Clin Mol Hepatol > Volume 29(2); 2023 > Article
Kasper, Demir, and Steffen: Screening strategies for non-alcoholic fatty liver disease: a holistic approach is needed
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, currently affecting around 32.4 % of the adult population [1]. In addition to the adult population, there has also been a significant increase in the incidence and prevalence of NAFLD among children and adolescents over the last decade, which was further aggravated by the COVID-19 pandemic [2,3]. The prevalence of NAFLD in children is estimated to range from 5–10% in the general population, rising up to 30% in young individuals with obesity [3].
Therefore, NAFLD represents a growing public health problem across all age groups of the population, causing a tremendous clinical and socio-economic burden [4,5].
NAFLD encompasses a spectrum of liver disorders ranging from simple hepatocellular steatosis (non-alcoholic fatty liver, NAFL) to more progressive steatohepatitis (NASH) with varying degrees of fibrosis, and ultimately cirrhosis [5]. NAFLD is considered as the hepatic component of the metabolic syndrome and is associated with an increased risk of the development of various liver-associated and cardiometabolic complications [4-7].
Individuals with NAFLD have an approximately two-fold higher risk of developing type 2 diabetes (T2DM) and NAFLD is associated with an increased long-term risk of fatal or non-fatal cardiovascular events [7,8].
Alongside the growing epidemics of obesity and metabolic syndrome, the NAFLD disease burden is expected to increase during coming years [9].
Global estimates currently suggest that the prevalence of NAFLD will continue to increase significantly through 2030, with a concomitant increase in the proportion of patients with advanced disease stages (e.g., advanced liver fibrosis), who are at the highest mortality risk [9]. In the Asian-Pacific region, cases of NAFLD will increase by up to 20% until 2030 and NAFLD-related mortality is projected to increase by more than 65% [10].
Due to the alarming surge in prevalence and incidence of NAFLD in various groups of the population and the associated major health risks, particularly in patients with progressive disease, it is time to consider screening programs for NAFLD.
In their comprehensive review, Zhang and colleagues [11] address this important issue and provide an up-to-date overview of screening strategies for NAFLD.
The authors discuss thoroughly general requirements for screening programs and their cost-effectiveness and describe current international guideline recommendations. Further, the authors provide a detailed overview of different screening modalities including their advantages and disadvantages (e.g., serum-based methods, ultrasonography, transient elastography, magnetic resonance imaging), and evaluate suitability of different techniques for screening purposes in clinical practice. The authors emphasize that non-invasive screening measures are particularly relevant in specific highrisk groups, including patients with T2DM, metabolic syndrome or persistently elevated liver enzymes, whereas screening of the total population is generally not advisable and not cost-effective.
Finally, the authors present a two-step-assessment scheme with serum-based fibrosis-4 index (FIB-4) or NAFLD fibrosis score (NFS) followed by an imaging test, i.e. vibration-controlled transient elastography, as an option to stratify the risk of liver related-complications.
Zhang et al. [11] provide a comprehensive and relevant review for everyday clinical practice. Non-invasive testing strategies using easily available laboratory data for detecting advanced NAFLD disease stages in distinctive risk groups are crucial, since these patients have a high mortality risk and frequently suffer from liver-related complications.
However, most NAFLD patients worldwide are not in advanced disease stages when NAFLD is diagnosed and do not die primarily from liver-related events.
The majority of patients suffer from early stages of NAFLD and–overall–cardiovascular diseases (CVD) are the leading cause of death in patients with NAFLD [7,9]. This can partly be explained by the fact that patients with NAFLD often exhibit multiple cardiovascular risk factors such as atherogenic dyslipidemia, T2DM or arterial hypertension, which are often neither recognized nor adequately controlled [12,13].
As there is growing evidence for NAFLD as a ‘multisystem’ disease, concomitant risk factors such as obesity and additional cardiometabolic disorders should also be considered in the context of planned screening measures.
Therefore, in addition to the identification of patients with advanced stages of liver fibrosis, particular attention should be paid to detection, treatment and adequate control of T2DM, hypertension, and atherogenic dyslipidemia, which are interrelated with NAFLD severity and key determinants of the individual cardiovascular risk [14].
Recent data clearly show, that with the increase in the proportion of adequately treated cardio-metabolic comorbidities, the rate of adverse CVD events as well as the CVD mortality dramatically decrease in patients with NAFLD [15,16].
Thus, optimal screening and management of cardiovascular comorbidities are imperative in this high-risk population and current liver-centered approaches need to be complemented by effective screening, diagnostic, and treatment strategies for cardiovascular comorbidities. Screening measures for CVD should include: i) evaluation of family history for CVD, smoking status, physical activity and alcohol consumption, ii) laboratory analysis of lipid levels (e.g., total cholesterol, low-density lipoprotein, triglycerides), glucose metabolism and glycemic control (e.g., fasting glucose, glycated hemoglobin) and renal function (e.g., glomerular filtration rate), iv) blood pressure measurement (preferred by office and 24-hour ambulatory blood pressure measurement in case of high normal office blood pressure or grade 1 hypertension to exclude masked or white coat hypertension), v) estimation of CVD risk by specific risk assessment models and scoring systems. Interestingly, FIB-4 as well as NFS have recently been shown to be predictive of all-cause and cardiovascular mortality [17].
Besides the important question “How should screening be performed?”, the question “Who should be screened? “ is also essential.
Screening programs should not only be carried out in adults, but also in children and adolescents.
Due to the ongoing global childhood obesity epidemic, it has become apparent, that NAFLD is also a major health problem in younger people with overweight or obesity and adversely affects the health of those individuals in the longterm.
Recent studies have clearly shown that children and young adults with biopsy-proven NAFLD had significantly higher rates of incident major adverse cardiovascular events later in life, including ischemic heart disease and congestive heart failure, when compared with matched controls without NAFLD [18]. In addition, children with NAFLD are at potentially higher risk for developing T2DM and dyslipidemia [19].
As metabolically unhealthy children will grow up into cardiometabolic ill adults when they get older, NAFLD screening measures should already be implemented in the pediatric population (e.g., school entry medical examination programs) to mitigate the incoming wave of young multimorbid NAFLD patients.
Although progression to end-stage liver disease generally takes decades, without selective measures there will be a substantial burden of liver disease and other cardiometabolic diseases in 50-year-olds in the near future.
In the debate on “who should be screened”, it is also important to establish specific cut-off values of the proposed non-invasive scoring systems.
Liver biopsy can securely be replaced only with a stepwise combination of noninvasive tests, otherwise the assessment of risk due to advanced fibrosis may be misleading in a clinically meaningful proportion of patients [20]. It is along that line that we believe a low positive predictive value and high false-positive rate can be tolerated [21]. Hence, even lower FIB-4 cut-off values, e.g., 1.0, may be more appropriate for screening purposes as proposed by Shah and colleagues [22]. Using the traditional FIB-4 cut-off of 1.3, the specificity for advanced fibrosis has been found to be unacceptably low in patients aged ≥65 years, and Zhang et al. have adopted the threshold of 2.0 for use in these patients as has been previously proposed [23].
When focusing upon the question “Who should perform screening?”, the task will now be to prime frontline primary care physicians for the projected NAFLD burden, who predominantly care for these patients in everyday clinical practice.
In addition to medical education programs, which must be established in order to train the practitioners in the detection of NAFLD patients, school education campaigns must also be created and superordinate structures (e.g., insurance companies, healthcare authorities, policy maker) must support the financing and implementation of such health programs. NAFLD screening requires multidisciplinary care and can only succeed with a multistakeholder approach. If the framework conditions are not optimal, every planned screening measure will fail.
In concrete terms, all users of screening measures must be provided with uniform algorithmic approaches including practical recommendations which can be used in everyday clinical practice. Here, it should be noted that primary noninvasive risk assessment tools and scoring systems (e.g., fatty liver index, FIB-4 index) can actually be used on a broad scale in the outpatient sector, since instrument-based procedures such as elastography are not broadly available in primary care. A provision of health services must be created where frontline primary care physicians can easily and effectively identify patients with NAFLD by using simple tools with further diagnostic evaluation of disease severity provided by specialized facilities.
Ultimately, it is also important that screening measures do not have to take place just once, but at regular intervals, for example as part of health insurance-based preventive programs.
In conclusion, given the growing global NAFLD burden, holistic screening approaches for NAFLD are needed, including a comprehensive assessment of important (cardiovascular) diseases beyond the degree of liver damage. Furthermore, successful implementation of screening measures requires an improvement in awareness of the health risks of NAFLD, which can only be achieved through the concerted action of different healthcare stakeholders.

FOOTNOTES

Authors’ contributions
PK wrote the manuscript, MD and HMS revised the manuscript critically for important intellectual content.
Conflicts of Interest
The authors have no conflicts to disclose.

Abbreviations

NAFLD
non-alcoholic fatty liver disease
NASH
non-alcoholic steatohepatitis
T2DM
type 2 diabetes
FIB-4
fibrosis-4
NFS
NAFLD fibrosis score
CVD
cardiovascular diseases

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