Dear Editor,

Together with the global epidemic of obesity and type 2 diabetes mellitus (T2DM), metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most common chronic liver disease, affecting over 30% of the global population [1,2]. In terms of geographical regions worldwide, there are the highest incidence and the largest increase in the prevalence of MAFLD over the past two decades in China [3]. In response, the Chinese Society of Hepatology, Chinese Medical Association has recently updated the guideline for the prevention and treatment of MAFLD (version 2024) [4]. The purpose of this commentary is to highlight the new recommendations (Table 1) as well as the similarities and differences between the new Chinese guideline and other regional guidelines (Table 2)

There has been a debate on the nomenclature, definition, and classification of fatty liver disease in the past few years. In 2023, a multi-society consensus recommended the use of steatotic liver disease as the overarching term, while metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) would replace the old term nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) [5]. The Chinese guideline highlights that the Chinese translation of MAFLD and MASLD is identical and considers the two terms interchangeable. The diagnostic criteria of MAFLD/MASH, and the classifications of secondary, mixed etiology and cryptogenic fatty liver disease are largely similar between the Chinese guideline and international consensus. Subtle differences in the diagnostic criteria and overlap with other liver disease by various guidelines and consensuses are listed in Table 2. In patients with alcohol-related liver disease or secondary fatty liver, we suggest that the diagnosis of MAFLD should be based on the presence of T2DM, obesity or metabolic syndrome instead of one single cardiometabolic risk factor. This is because excessive alcohol consumption and some secondary causes (e.g., systemic corticosteroids) are known to cause high blood pressure, glucose, and lipids. Our view is similar to that of the Expert Panel on Alcoholrelated Liver Disease, which cautioned against the reliance of a single cardiometabolic risk factor to diagnose MASLD in this context [6].

One important new development in the MASLD nomenclature was the introduction of an entity titled MASLD with increased alcohol intake (MetALD) for men and women who consume 30–60 g and 20–50 g of alcohol per day, respectively [5]. Regardless of the severity of metabolic dysfunction, patients with alcohol consumption exceeding the above thresholds are classified as alcohol-related liver disease (ALD). In principle, the Chinese guideline considers it important that clinicians recognize that over-nutrition related metabolic dysfunction and harmful alcohol use can contribute to liver injury at the same time. One potential limitation of the MetALD-ALD distinction is that the contribution of cardiometabolic risk factors to the progression of ALD is downplayed. Therefore, instead of adopting the term MetALD, the Chinese guideline allows MAFLD to coexist with ALD for the following reasons: (1) Moderate alcohol consumption is known to increase serum triglycerides and blood pressure, independently of insulin resistance [7]. (2) In patients with heavy drinking and obesity/sarcopenic obesity or T2DM or metabolic syndrome, the term ALD ignores the contribution of metabolic factors to liver injury. (3) The quantification of alcohol consumption in routine clinical practice is inaccurate [8]. (4) Alcohol consumption can be dynamic, and a classification based on current alcohol consumption may result in changing disease labels over time, which could be confusing for both clinicians and patients [9]. The implementation of the classification of MetALD would require a consensus on the period of alcohol assessment and how to handle historical heavy drinking.

On top of metabolic dysfunction-associated simple fatty liver, MASH and metabolic dysfunction-associated cirrhosis, the Chinese guideline introduced the concept of metabolic dysfunction-associated liver fibrosis, defined by histological and noninvasive test evidence of significant or advanced fibrosis, regardless of the presence of elevated liver enzymes or MASH [4]. Similar to the American and multi-society European guidelines [10,11], the Chinese guideline recommends the use of Fibrosis-4 index (FIB-4) and liver stiffness measurement by transient elastography to assess clinical staging of MAFLD based on their availability and proven diagnostic and prognostic performance [12]. The FIB-4 cutoff of 1.3 is the threshold to trigger transient elastography or other fibrosis assessment, and it is recognized that a cutoff of 2.0 would yield fewer false-positive results in patients older than 65 years [13,14]. The Chinese guideline also recognizes the role of the FibroScan-aspartate aminotransferase score to detect “at-risk” MASH [15].

Both the Chinese and Western guidelines emphasize the multisystem nature of MAFLD, and the central role of weight reduction and glycemic control in the management of MAFLD. The Chinese guideline also covered the role of lipid lowering drugs, antihypertensives, antiplatelet drugs, and treatment of clinically significant portal hypertension in patients with the corresponding indications. Resmetirom, a thyroid hormone receptor-β agonist, achieved both MASH resolution and fibrosis improvement in the phase 3 MAESTRO-NASH study [16], and became the first approved drug by the US Food and Drug Administration for the treatment of MASH with F2-F3 fibrosis. Because resmetirom is yet to become available in China, the Chinese guideline recommends patients with “at-risk” MASH to consider hepatoprotectants such as silymarin or participate in clinical trials. The Chinese guideline highlights the importance of a multidisciplinary approach in the management of MAFLD, suggests the preferential use of cardiometabolic drugs benefit multiple organs including cardiovascular-kidney-liver diseases [17], and discusses the indications and precautions of metabolic surgery and liver transplantation.

In terms of treatment monitoring, the Chinese guideline emphasizes that the target should be an improvement in general health, with improvements in not only major adverse liver outcomes but also cardiovascular-kidney-metabolic diseases, and reduced risk for extrahepatic cancers. This should be accompanied by improvements in patient reported outcomes and health-related quality of life. The assessment should encompass lifestyle evaluation, anthropometric measurements, biochemical assays for liver-kidney-metabolic parameters, and noninvasive tests of hepatic steatosis and fibrosis. If a patient has over 5% weight reduction but no improvement in insulin sensitivity and other cardiometabolic parameters during follow-up, clinicians should consider the possibilities of sarcopenia, worsened glycemic control, thyrotoxicosis, and other catabolic conditions. In particular, sarcopenia is a well-recognized feature in patients with cirrhosis and is associated with increased mortality [18]. In patients with MASH, low body weight is associated with lower survival after liver transplantation [19]. In contrast, if a patient has weight reduction and improved cardiometabolic profile but there is no improvement in liver enzymes, concomitant liver insults such as underreported alcohol consumption, autoimmune liver diseases and hereditary liver diseases should be considered. Additionally, liver enzymes and hepatic steatosis can decrease in patients progressing to cirrhosis. Therefore, it is imperative to follow patients with noninvasive tests of liver fibrosis.

While international guidelines recommend surveillance for hepatocellular carcinoma (HCC) only in patients with cirrhosis or chronic hepatitis B infection together with highrisk features [20,21], the Chinese guidelines recommend HCC surveillance in patients with MAFLD and advanced fibrosis. As highlighted in the Baveno consensus, it is sometimes difficult to distinguish between advanced fibrosis and cirrhosis by noninvasive tests or even histology [22]. That is why the term compensated advanced chronic liver disease was introduced to highlight that it was a continuum. In the prospective NASH Clinical Research Network cohort, patients with advanced fibrosis did not have lower incidence of HCC than those with cirrhosis [23]. Additionally, abdominal ultrasonography and follow-up imaging such as computed tomography or magnetic resonance imaging can be performed at low costs in China, thus making a case for more liberal surveillance.

Finally, the Chinese guideline adopts local definitions of overweight, obesity, and central obesity based on ethnicspecific cutoffs for body mass index and waist circumference, and recommends the modified criteria of metabolic syndrome components (Table 2). Given that a significant proportion of MASH-related HCC can arise before the development of cirrhosis [24], liver cancer surveillance may be considered in patients with advanced fibrosis, especially as abdominal ultrasonography is relatively inexpensive and wide available in China.