Introduction
Non-alcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease globally. In China, it is the leading cause of hepatic disease, with a significantly increasing prevalence estimated to be 29.6%.1 This global rise constitutes a public health issue and is often attributed to modern lifestyles and the alarmingly increasing worldwide rates of obesity.
Consequently, in recent years, NAFLD has gained considerable scientific attention, with several newly published recommendations to guide diagnosis and patient management.2 Intense research has raised further questions regarding the criteria for definition, the spectrum of the disease, and the optimal methods of diagnosis and treatment. At the same time, different scientific societies have introduced new terms to address the subtypes of steatotic liver disease.
Recently, the Chinese Society of Hepatology and the Chinese Medical Association published a Guideline for the Prevention and Treatment of Metabolic Dysfunction-associated Fatty Liver Disease (MAFLD).3 This Guideline provides clear definitions, indicates which patients should be screened to increase diagnosis rates, suggests an algorithm for diagnostic assessment, and summarizes the available therapeutic interventions. Most importantly, it provides an opportunity to raise awareness among non-experts regarding the significance of early diagnosis and the efficient management of the continuously increasing population with steatotic liver disease.
The aim of this commentary was to provide a brief review of this recently published Guideline,3 highlight the most important clinical points, and determine future directions.
Definitions and terminology
According to the Guideline,3 the general term “fatty liver disease” (FLD) encompasses all heterogeneous diseases characterized by the presence of diffuse fatty liver on imaging techniques or histological features of significant macrovesicular steatosis. The term MAFLD is also introduced to describe chronic metabolic stress-induced liver disease caused by over-nutrition and insulin resistance in genetically susceptible individuals. In the Guideline,3 the terms MAFLD and the new term “metabolic dysfunction-associated steatotic liver disease” (MASLD) proposed by the recent Delphi Consensus2 can be translated as “代谢相关脂肪性肝病” in Chinese. It should be noted that the main difference between MAFLD/MASLD and the previous term NAFLD4 is primarily based on their diagnostic criteria and emphasis on metabolic dysfunction (Table 1). In the Guideline,3 the diagnosis of MAFLD, similarly to MASLD,2 requires steatotic liver disease defined by imaging techniques or histology, in the presence of one or more cardiometabolic risk factor(s) and the absence of other causes of FLD, including harmful alcohol intake.2,3
Table 1Comparison of previous and current international scientific guidelines for steatotic liver disease
| 2016 EASL-EASD-EASO Clinical Practice Guidelines for NAFLD4 | 2023 EASL–EASD–EASO Clinical Practice Guidelines for MASLD2 | 2024 Chinese Guideline for MAFLD3 |
|---|
| Definition | Hepatic steatosis; Exclusion of daily alcohol consumption ≥ 30 g for men and 20 g for women; Exclusion of secondary causes | Hepatic steatosis; At least one cardiometabolic factor; Exclusion of other causes for steatosis including alcohol consumption >30 g for males and >20 g for females and other causes of secondary steatosis | Hepatic steatosis; At least one cardiometabolic factor; Exclusion of causes for secondary steatosis including daily alcohol consumption ≥ 30 g for men and 20 g for women; Possible coexistence of MAFLD with other causes of steatotic disease (i.e. ALD) |
| Definition of metabolic syndrome | Any three of the following five features associated with insulin resistance: 1) Waist circumference ≥94 cm for men and ≥80 cm for women (Europid); 2) Arterial pressure ≥130/85 mmHg or treatment for hypertension; 3) Fasting glucose ≥100 mg/dl (5.6 mmol/L) or treatment for type 2 diabetes mellitus (T2DM); 4) Serum triacylglycerols >150 mg/dl (>1.7 mmol/L); 5) HDL cholesterol <40 mg/dl for men and <50 mg/dl for women (<1.0 mmol/L for men and <1.3 mmol/L for women) | At least three of the following criteria: 1) Body mass index (BMI); >−25 kg/m2 (>−23 kg/m2 in people of Asian ethnicity) Abdominal obesity: Waist circumference >94 cm in men and >80 cm in women (Europeans); >90 cm in men and >80 cm in women (South Asians and Chinese); >85 cm in men and >90 cm in women (Japanese); or >102 cm in men and >88 cm in women; 2) Elevated triglycerides: >1.7 mmol/L (>150 mg/dL) or on treatment for elevated triglycerides; 3) Reduced HDL cholesterol: <1.0 mmol/L (<39 mg/dL) in men and <1.3 mmol/L (<50 mg/dL) in women or on treatment for reduced HDL cholesterol; 4) Elevated blood pressure: >130/85 mmHg or on treatment for hypertension; 5) Prediabetes: HbA1c 39–47 mmol/mol (5.7–6.4%) or fasting plasma glucose 5.6–6.9 mmol/L (100–125 mg/dl) or 2-h plasma glucose during OGTT 7.8–11 mmol/L (140–199 mg/dl) or Type 2 diabetes: HbA1c >−48 mmol/mol (>−6.5%) or fasting plasma glucose >−7.0 mmol/L (>−126 mg/dl) or 2-h plasma glucose during OGTT >−11.1 mmol/L (>−200 mg/dl) or Treatment for type 2 diabetes | Three or more of the following conditions: 1) Overweight/Obesity: BMI ≥ 24.0 kg/m2, or waist circumference ≥ 90 cm (male) and ≥ 85 cm (female), or excessive body fat content and percentage; 2) Blood pressure ≥ 130/85 mmHg, or undergoing antihypertensive medication therapy; 3) Dysglycemia or Type 2 Diabetes Mellitus: Fasting plasma glucose ≥ 6.1 mmol/L, or 2-h postprandial plasma glucose ≥ 7.8 mmol/L, or HbA1c ≥ 5.7%, or history of type 2 diabetes mellitus, or HOMA-IR ≥ 2.5; 4) Plasma Triglycerides (TG): Plasma TG ≥ 1.70 mmol/L, or undergoing lipid-lowering medication therapy; 5) HDL-Cholesterol: Plasma HDL-cholesterol ≤ 1.0 mmol/L (male) and 1.3 mmol/L (female), or undergoing lipid-lowering medication therapy |
| Criteria for screening: | Insulin resistance and/or metabolic risk factors (i.e., obesity or metabolic syndrome | 1) T2DM; 2) Abdominal obesity and ≥1 additional metabolic risk factor(s); 3) Persistently elevated liver enzymes | 1) Obesity (for Asians BMI ≥ 28 kg/m2); 2) T2DM; 3) Metabolic syndrome characterized by three or more cardiometabolic risk factors or 4) Elevated serum aminotransferases without symptoms |
| Alcohol consumption | Exclusion of excessive alcohol consumption or harmful alcohol use | 1)Introduction of MetALD: alcohol consumption is 20–50 g/day in women and 30–60 g/day in men + ≥1 cardiometabolic factor; 2)ALD when alcohol consumption is >50 g/day in women and >60 g/day in men regardless of cardiometabolic criteria | If alcohol consumption is ≥ 210g /week in men and ≥ 140g/week in women combined with obesity/T2DM/ Metabolic syndrome, the diagnosis is MAFLD and ALD (mixed etiology of steatotic disease) |
Another key point regarding the definitions provided in the Guideline3 is the reference to the possible mixed etiology of FLD in cases of chronic liver disease caused by two or more coexisting factors. The scenario of coexisting liver-toxic factors [e.g., obesity, type 2 diabetes mellitus (T2DM), alcohol] should always be examined based on the detailed history of the patient. This is in accordance with the recently published Clinical Practice Guidelines by the European Association for the Study of the Liver on the management of MASLD, where the term “metabolic dysfunction and alcohol-related liver disease” (MetALD) was introduced to describe hepatic disease associated with the combined effect of excessive alcohol and metabolic disorder.2
Screening and diagnosis
Who should be screened for MAFLD?
Any patient with: 1) obesity [for Asians, body mass index (BMI) ≥ 28 kg/m2], 2) T2DM, 3) metabolic syndrome characterized by three or more cardiometabolic risk factors, or 4) elevated serum aminotransferases without symptoms should be screened for MAFLD and liver fibrosis.3 The above criteria are adjusted to the characteristics of the Chinese population with MAFLD to achieve optimal sensitivity for screening,3 since, according to epidemiological data from China, the prevalence of NAFLD was 66.2% and 51.8% among obese individuals and those with T2DM, respectively.1 Moreover, in a study by Zhang et al., the hazard ratio for MAFLD was estimated to be higher for patients with three metabolic components [hazard ratio 3.51 (95% confidence interval 3.15, 3.91)] compared to patients with fewer than three or none.5 Obesity, T2DM, and the presence of three metabolic factors have also been associated with a higher risk for advanced fibrosis.6 Consequently, the application of these screening criteria in the Chinese population will facilitate the identification of individuals with MAFLD and those at higher risk for liver-related complications.
On the other hand, the European guidelines2 suggest screening in: a) patients with T2DM, b) when abdominal obesity (based on waist circumference) coexists with at least one cardiometabolic factor regardless of its type, and c) in case of abnormal liver tests (Table 1). These criteria have been associated with a higher risk for hepatic fibrosis and liver-related outcomes, and aim to identify patients at risk for these complications.7,8
The importance of alcohol consumption
Another interesting point is that, according to the Chinese Guideline,3 excessive alcohol consumption is the first factor that should be ruled out before further investigation of a patient with a possible MAFLD diagnosis. The cut-off values for the definition of excessive alcohol consumption are similar to the respective cut-offs used for the definition of MetALD in the European Guidelines (≥210 g/week for men and ≥140 g/week for women). In general, a detailed history of both current and past alcohol consumption in every patient with FLD is required in the latest Guidelines worldwide.3,9 This approach highlights the significant effect of alcohol on liver function and the importance of accurate quantification of alcohol use. It is interesting to note that alcohol abuse rates have rapidly increased in the Chinese population in the last two decades,1 while it has been proven that even moderate alcohol consumption may worsen the prognosis of patients with MAFLD.10
How can we assess hepatic fibrosis?
The preferred methods for the assessment of liver damage and fibrosis in patients with an initial diagnosis of MAFLD are the non-invasive fibrosis scores, which can be used as a primary screening tool. The diagnostic algorithm is common among different international guidelines2,3 and is based on the fact that blood biomarker-derived scores [specifically the fibrosis-4 index] and elastography should be used to exclude advanced fibrosis, while elastography is more suitable for predicting advanced fibrosis and identifying patients at increased risk for liver-related complications who need more aggressive treatment and stricter follow-up.
Liver-related complications
Hepatic decompensation and hepatocellular carcinoma (HCC) are the main liver-related complications of MAFLD. Patients with advanced fibrosis or cirrhosis are at increased risk for both and should be followed closely in specialized centers. Surveillance is typically based on biannual ultrasound examinations, but since the cost of computed tomography and magnetic resonance imaging is decreasing in China, both techniques can be performed when necessary. Interestingly, MAFLD-associated HCC can develop in the absence of cirrhosis in 30–50% of cases.11 This is why the inclusion of patients with advanced (F3) fibrosis in HCC surveillance, as suggested by the Chinese Guideline, is of great importance.3 Patients with F3 fibrosis constitute a borderline population and are not always included in HCC screening protocols. Nevertheless, it should be noted that the definitive diagnosis of the F3 fibrosis stage is often challenging when histological results are not available, making the need for reliable non-invasive tests for this population compelling.
Patient management and treatment
As previously mentioned, the key concept for the management of patients with MAFLD is a multidisciplinary approach. The available therapies aim to reduce body weight, improve insulin resistance, manage metabolic syndrome and T2DM, alleviate liver inflammation, and reverse fibrosis. These therapies can be categorized into: a) lifestyle modifications, b) pharmacological therapy, and c) surgical interventions (bariatric surgery) (Fig. 1). Incretin-based treatments are specifically recommended as weight-loss medications for MAFLD patients with T2DM and/or BMI > 28 kg/m2.3 Finally, all patients with decompensated disease should be evaluated for liver transplantation.
Which treatments can reverse fibrosis?
Among the available therapeutic approaches for MAFLD, weight loss > 10%, bariatric surgery, and a few pharmacological treatments have been associated with improvements in fibrosis. Specifically, resmetirom, a recent FDA-approved agent for non-cirrhotic patients with MAFLD and significant fibrosis, has demonstrated histological efficacy in reducing steatohepatitis and fibrosis.12 Interestingly, there are numerous effective treatments for the components of metabolic syndrome (T2DM, obesity, hypertension, dyslipidemia) that may have a beneficial effect on MAFLD if offered before the development of fibrosis. However, there is a need for more treatments that can reverse significant liver damage once it is established. Fortunately, several agents have shown promising results in this field, and the results from phase 3 studies are expected to further elucidate these possibilities, as discussed below.
Future directions
Considering the increasing prevalence of MAFLD, national policies should be deployed to create points of care where screening and diagnosis can be performed widely using accessible and efficient methods. The efficient identification of high-risk patients based on the proposed criteria is crucial to increasing diagnosis rates. Specific referral pathways should also exist to connect patients to specialized centers when indicated, while different specialties should be engaged in the cascade of treatment to achieve multidisciplinary management.
The elucidation of predisposing factors (genetic and environmental) for the development of MAFLD and the progression of fibrosis is also needed. A personalized risk stratification system for liver-related outcomes and HCC occurrence should be developed, especially for non-cirrhotic patients. The different impacts of each cardiometabolic factor on disease progression should be taken into account for patient prognosis and prioritized treatment. It is known that T2DM, abdominal obesity, male gender, age > 50 years, persistently elevated liver enzymes, and genetic factors (patatin-like phospholipase domain-containing protein 3, the variant p.I148M, and Transmembrane 6 superfamily member 2) are associated with fibrosis progression.2 Specifically, in the Asian population, where the prevalence of lean MAFLD is higher, the BMI cut-off of <23 kg/m2 (for lean MAFLD) is currently questioned due to the intense westernization of the Asian lifestyle and the increasing prevalence of metabolic syndrome in recent years.13 However, we have not yet fully understood individual susceptibility to MASLD and the specific determinants of fibrosis progression to achieve optimal risk stratification. The role of alcohol in the natural course of MAFLD should also be clarified since a significant proportion of the MAFLD population consumes increased amounts.14 Conversely, a significant proportion of patients with alcohol-related liver disease have metabolic syndrome,14 while alcohol consumption may worsen metabolic dysfunction by increasing blood pressure and triglycerides.15 It has been proven that the combined effect of alcohol and metabolic dysfunction negatively affects patient prognosis and requires combined therapeutic interventions.14 In this direction, determining optimal cut-off values for alcohol consumption and developing accurate quantification methods are of great importance.10 The quantification of alcohol consumption is often based on self-reporting questionnaires, such as the Alcohol Use Disorders Identification Test or the Lifetime Drinking History, but the reports may not be precise and could be biased due to memory issues or underestimation of consumption.16 The recently introduced blood phosphatidylethanol (PEth) test as a marker of drinking patterns and chronicity could contribute to accurate diagnosis.17 A recent head-to-head study showed that PEth offers significantly superior accuracy in detecting MetALD among patients with SLD compared to traditional questionnaires.16 Moreover, a recent position statement for MetALD suggests serial PEth testing over three months to efficiently capture alcohol use.9 Specific patient characteristics, such as ethnicity (Asian vs. non-Asian), gender, and socioeconomic factors, should also be considered when evaluating drinking habits and planning lifestyle modifications.14 Patient management and therapeutic interventions should be adjusted and individualized based on these factors.
Non-invasive fibrosis scores have gained significant ground in the management of MAFLD, so they should be thoroughly validated, associated with histological results, and eventually implemented in clinical trials for therapeutic agents as surrogate markers of response and hard clinical outcomes. The standardization of existing, easy-to-access, and cost-effective scores, and perhaps the development of new ones, especially for the F3 population, will facilitate diagnosis and allow the active involvement of non-experts in the cascade of patient management.
Regarding therapy, a number of clinical trials are underway to evaluate the effect of glucagon-like peptide-1 (GLP-1) mono- or dual/triple agonists and other agents such as sodium-glucose transport proteins inhibitors in patients with fibrosis stage 2 or 3.18–20 GLP-1 agonists have shown potential benefits in reducing liver fat and improving fibrosis,18 especially when combined with substantial weight loss. Furthermore, there are promising results from the dual agonist of the glucose-dependent insulinotropic polypeptide and GLP-1 receptors (e.g., tirzepatide) and the dual agonist of glucagon and GLP-1 receptors (e.g., survodutide).19 Additional results are expected from phase 3 trials (Table 2). Recently, efruxifermin, a Fibroblast growth factor 21, showed significant anti-fibrotic effects in MAFLD patients (Table 2).20
Table 2Ongoing phase 3 clinical trials for metabolic dysfunction-associated fatty liver disease
| Drug | Mechanism of action | Fibrosis stage | Study name | Size | End date (estimated) |
|---|
| Resmetirom | THR-β agonist | F1-F3 | MAESTRO-NASH (NCT03900429) | 2,000 | 1/2028* |
| Semaglutide | GLP-1 agonist | F2-F3 | ESSENCE (NCT04822181) | 2,000 | 4/2029* |
| Survodutide | GLP-1/Glucagon agonist | F2-F4 | LIVERAGE (NCT06632444) | 1,800 | 12/2031 |
| Efruxifermin | FGF-21 agonist | F4 | SYNCHRONY-Outcomes (NCT06528314) | 1,150 | 10/2029 |
| | F2-F3 | SYNCHRONY-Histology (NCT06215716) | 1,650 | 11/2032 |
| Pegozafermin | FGF-21 agonist | F2-F3 | ENLIGHTEN-Fibrosis (NCT06318169) | 1,050 | 2/2029 |
| | F4 | ENLIGHTEN-Cirrhosis (NCT06419374) | 762 | 8/2031 |
| Denifanstat | Fatty acid synthase inhibitor | F2-F3 | FASCINATE-3 (NCT06594523) | 1,260 | 12/2030 |
| | F1-F4 | FASCINIT (NCT06692283) | 2,000 | 6/2027 |
| Lanifibranor | PPΑR α, γ, δ agonist | F2-F3 | NATiV3 (NCT04849728) | 2,000 | 9/2026 |
MAFLD-associated healthcare costs are rising, especially for patients with advanced fibrosis and cirrhosis. MAFLD is globally responsible for the highest increase in disability-adjusted life years compared to other causes of liver disease.21 Lifestyle interventions are cheaper than more invasive therapies but offer long-term weight loss for fewer than 10% of patients. On the other hand, bariatric surgery is more expensive but highly effective, with sleeve gastrectomy estimated to be the most cost-effective among other surgical options.22 Regarding pharmaceutical treatments, a recent American study showed that the annual drug cost for a cost-effective NAFLD treatment should not exceed $12,000.23 Cost-effectiveness data for the new treatments are not currently available, but since their administration will likely be long-term, economically justifiable prices are needed to address the socio-economic burden of the disease.
Conclusively, there are initial positive results toward the improvement of steatosis and fibrosis, but ongoing trials will clarify if this improvement can be translated into a decrease in liver-related complications, improved cardiometabolic function, and better overall survival (Table 2). Moreover, since the proportion of patients that respond is still relatively low (one in three patients), additional strategies such as a combination of agents, identification of prognostic factors for treatment response, and perhaps longer durations of therapy19,20 are needed to maximize the therapeutic effect and ensure the safety profile. Regarding cirrhotic patients, the data on pharmacological treatments are scarce, and further investigation is needed. Finally, the cost of the new therapeutic agents is a concerning issue, as the prevalence of the disease is increasing, and its treatment may become a significant financial burden for health economics policy.
Declarations
Funding
None to declare.
Conflict of interest
EC has been an Associate Editor of Journal of Clinical and Translational Hepatology since 2023. The other author has no conflict of interests related to this publication.
Authors’ contributions
Article concept and design (EC), acquisition of data (MT, EC), analysis and interpretation of data (MT, WC), drafting of the manuscript (MT), critical revision of the manuscript for important intellectual content (EC), supervision (EC). All authors have made a significant contribution to this study and have approved the final manuscript.