are needed to determine the role of these interventions in NASH management.

There are several investigational drugs under evaluation for safety and efficacy in NASH, a few of which have reached phase 3⁷⁷. Some of these agents, such as the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide, and the dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist tirzepatide have been approved as weight loss and type 2 DM therapies, and their cost-effectiveness in NASH remains to be determined. The current investigational efficacy endpoints for accelerated approval in NASH are based on histological improvement of fibrosis and resolution of NASH. However, it remains unclear whether these surrogate endpoints will translate to a decreased risk of cirrhosis and related complications, fewer comorbidities and better quality of life. More importantly, the appropriate length of treatment beyond the trial period remains uncertain. Whether treatment will be applied for a finite time until NASH resolution is achieved or given as lifelong maintenance, akin to diabetes or hypertension, will have huge implications on lifetime costs. For example, a 2-year treatment with a drug that results in NASH resolution followed by long-term maintenance of this histologic endpoint might be superior to a short-term treatment that reduces fibrosis but may not eliminate the risk of future disease progression after discontinuation⁷⁸. Furthermore, metabolic drugs that favorably impact the cardiovascular risk by reducing insulin resistance and weight might have a greater impact on mortality and morbidity than those with antifibrotic or antiinflammatory mechanism of action.

In another simulation of a cohort with 21-year life expectancy, for a pharmaceutical intervention to be considered cost-effective in reducing fibrosis and mortality, annual drug cost should not exceed $12,000. For an annual cost of $36,000 for example, the ICER would be $2,517,676/QALY gained, which exceeds an economically justifiable price⁷⁹.

Gaps in NAFLD global cost estimates

Most of the data reporting the healthcare and economic costs associated with NAFLD come from Europe, Hong Kong and USA, leaving a large gap in estimation of the global situation. Existing data cannot be extrapolated due to substantial heterogeneity in populations, health systems, costs, practice patterns, access to quality testing and care between and within countries, especially between low- and high-income settings. Therefore, data generation from all regions of the world is critical, as action plans to reduce the care costs and prevalence need to be developed and prioritised based on country and sub-national-specific evidence. This heterogeneity has been found in other key comorbid conditions such as T2DM⁸⁰ and cardiovascular disease⁸¹.

Some of the strongest evidence is from the Organisation for Economic Co-operation and Development (OECD), which has developed models that show positive effects of heath policies on economic metrics in liver diseases of all causes in the 27 European Union member states plus Iceland, Norway, Russia, Switzerland and the United Kingdom, for the period 2020–2050. Policy interventions such as food reformulation, alcohol pricing and taxation are among the most effective in improving health expenditure, years of life lost, DALYs and workforce productivity, with an estimated €31 billion in potential economic gains⁸². Similar investment studies that systematically estimate the potential impact of policy interventions in lowering costs should be developed for NAFLD, to identify which actions are cost-effective and their returns on investment, in order to develop policies with net benefit.

A call for a NAFLD/NASH investment framework

Assessing the socioeconomic and healthcare burden of NAFLD is a necessary first step in understanding and subsequently reducing the magnitude of the problem. Almost no country globally has a written strategy for addressing the disease⁸³, while it is absent from key global policies, including the World Health Organization’s Global Action Plan for the Prevention and Control of Non-Communicable Diseases (NCDs). To address the challenge of growing prevalence and further increasing costs, a first step is to develop a NAFLD/NASH investment framework, consisting of policies and other actions to guide an efficient policy response. Such a framework should focus on the high-level inputs that are critical to enabling a political and financial environment that support country-level implementation of NAFLD/NASH strategies, across all settings. Similar disease-specific investment cases, using real world case studies and modelling, have already been developed for HIV⁸⁴, obesity⁸⁵, diabetes⁸⁶, viral hepatitis B⁸⁷, C^88–90 and other conditions. We believe that a NAFLD-specific investment framework is essential in addressing liver-related goals as they are not included in those developed for obesity or diabetes. This should incorporate activities such as increasing awareness of liver disease in those with risk factors, the use of NITs to identify those at high risk for fibrosis, optimisation of clinical care pathways which include efficient diagnosis, referral strategies and longitudinal monitoring, in addition to aspects of NASH-related therapeutics that are expected to be approved in the near future. These issues are not currently addressed in investment frameworks of other diseases and essential in NAFLD management and the ultimate goal of decreasing the burden of liver disease and related complications. A NAFLD/NASH-specific investment framework can identify key synergies between prevention and treatment strategies and opportunities to progress towards the Sustainable Development Goals (SDGs) and achieve universal health coverage, which is central to the SDGs and in line with global health priorities set by WHO.

Conclusions

The chronic and long-term nature of NAFLD, the multiple associated comorbidities and costs, and the lack of effective therapies to stop fatty liver disease progression or improve outcomes present particular healthcare and socioeconomic challenges. It is imperative to mobilise efforts to place fatty liver disease on the global health and development agenda, create action plans to implement cost-effective patient care pathways for disease identification at an early stage, and to address social, economic and environmental determinants of health. Given the high and increasing prevalence of NAFLD and the lack of national and global strategies, coordinated, transformative efforts are needed on how to mitigate non-sustainable escalating costs and expected disparities between and within countries. We propose developing a global fatty liver disease investment framework that sets out achievable yet ambitious country-specific targets and strategic actions to optimise resource allocation and embed these within the United Nations’ Sustainable Development Goals. Such solutions to the global NAFLD burden should be framed as a matter of whole-of-society responsibility and not solely that of a provider or patient.

Key points.

1. The estimated healthcare costs associated with NAFLD and NASH are high and estimated to increase in the regions where modeling has been applied: United States, Europe and Hong Kong, whereas there is a gap in assessment in the other regions.

2. The costs, mostly arising from testing and hospitalisations, are highest in advanced fibrosis and end-stage liver disease.

3. Very few studies have analysed the impact of NAFLD/NASH on healthcare costs independent of metabolic comorbidities, which can contribute to an overestimation.

4. Globally, among all causes of liver disease, NAFLD is accountable for the highest increase in disability-adjusted life years (DALYs).

5. Socioeconomic disadvantage is associated with higher risk of NAFLD and disease progression, which in turn exacerbate the economic burden.

6. Cost-effectiveness estimates of drug therapies remain uncertain in the absence of approved treatments with impact on liver events and mortality.

7. Modeling in patients with NASH cirrhosis estimate sleeve gastrectomy to be the most cost-effective among bariatric surgery procedures when compared to intensive life-style interventions.

8. To address the challenge of increasing prevalence and healthcare costs, we call for an investment framework to raise the profile of NAFLD/NASH and yield significant cost-efficiencies by guiding decision-makers on which actions should be implemented.