Redefining fatty liver as metabolic dysfunction-associated steatotic liver disease: Implications of nomenclature changes for patients with diabetes

Abstract

The evolving nomenclature from non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated steatotic liver disease (MASLD) aims to better encompass the metabolic context of the disease. This change has significant implications for patients with type 2 diabetes mellitus (T2DM), given the frequent overlap between these conditions. This minireview explores the rationale behind the change, compares diagnostic criteria, and evaluates the impact of the MASLD framework on disease prevalence, characterization, and outcomes in T2DM patients. The updated MASLD criteria include all individuals with T2DM and hepatic steatosis, emphasizing metabolic dysfunction as the primary driver. In contrast, the NAFLD definition necessitates excluding other chronic liver diseases and verifying the absence of significant alcohol consumption, leading to a narrower diagnostic framework. Both metabolic dysfunction-associated fatty liver disease and MASLD identify a higher prevalence of steatotic liver disease, particularly among T2DM patients, compared to NAFLD. Notably, the MASLD framework introduces metabolic and alcohol-associated liver disease to account for dual etiologies involving alcohol use, which is common in T2DM populations but previously excluded under NAFLD criteria. While the new definitions enhance clinical relevance and inclusivity, they also highlight challenges such as unrecognized medication-induced steatosis and the need for reclassification in ongoing T2DM clinical trials. Emerging evidence supports enhanced screening strategies (e.g., fibrosis-4) and metabolic-targeted treatments for MASLD in T2DM patients. The successful integration of MASLD into clinical practice will require system-wide reeducation, standardization, and multidisciplinary collaboration to improve outcomes for T2DM patients.

Key Words: Non-alcoholic fatty liver disease; Fatty liver; Diabetes mellitus; Metabolic dysfunction-associated steatotic liver disease; Type 2 diabetes mellitus

Core Tip: The transition from non-alcoholic fatty liver disease to metabolic dysfunction-associated steatotic liver disease refocuses diagnosis on metabolic dysfunction, capturing a broader spectrum of patients with type 2 diabetes mellitus and hepatic steatosis. Metabolic dysfunction-associated steatotic liver disease and its related category, metabolic and alcohol-associated liver disease, improve disease recognition, prevalence estimation, and management strategies compared to non-alcoholic fatty liver disease. This minireview highlights the clinical implications of these changes, including the need for reclassification in trials, metabolic-targeted treatments, and multidisciplinary approaches to enhance screening and outcomes in type 2 diabetes mellitus populations.

INTRODUCTION

Steatotic liver disease (SLD) is defined by an excessive hepatic fat accumulation and evidence of steatosis based on imaging or histology[1]. Non-alcoholic fatty liver disease (NAFLD) has long been recognized as a leading cause of chronic liver disease worldwide, with its prevalence closely mirroring the rise in obesity and type 2 diabetes mellitus (T2DM)[2]. The pooled prevalence of NAFLD in both the United States and worldwide is approximately 30%, reflecting a more than 50% increase from 1990-2006 to 2016-2019[3]. Similarly, the prevalence of obesity among United States adults increased from 30.5% in 1999-2000 to 41.9% in 2017-2020, while the prevalence of diabetes increased from 10.2% in 2012 to 12.1% in 2022[4,5].

The presence of SLD is a known risk factor for the development of T2DM, while existing diabetes contributes to the progression of SLD into more advanced stages, including steatohepatitis, cirrhosis, and hepatocellular carcinoma[6]. Although hepatic steatosis is closely related to obesity and diabetes, the exclusionary diagnostic criteria of NAFLD, which require excluding other chronic liver diseases and significant alcohol consumption, often result in diagnostic challenges and potential underestimation of the true burden of disease[7]. In response, a multisociety Delphi consensus proposed a change in nomenclature from NAFLD to metabolic dysfunction-associated SLD (MASLD) in late 2023, aiming to shift the focus towards metabolic dysfunction as the primary driver while also mitigating potential stigmatization of “fatty liver”[8]. This change is particularly relevant for T2DM patients, who frequently present with metabolic and hepatic abnormalities[9].

RATIONALE BEHIND THE TRANSITION TO MASLD

The MASLD nomenclature was proposed to address some limitations inherent to the NAFLD definition: (1) Inclusivity of metabolic dysfunction: Unlike NAFLD, MASLD does not necessarily require exclusion of other liver diseases or alcohol use, instead focusing on the presence of metabolic dysfunction. When hepatic steatosis is present, identifying any cardiometabolic risk factor supports a diagnosis of MASLD; and if other contributing factors are present, the steatosis is considered to have a combined etiology[10]. The increasing prevalence of MASLD underscores its frequent coexistence with other chronic liver diseases, challenging the approach of diagnosing it solely by excluding other conditions[11,12]. This makes the diagnosis more applicable to real-world clinical scenarios; (2) Clinical relevance: The emphasis on metabolic derangements aligns better with the pathophysiological mechanisms underlying SLD, particularly in populations with T2DM and obesity[9]; (3) Simplification of diagnosis: By using positive criteria, such as evidence of hepatic steatosis combined with T2DM, overweight/obesity, or metabolic dysregulation, MASLD facilitates earlier and more straightforward identification of at-risk individuals[12,13]; and (4) Avoiding stigma: One of the major motivations for the nomenclature change was to eliminate potentially stigmatizing language; specifically, to move away from terms like “fatty” or “alcoholic”[14]. Although the term metabolic dysfunction-associated fatty liver disease (MAFLD) shifts the focus toward metabolic dysfunction rather than the exclusion of alcohol use, it still retained the stigmatizing label “fatty”[7]. However, perceptions of NAFLD-related stigma vary widely among patients, healthcare providers, regions, and medical sub-specialties[14].

COMPARISON OF DIFFERENT DIAGNOSTIC CRITERIA

The diagnostic frameworks for NAFLD, MAFLD, MASLD, and metabolic and alcohol-associated liver disease (MetALD) differ significantly (Figure 1). The diagnosis of NAFLD requires evidence of hepatic steatosis through histological examination, imaging, or blood biomarkers in the absence of other liver diseases, and verification of minimal alcohol consumption[15]. In contrast, the criteria for MAFLD also include the presence of hepatic steatosis but emphasizes the necessity of metabolic factors for diagnosis. These metabolic risk factors, according to the MAFLD guidelines, include T2DM and overweight/obesity (body mass index ≥ 25 kg/m² in Caucasians or ≥ 23 kg/m² in Asians)[10]. For individuals with a normal weight and no diabetes, the MAFLD diagnosis requires the presence of at least two of the seven risk factors, which include waist circumference, blood pressure, plasma triglycerides, plasma high-density lipoprotein-cholesterol, prediabetes, insulin resistance (IR), and plasma high-sensitivity C-reactive protein[10]. Table 1 outlines the definitions of the metabolic parameters and their incorporation into the MAFLD and MASLD consensus statements.

Figure 1 The diagnostic frameworks for non-alcoholic fatty liver disease, metabolic dysfunction-associated fatty liver disease, metabolic dysfunction-associated steatotic liver disease, and metabolic and alcohol-associated liver disease differ significantly. ALD: Alcohol-associated liver disease; HBV: Hepatitis B virus; HCV: Hepatitis C virus; NAFLD: Non-alcoholic fatty liver disease; MAFLD: Metabolic dysfunction-associated fatty liver disease; MetALD: Metabolic and alcohol-associated liver disease; MASLD: Metabolic dysfunction-associated steatotic liver disease; T2DM: Type 2 diabetes mellitus; HDL: High-density lipoprotein; BMI: Body mass index; WC: Waist circumference; HOMA-IR: Homeostatic model assessment for insulin resistance.

Table 1 Definitions for metabolic risk factors and their incorporation into the metabolic dysfunction-associated fatty liver disease and metabolic dysfunction-associated steatotic liver disease consensus statements.

Metabolic risk factors	Definition	MAFLD	MASLD
Body mass index	≥ 25 kg/m2 in Caucasians or ethnicity adjusted	Yes	Yes
Diabetes	According to widely accepted international guidelines	Yes	Yes
Waist circumference	Elevated measures in Caucasians or ethnicity adjusted	Yes; ≥ 102/88 cm in Caucasian men and women	Yes; ≥ 94/80 cm in Caucasian men and women
Blood pressure	≥ 130/85 mmHg or specific drug treatment	Yes	Yes
Plasma triglycerides	≥ 150 mg/dL or specific drug treatment	Yes	Yes
Plasma HDL-cholesterol	< 40 mg/dL for men and < 50 mg/dL for women or specific drug treatment	Yes	Yes
Prediabetes	Fasting glucose levels 100 mg/dL to 125 mg/dL, or 2-hour post-load glucose levels 140 mg/dL to 199 mg/dL or HbA1c 5.7% to 6.4%	Yes	Yes
Homeostasis model assessment of insulin resistance score	≥ 2.5	Yes	No
Plasma high-sensitivity C-reactive protein level	> 2 mg/L	Yes	No

HDL: High-density lipoprotein; MASLD: Metabolic dysfunction-associated steatotic liver disease; MAFLD: Metabolic dysfunction-associated fatty liver disease; HbA1c: Glycated hemoglobin.

Concerns were raised regarding the term MAFLD, particularly its requirement of at least two metabolic risk factors and its lack of consideration for regular alcohol consumption[16]. To address these limitations, the term MASLD was introduced, broadening the definition to include individuals with at least one of five cardiometabolic risk factors[8]. Additionally, a new category, MetALD, was established to describe individuals who meet the criteria for MASLD but also consume moderate to high amounts of alcohol (140-350 g/week for females and 210-420 g/week for males)[8]. Alcohol consumption exceeding 350 g/week in females and 420 g/week in males is generally considered to indicate predominantly alcoholic liver disease. Lastly, as opposed to the MAFLD consensus, the newer MASLD consensus excludes serum biomarkers, such as the fatty liver index, from its diagnostic algorithm, relying instead on imaging or liver biopsy for detection of steatosis[8,10].

IMPLICATIONS FOR T2DM PATIENTS

The MAFLD and MASLD criteria emphasize unique phenotypic and metabolic features of SLD, such as IR measured by homeostatic model assessment, as well as the presence of prediabetes and diabetes[7,8]. This metabolically focused approach reveals a higher prevalence of MAFLD compared to NAFLD. A recent meta-analysis estimated an overall MAFLD prevalence of 39.2%, compared to 33.9% for NAFLD[17]. Moreover, patients with MAFLD were significantly more likely to have diabetes than those with NAFLD[17,18]. A longitudinal cohort study revealed a 68.9% (n = 2032) increase in the diagnosis of steatotic liver among individuals with T2DM following the transition to MAFLD[19]. This increase is closely linked to the high global prevalence of T2DM, affecting around 6.3% of the population worldwide[20]. Additionally, it is estimated that around 10%-25% of patients with T2DM consume alcohol, which may have been excluded or overlooked under the previous NAFLD criteria[21,22].

Another meta-analysis adopting the MASLD terminology reported a prevalence of 39.4% in the general population and 68.7% among individuals with T2DM[23]. Based on a study using NHANES data, both MAFLD and MASLD were associated with a similar increased risk of all-cause mortality [adjusted hazard ratio (aHR) = 1.18, 95% confidence interval (CI): 1.04-1.33 for MAFLD and 1.19, 95%CI: 1.06-1.34 for MASLD], but MASLD identified a slightly larger number of individuals compared to MAFLD[24]. Another study comparing MASLD and NAFLD found a high concordance in both prevalence and outcomes, although approximately 5% of individuals classified as having NAFLD did not meet the diagnostic criteria for MASLD[25]. This included diabetes-related mortality rates of 1.37 and 1.45 per 1000 person-years in NAFLD and MASLD, respectively, along with diabetes prevalence rates of 18.3% and 19.3%[25]. A prospective cohort study showed that, compared to non-NAFLD/MAFLD/MASLD individuals, those with pure MAFLD or pure MASLD had a significantly increased risk of developing diabetes (hazard ratio = 4.803, 95%CI: 3.518-6.557 and 4.904, 95%CI: 2.384-10.086; respectively), while the pure NAFLD group did not show an increased risk[26]. This highlights that the newer diagnostic criteria may more accurately identify individuals at higher risk for diabetes during a mean follow-up of six years[26].

With a more comprehensive diagnostic criteria, it is expected that an increasing number of patients will present with dual (or multiple) etiologies of SLD. Studies show that 39% of non-viral advanced liver disease cases are associated with a combination of metabolic risk factors and moderate alcohol consumption[27]. A recent study evaluated MAFLD patients with significant alcohol consumption and found they exhibited more hepatic steatosis compared to those with MAFLD without coexisting liver disease[28]. While MAFLD embraces a dual etiology framework with alcohol consumption, the MASLD classification introduces the term MetALD to describe individuals with both metabolic dysfunction and excessive alcohol consumption, a condition with an estimated prevalence of 2.5% based on NHANES 2017-2020 data[29]. In both frameworks, the associations of different etiologies can be broadly assessed, as the previous NAFLD criteria required exclusion of coexisting liver diseases. A meta-analysis found that approximately one in eight individuals with alcohol use disorders also has T2DM, with a prevalence of 12.4%[30]. This is particularly important as alcohol consumption has been shown to impair blood sugar control, leading to worse outcomes especially for individuals with MetALD and MASLD who consume alcohol[21].

Different studies have been conducted to evaluate the outcomes of patients with MAFLD. T2DM patients classified as MAFLD(+)/NAFLD(-) demonstrated a higher risk of advanced fibrosis, major adverse cardiovascular events, and both all-cause and cardiovascular-related mortality compared to those classified as MAFLD(+)/NAFLD(+)[19]. Kim et al[31] also revealed that individuals with MAFLD had a 17% higher risk of all-cause mortality, as NAFLD alone did not increase the risk of all-cause mortality. Zhao and Deng[32] reported that both MASLD (aHR = 1.127, 95%CI: 1.056-1.201) and MAFLD (aHR = 1.102, 95%Cl: 1.028-1.182) were independently and simultaneously associated with an increased risk of all-cause mortality. Since the diagnostic criteria for NAFLD do not actively include IR or hyperglycemia, the broader definitions of MAFLD and MASLD may be more strongly associated with all-cause mortality, potentially due to the systemic release of proinflammatory cytokines, dysregulated adiponectin levels, and increased oxidative and endoplasmic reticulum stress in patients with diabetes[31].

Although the new diagnostic criteria offer a more inclusive and clinically relevant framework, they do not account for other potential causes of SLD that may particularly occur in patients with T2DM. First, many medications can contribute to the development of SLD, including glucocorticoids, tamoxifen, aspirin, amiodarone, ibuprofen, and various antiretroviral drugs[33]. Patients with T2DM often take different medications, which may further increase the risk of developing or exacerbating SLD[34]. A Danish cohort study found that approximately 20% of patients with T2DM were using nonsteroidal anti-inflammatory drugs, while 7% were taking systemic glucocorticoids[34]. In some cases, rapid weight loss and starvation can also trigger the release of fatty acids from fat stores, which can be toxic to the liver and exacerbate the condition[35]. With advancements in T2DM treatment and weight loss strategies, these phenomena may occur in certain patients, potentially resembling MASLD.

However, the reclassification to MASLD can promote a more comprehensive therapeutic focus on the metabolic aspects of the disease. In the past, the standard approach to managing liver steatosis was largely limited to lifestyle modifications, including diet and exercise, and they remain fundamental interventions, specifically tailored to address metabolic dysfunction and diabetes[36]. However, emerging therapies targeting IR and diabetes show promise in advancing the management of liver steatosis, including tirzepatide and pioglitazone[37,38]. Furthermore, the heightened emphasis on the metabolic aspects of MASLD underscores the importance of vigilant screening for advanced liver fibrosis, particularly in high-risk populations such as those with T2DM. The joint guideline from the American Association for the Study of Liver Diseases and the American Association of Clinical Endocrinology recommends screening adults with T2DM for clinically significant fibrosis (F2-F4) using the fibrosis-4 index, regardless of normal liver enzyme levels[39].

CHALLENGES AND FUTURE DIRECTIONS

The adoption of MASLD criteria requires standardization across healthcare systems and re-education of clinicians and patients[40]. In the future, leveraging artificial intelligence and integrating clinical care pathways into electronic health records could greatly improve identification, screening, and treatment of T2DM patients. This approach would require a multidisciplinary team involving specialists such as endocrinologists, hepatologists, and primary care providers, as well as support from ancillary staff like patient navigators and registered dietitians to ensure comprehensive care. Additionally, integrating MASLD into existing clinical guidelines for diabetes management remains a work in progress, as the 2024 American Diabetes Association guidelines continued to use the term NAFLD[41]. As highlighted by the MASLD consensus, further initiatives are needed to subphenotype patients with MASLD, aiming to enhance precision patient management and establish effective pathways between primary care and liver clinics. These features underscore the need for further targeted risk stratification and management in T2DM patients with MASLD (Figure 2).

Figure 2 Challenges and future directions. AI: Artificial intelligence; EHRs: Electronic health records; T2DM: Type 2 diabetes mellitus; MASLD: Metabolic dysfunction-associated steatotic liver disease; NAFLD: Non-alcoholic fatty liver disease.

Although the NAFLD, MAFLD, and MASLD share common disease features, they are distinct and do not represent the same population[42]. This distinction carries significant implications for future research and the design of clinical trials. Numerous published and ongoing clinical trials evaluate the effects of anti-diabetic agents on NAFLD[38,43]. A change in nomenclature could significantly impact the inclusion criteria for many of these trials and potentially delay the approval of effective therapies for SLD[44]. With different inclusion criteria, further studies are needed to validate previous findings on therapeutic interventions and biomarkers within the newly defined MASLD population.

CONCLUSION

The evolution from NAFLD to MAFLD and now MASLD represents a significant change in the understanding of SLD and IR. By emphasizing the metabolic context, MASLD provides a more inclusive and clinically relevant framework, particularly for patients with T2DM. This shift holds promise for improving disease recognition, risk stratification, and targeted management among T2DM patients. However, successful implementation requires continued research, clinician education, and integration into broader public health initiatives.