A paradigm shift in the concept of fatty liver disease, from an exclusion-based definition to a positive, metabolism-focused diagnostic framework, is reflected in metabolic dysfunction-associated fatty liver disease (MAFLD)^[1-3]. Non-alcoholic fatty liver disease (NAFLD) was the previous exclusionary term in a number of overlapping terminologies. While Metabolic Dysfunction-Associated Steatohepatitis (MASH) refers to the histological entity of steatohepatitis within these frameworks, MAFLD and metabolic dysfunction-associated steatotic liver disease (MASLD) represent a more recent, positive diagnostic framework that emphasizes metabolic risk factors^[1,4]. Lean MAFLD (L-MAFLD), which has drawn more attention as a clinically significant and mechanistically unique subgroup, is one of the various phenotypes that may be recognized using this positive paradigm, which more accurately captures the variety of patients found in clinical practice^[1,5].

L-MAFLD is prevalent in a number of populations, defying the notion that a normal body mass index (BMI) indicates metabolic wellness. Its incidence in European cohorts is influenced by variations in body composition. Asian cohorts have demonstrated different metabolic thresholds for susceptibility and lower BMI cutoffs, which further suggests geographical diversity in disease manifestation^[5,6]. Visceral adeposity, poor adipose tissue growth, sarcopenia, and reduced metabolic flexibility are all distinctive characteristics of people with L-MAFLD. In the context of maintained body weight, these characteristics are prone to insulin resistance and hepatic fat accumulation^[6-8]. In addition to these systemic changes, this subgroup is more susceptible to steatosis and progressive liver injury due to genetic and epigenetic factors, most notably the Patatin-like phospholipase domain-containing protein 3 (PNPLA3)^[8-10].

L-MAFLD is neither a benign nor an attenuated form of MAFLD, and it should not be regarded simply as “MAFLD without obesity.” Rather, it represents a distinct metabolic phenotype driven by body-composition abnormalities and maladaptive responses. Although shared mechanisms - including insulin resistance, oxidative stress, mitochondrial dysfunction, and dysbiosis - operate across all phenotypes, in lean individuals these processes are disproportionately driven by an elevated visceral-to-subcutaneous fat ratio, sarcopenia, and ectopic lipid deposition despite a normal BMI. Limited expandability of adipose tissue, consistent with the “lipid overflow” paradigm, impairs the capacity of subcutaneous fat to buffer excess energy, resulting in lipid spillover into the liver and skeletal muscle^[11-13]. Additionally, myosteatosis, defined as the infiltration of fat into muscle tissue, further impairs insulin sensitivity and accelerates fibrosis progression^[14,15]. These processes suggest that, in L-MAFLD, metabolic risk depends not only on body size but also on body composition and ectopic lipid distribution. Mechanistically, endotoxin-induced epigenetic reprogramming, mitochondrial dysfunction, and dysregulation of the gut-liver axis may impair the ability to adapt to fluctuations in nutrient availability, resulting in patterns of liver injury similar to those observed in obese individuals with MAFLD, despite the presence of fewer conventional metabolic risk factors^[16,17]. Clinically, these abnormalities may be characterized using imaging-based assessments of visceral adiposity and muscle composition, non-invasive biomarkers of metabolic flexibility, and emerging body composition indices. These findings highlight the need for phenotype-specific strategies for risk stratification, surveillance, and management in L-MAFLD. Unlike previous studies, we conducted a structured literature search of PubMed, Scopus, and Web of Science covering publications from 2000 to 2025 and restricted to English-language articles. The search used relevant free-text keywords, including “lean MAFLD”, “NAFLD”, “metabolic dysfunction”, “fibrosis”, “cardiometabolic outcomes”, and “sarcopenia.” We included original research articles, meta-analyses, and consensus statements relevant to L-MAFLD, while excluding case reports, non-peer-reviewed publications, and studies lacking clearly defined diagnostic criteria. Given the narrative nature of this review, the search aimed to provide broad and comprehensive coverage rather than follow a systematic review protocol. The findings were therefore synthesized qualitatively without quantitative pooling.

In this review, we adopt the MAFLD definition to emphasize metabolic dysfunction as a central driver of disease. We acknowledge the expanding literature using the MASLD terminology and the increasingly recognized differences between populations identified by the two diagnostic frameworks. Recent head-to-head studies suggest that MAFLD criteria may more consistently identify lean individuals at risk of advanced disease progression^[18,19], whereas other studies suggest that MASLD criteria may be more effective in identifying such patients^[20]. Against this background, we synthesize contemporary evidence on the biological mechanisms, clinical risks, and therapeutic approaches relevant to L-MAFLD, incorporating pertinent studies conducted under the MASLD framework. Our aim is to develop a practical roadmap for clinical care that accounts for the distinctive characteristics of this phenotype.

According to the MAFLD framework, the diagnosis of L-MAFLD requires the coexistence of hepatic steatosis (≥ 5% on imaging or histology) and metabolic dysregulation. This includes type 2 diabetes mellitus (T2DM), overweight/obesity, or metabolic dysregulation in individuals who meet ethnicity-specific criteria for normal weight^[3,5]. Lean status is defined as a BMI < 25 kg/m² in Caucasians and < 23 kg/m² in Asians. Some studies additionally incorporate the normal range of waist circumference (< 102/88 cm in Caucasian men/women and < 90/80 cm in Asian men/women) to exclude overt central obesity^[21-23]. L-MAFLD is diagnosed in individuals who exhibit steatosis together with T2DM or at least two metabolic risk abnormalities - such as increased waist circumference, hypertension, dyslipidemia, prediabetes, insulin resistance, or elevated high-sensitivity C-reactive protein (hs-CRP) - irrespective of alcohol intake or other liver disease etiologies^[2,21].

Recently, the concept of L-MAFLD has been refined with greater emphasis on body composition rather than simple anthropometric measures. Studies in both Asian and Western cohorts consistently demonstrate a disproportionately high visceral-to-subcutaneous fat ratio and an unfavorable fat distribution despite a normal BMI^[24]. Furthermore, patients with L-MAFLD have significantly greater visceral fat, reduced skeletal muscle mass, and increased ectopic fat deposition compared with metabolically healthy lean controls^[5].

L-MAFLD was first recognized in global epidemiological studies showing that fatty liver disease can occur in individuals with a normal BMI^[1]. It accounts for 10%-20% of the total global MAFLD burden^[25]. A large meta-analysis suggested that L-MAFLD may affect as much as 5% of the general population, underscoring its substantial worldwide burden^[26]. Ethnic variation is evident, with Asian cohorts consistently reporting higher prevalence rates. This is attributable to differences in visceral adiposity and lower BMI thresholds for metabolic risk^[27].

Further analyses indicate that lean patients have similar or even higher cardiometabolic risks compared with non-lean MAFLD individuals, highlighting the pathogenic roles of visceral fat and sarcopenia rather than total body fat^[28]. Long-term data also show that rates of advanced fibrosis, liver-related events, and mortality in L-MAFLD are comparable to those in non-lean MAFLD^[29].

L-MAFLD exhibits the same histological continuum as other MAFLD phenotypes - from steatosis to steatohepatitis to centrilobular-predominant fibrosis - despite the absence of excess adiposity. This pattern closely resembles the histological architecture of metabolic steatohepatitis^[2,30,31]. Such alignment indicates that L-MAFLD represents a metabolic steatohepatitis phenotype driven by metabolic dysfunction rather than anthropometric measures, and that histological interpretation is most accurately performed within the MAFLD framework rather than BMI-based classifications^[32].

Lean patients typically display lower grades of steatosis on biopsy than non-lean counterparts, while still meeting MAFLD criteria for hepatic fat accumulation^[29]. Observational and biopsy-validated cohorts consistently demonstrate that macrovesicular steatosis occurs in lean individuals, albeit to a lesser extent. This reinforces the notion that lipid accumulation alone does not fully explain downstream necroinflammation in this phenotype^[33,34]. Compositional analyses further suggest that L-MAFLD may harbor distinct metabolic signatures and body-composition profiles that modulate steatosis burden without reducing inflammatory activity^[2,6,34].

Once steatohepatitis is established, lobular inflammation and hepatocellular ballooning occur at frequencies comparable to those in non-lean MAFLD, indicating that BMI does not meaningfully alter the necroinflammatory signature of MASH in the lean state^[26,34]. Consistent with previous meta-analyses, rates of ballooning and inflammatory activity are equivalent to those observed in obese MAFLD, emphasizing the primacy of metabolic drivers over adiposity in determining liver injury^[35].

Regarding fibrosis, centrilobular (zone 3) predominance remains characteristic, paralleling other MAFLD subtypes and reflecting the metabolic steatohepatitis scaffold^[2,35]. Lean cohorts exhibit fibrosis rates similar to those of non-lean phenotypes^[4,36,37]. Cross-sectional studies have reported comparable or even higher proportions of significant fibrosis in L-MAFLD, particularly in the presence of abnormal liver biochemistry^[38-40]. These findings support a phenotype-first approach based on MAFLD criteria for staging and risk assessment, independent of BMI.

Mechanistically, L-MAFLD appears to be shaped by differential metabolic adaptation, in which impaired responses to nutrient flux and endotoxin exposure amplify hepatocellular stress and fibrogenic signaling. This results in histological injury profiles that are comparable to, or indistinguishable from, those of non-lean MAFLD^[2,30]. Experimental and translational data indicate that endotoxemia-driven epigenetic reprogramming contributes to necroinflammation and fibrosis in L-MAFLD, providing a biologically coherent explanation for the paradox of severe histology in individuals of normal weight^[41,42].

Genetic predisposition is a major determinant of histological severity in L-MAFLD. The PNPLA3 I148M variant is overrepresented in this phenotype and is associated with increased steatosis and more advanced fibrosis at any given metabolic burden^[42,43]. This variant impairs triglyceride hydrolysis, promotes lipid retention, and induces hepatocellular stress^[43]. Similarly, the TM6SF2 E167K variant reduces very-low-density lipoprotein (VLDL) secretion, thereby exacerbating intrahepatic fat deposition and promoting fibrogenesis^[44]. Other genetic factors also contribute to susceptibility beyond these pathways. Genome-wide association studies (GWAS) have identified novel signals in the human leukocyte antigen (HLA) region in lean cohorts, while exome sequencing studies have linked variants in the PEMT gene to lean phenotypes^[45]. In addition, loci such as MBOAT7 rs641738 disrupt hepatic phosphatidylinositol remodeling, further contributing to lipid dysregulation, membrane instability, and progressive liver injury^[46].

Beyond single-gene effects, GWAS have identified additional susceptibility loci in L-MAFLD cohorts, reinforcing the role of genetic predisposition^[43]. Mechanistic studies further indicate that epigenetic reprogramming driven by activation of innate immune pathways - particularly Toll-like receptor 4 (TLR4)-mediated inflammatory cascades - is an important effector of hepatocellular injury and fibrogenesis in L-MAFLD^[47]. Clinical cohort studies and meta-analyses have underscored the severity of this phenotype, demonstrating that lean individuals face a significantly elevated risk of severe liver disease^[48], adverse cardiovascular outcomes^[49], accelerated cellular aging linked to telomere shortening^[50], and poorer outcomes on the liver transplantation waitlist^[51].

Epigenetic and immune-metabolic dysfunction further sensitize the liver to metabolic stress and promote fibrotic progression. These mechanisms include aberrant DNA methylation, microbe-derived small RNAs, and altered histone modification profiles^[47-51]. Mitochondrial dysfunction has also been associated with adverse outcomes in L-MAFLD. Histone modifications, including histone H4 lysine 16 (H4K16) lactylation, act synergistically with glycolytic flux to promote hepatic lipid accumulation and metabolic stress^[52]. Additionally, small RNAs of both microbial and host origin influence disease activity through interactions with the gut microbiome; liver-derived microRNA (miRNA) isomiRs have been linked to the modulation of fibrogenic pathways and the degree of fibrosis in MAFLD cohorts^[53].

Analyses of a plasma lipid profile comprising 179 lipid species across 13 subclasses identified genetically predicted increases in phosphatidylcholine and triacylglycerol levels as potential causal risk factors for MAFLD^[54].

Beyond lipid metabolism, integrated bioinformatics and genetic approaches have identified potential therapeutic targets. One study combined differential gene expression analysis, protein-protein interaction networks, two-sample MR, and colocalization to identify 10 hub genes^[55]. Among these, UHRF1 emerged as a potential causal contributor to MAFLD, with colocalization supporting a shared causal locus. Molecular docking of diosgenin and preclinical experiments further suggested that targeting the UHRF1-related pathway may attenuate hepatic lipid accumulation, inflammation, and fibrosis. These findings provide a basis for further translational investigation.

Another MR study identified bidirectional causal associations between genetically predicted endotoxin biomarker levels and MAFLD risk, supporting a potential self-perpetuating inflammatory cycle involving gut-derived endotoxemia and innate immune activation^[56]. This evidence highlights the gut-liver axis as a potential therapeutic target. However, most genetic studies have examined general MAFLD populations rather than L-MAFLD, limiting the direct applicability of their findings to the lean phenotype.

Emerging evidence suggests that chronic exposure to gut-derived endotoxins may contribute to adverse outcomes in L-MAFLD through epigenetic reprogramming of hepatic and skeletal muscle cells^[41]. This process may disrupt lipid metabolism, impair mitochondrial function, and promote muscle catabolism. In lean individuals with limited metabolic reserve, these alterations could compromise adaptation to metabolic stress, potentially accelerating fibrosis, sarcopenia, and cardiometabolic complications. Such mechanisms may help explain why adverse outcomes can occur despite a lower prevalence of conventional metabolic risk factors. However, their specific contribution to L-MAFLD remains to be established.

Mechanistically, lipopolysaccharide (LPS) activates TLR4 signaling, triggering nuclear factor-κB (NF-κB)-mediated inflammation and potentially altering DNA methylation and histone modifications, including H4K16 acetylation and lactylation. These changes may impair mitochondrial β-oxidation, disrupt hepatic lipid handling, and accelerate muscle wasting^[41]. Together, these processes may contribute to a loss of metabolic adaptation, particularly when genetic susceptibility interacts with dietary and microbial exposures. Nevertheless, direct evidence linking these mechanisms specifically to L-MAFLD remains limited, underscoring the need for phenotype-specific mechanistic studies.

Beyond genetic predisposition, dietary composition and nutrient flux further modulate these maladaptive pathways, thereby increasing vulnerability among patients with L-MAFLD. Patients with L-MAFLD typically consume diets that are high in carbohydrates and low in protein, with inadequate intake of essential micronutrients and antioxidants^[57-59]. Such dietary patterns promote hyperinsulinemia, de novo lipogenesis, and oxidative stress, creating a metabolic environment that favors hepatic steatosis, even in individuals with a normal BMI^[60]. Cross-sectional studies have demonstrated significant associations between dietary cholesterol and saturated fat intake and the severity of L-MAFLD, suggesting that these factors may contribute to disease progression^[61].

Imbalances in macronutrient intake and other qualitative dietary factors, particularly high consumption of saturated fat and cholesterol, have been independently associated with disease severity in L-MAFLD. These findings suggest that, in addition to caloric excess, dietary composition is an important determinant of metabolic injury in this phenotype^[62,63]. This is consistent with the MAFLD concept, which emphasizes the role of nutrient-induced metabolic dysregulation in determining disease phenotype across different body-size categories^[2].

Metabolic flexibility, defined as the capacity of mitochondrial and whole-body metabolism to adapt fuel oxidation according to nutrient availability, is impaired in L-MAFLD. Under normal conditions, metabolism shifts from carbohydrate utilization in the fed state to lipid oxidation during fasting or energy deficit. The loss of this flexibility represents a major biological derangement in metabolically active individuals with L-MAFLD, as impaired substrate switching promotes hepatic lipid accumulation and systemic metabolic stress^[2,36].

Physical inactivity further compounds the risks associated with an unfavorable diet. Global surveillance data indicate that L-MAFLD is frequently associated with low levels of physical activity, which may aggravate muscle wasting and visceral adiposity^[64]. Interventional studies have shown that combining resistance training with adequate protein intake can improve muscle mass, reduce hepatic fat, and enhance insulin sensitivity, even in lean phenotypes^[65]. In accordance with the MAFLD paradigm, multidimensional strategies should therefore promote adequate protein intake, reduce consumption of refined carbohydrates, incorporate antioxidant-rich foods, and include structured exercise programs to combat sarcopenia and restore metabolic flexibility^[57,65].

The MAFLD framework recognizes gut microbiota dysregulation as an important contributor to disease pathogenesis, interacting with lipotoxicity, mitochondrial dysfunction, and oxidative stress to drive hepatic injury regardless of adiposity^[66]. Emerging evidence suggests that the gut microbiome in L-MAFLD differs from that observed in obese phenotypes, although the reproducibility of these findings remains limited. Desulfovibrionaceae has been reported to be reduced in the lean phenotype, whereas the family Succinivibrionaceae has shown opposite correlations in lean and obese groups^[67]. In addition, significant reductions in Faecalibacterium prausnitzii, Ruminococcus, Lactobacillus, Lachnospira, and Subdoligranulum, together with an increase in the pro-inflammatory genus Escherichia-Shigella, have been described in L-MAFLD but not in the obese counterpart^[68].

These dysbiotic signatures may impair gut-barrier integrity, induce endotoxemia, and alter bile-acid and short-chain fatty-acid metabolism, thereby promoting hepatic injury independently of BMI. However, substantial variability exists across populations, and some studies have failed to replicate consistent taxonomic shifts. This inconsistency likely reflects the influence of dietary composition, geographic location, and host genetic factors, including PNPLA3 polymorphisms, on the gut microbial differences observed^[68,69].

L-MAFLD is clinically heterogeneous but exhibits several recurring features across populations. Compared with lean individuals without hepatic steatosis, those with L-MAFLD have a higher prevalence of insulin resistance, impaired fasting glucose or T2DM, hypertension, and atherogenic dyslipidemia [Figure 1]^[5,27,70]. Although metabolic syndrome components are less prevalent than in non-lean MAFLD, they remain significantly more common than in metabolically healthy lean individuals. Previous studies have linked these abnormalities to increased visceral adiposity, hepatic fat accumulation, and muscle loss^[5,6,70]. Together, these factors may contribute to the pronounced insulin resistance and metabolic inflexibility characteristic of this phenotype.

Reported prevalence estimates and effect sizes vary across meta-analyses because of differences in diagnostic criteria and study populations. Notably, the apparent discrepancy between liver-related complications and liver-related mortality remains difficult to explain. It may reflect methodological limitations, competing risks, or differences in ethnic and clinical case mix rather than true biological differences^[71]. The reported paradox of a lower prevalence of traditional metabolic risk factors but a higher relative risk of liver-related and all-cause mortality warrants cautious interpretation. It also highlights the importance of accounting for diagnostic heterogeneity when evaluating systemic risks in L-MAFLD.

Lean phenotypes have also been associated with an increased risk of gastrointestinal and colorectal neoplasia [Figure 1]^[70,72]. This association may reflect shared pathways linking metabolic dysfunction, chronic low-grade inflammation, and carcinogenesis.

L-MAFLD has also been hypothesized to be associated with accelerated biological aging. Although L-MAFLD has been linked to adverse clinical outcomes, direct evidence of altered telomere biology or cellular senescence in this specific population remains limited^[50]. Shorter telomeres have been associated with more advanced hepatic fibrosis, suggesting a potential link between cellular aging and disease progression^[73]. Epigenetic alterations, including changes in DNA methylation and chromatin remodeling, have also been implicated in liver fibrosis and may contribute to premature aging signatures^[74]. However, these findings cannot be directly extrapolated to L-MAFLD because lean populations have not been consistently investigated. Moreover, the heterogeneity of L-MAFLD may influence susceptibility to accelerated aging. This phenotype encompasses individuals with substantial cardiometabolic burden as well as those whose disease may be driven predominantly by genetic susceptibility or altered body composition. Further studies are needed to determine whether these subgroups differ in their biological aging trajectories.

Sex differences in MAFLD remain incompletely characterized, particularly in the lean phenotype, despite their potential influence on disease prevalence and progression. A recent study using the MAFLD definition found that the disease was more prevalent in men, whereas women with MAFLD, particularly after menopause, had a higher risk of cardiovascular events and mortality. These findings suggest sex-specific vulnerability despite a lower overall disease prevalence. Estrogen plays a protective role in hepatic lipid metabolism and insulin sensitivity. Its decline with aging may promote visceral adiposity, insulin resistance, and fibrosis progression^[75].

Sex-related differences extend beyond hepatic outcomes. Much of the current evidence, however, comes from NAFLD/MASLD cohorts^[76-78]. These studies have identified differences in metabolic risk, muscle loss, and disease severity. Postmenopausal women appear particularly vulnerable to cardiovascular disease, whereas men may be more susceptible to muscle wasting, advanced fibrosis, and hepatocellular carcinoma (HCC)^[70,72,76]. Recognizing these differences may help refine risk assessment, surveillance, and management strategies in L-MAFLD.

L-MAFLD may carry a distinctive risk profile for liver-related outcomes that is not fully explained by its cardiometabolic burden. This observation has been discussed in the context of the “obesity paradox”, whereby lean patients with fatty liver disease sometimes experience higher mortality than their overweight or obese counterparts^[79]. Further analyses suggest that this association may persist after adjustment for potential confounders. Systematic reviews and meta-analyses have also reported increased risks of hepatic decompensation and liver-related mortality in lean individuals, despite a comparatively less pronounced cardiovascular risk profile^[49]. These findings highlight the clinical heterogeneity of L-MAFLD.

Recent studies in MASLD have used data-driven clustering and machine-learning approaches to identify phenotypic subgroups with different risks of hepatic and extrahepatic outcomes. Similar approaches may help characterize L-MAFLD, in which conventional risk factors may not adequately capture disease severity^[4,5]. Identifying lean-specific clusters based on genetic susceptibility, body composition, and cardiometabolic burden could improve risk stratification and inform individualized surveillance and management.

Fibrosis severity is a major prognostic determinant in L-MAFLD and strongly influences the risk of cirrhosis and its complications. Although patients with compensated cirrhosis may remain stable for years, the risk of adverse outcomes increases as portal hypertension and hepatic dysfunction progress^[80,81]. Portal hypertension can cause splenomegaly, hypersplenism-related thrombocytopenia, and gastroesophageal varices, which may lead to life-threatening hemorrhage^[82]. Decompensated cirrhosis is characterized by complications such as ascites, spontaneous bacterial peritonitis (SBP), hepatic encephalopathy, and variceal bleeding. These events substantially reduce survival and quality of life. Ascites is a common initial manifestation of decompensation, although the clinical presentation varies among patients^[82,83].

Cirrhosis is also a major risk factor for HCC, irrespective of BMI or the presence of overt metabolic syndrome. Evidence suggesting adverse outcomes in lean individuals highlights the potential for clinically silent disease progression. Accordingly, HCC surveillance should be based on established risk criteria rather than body size alone. Patients with cirrhosis who meet surveillance criteria should undergo liver ultrasonography, with or without alpha-fetoprotein (AFP), every six months to facilitate early detection and potentially curative treatment^[84]. Inadequate surveillance may delay diagnosis, limit treatment options, and worsen outcomes.

CVD is a major cause of mortality in MAFLD, including its lean phenotype. Insulin resistance, hypertension, atherogenic dyslipidemia, and systemic inflammation may contribute to atherosclerosis and vascular dysfunction^[26,83]. Cohort studies have reported increased cardiovascular events and mortality in some L-MAFLD populations, challenging the assumption that a lean phenotype necessarily indicates a benign metabolic profile^[5,6]. Cardiovascular risk may also remain substantial in patients with L-MAFLD-related cirrhosis^[7]. Potential mechanisms include oxidative stress, endothelial dysfunction, and proinflammatory signaling, although their relative contributions to cardiovascular injury in this specific phenotype require further investigation^[81].

Nevertheless, cardiovascular outcomes in L-MAFLD vary across studies. Some report increased cardiovascular mortality, whereas others find comparable or lower event rates. These discrepancies may reflect differences in comparator groups, diagnostic definitions, adjustment for body composition, and study design. One study reported higher cardiovascular mortality without a significant increase in major adverse cardiovascular events, while another found a lower cumulative event risk in an Asian cohort^[85,86]. More recent studies have examined the modifying effects of visceral adiposity, sarcopenia, and baseline fibrosis severity on long-term outcomes^[87-89].

Overall, cardiovascular risk in L-MAFLD appears heterogeneous but remains clinically important. Assessment should therefore extend beyond BMI and include blood pressure, lipid profiles, glycemic status, and other established cardiovascular risk factors. Management should prioritize appropriate blood pressure control, lipid optimization, and individualized lifestyle interventions, while recognizing the limitations of the current evidence [Table 1].

CKD is another important extrahepatic complication of L-MAFLD. Shared mechanisms may include insulin resistance, systemic inflammation, endothelial dysfunction, and alterations in renal hemodynamics, which can contribute to progressive kidney injury. Some cohorts have reported a higher prevalence or progression of CKD in L-MAFLD than in non-lean MAFLD, particularly among patients with advanced fibrosis^[5,7]. Recent data also indicated a higher risk of renal decompensation in L-MAFLD than in non-lean MAFLD [adjusted odds ratio (aOR), 1.25; 95% confidence interval (CI): 1.20-1.30]^[89]. These findings support routine assessment of estimated glomerular filtration rate (eGFR) and urine albumin excretion, irrespective of body size^[90].

Emerging evidence suggests that L-MAFLD may be associated with an increased risk of gastrointestinal malignancies, including colorectal neoplasia^[8]. Proposed mechanisms include chronic low-grade inflammation, insulin resistance, and gut microbiome alterations that may promote carcinogenesis. Some patients without conventional risk factors may present with advanced disease, raising concerns about delayed detection^[91,92]. However, further studies are needed to establish the magnitude of these associations and determine whether the lean phenotype independently contributes to cancer risk.

Sarcopenia is an important feature of L-MAFLD and may contribute to greater fibrosis severity, hepatic decompensation, and adverse cardiometabolic outcomes^[41,63]. Reduced muscle mass and strength may also aggravate metabolic dysfunction, creating a potentially self-reinforcing cycle of metabolic maladaptation and chronic inflammation. Sarcopenia should therefore be considered in prognostic assessment and clinical management.

Because sarcopenia may remain clinically unrecognized, assessment should incorporate validated measures of muscle strength and mass. Handgrip strength provides a practical measure of muscle function, while appropriate imaging methods can quantify muscle mass. Observational studies have linked sarcopenia in L-MAFLD to higher fibrosis scores and poorer cardiometabolic outcomes^[41,63]. These findings support the inclusion of muscle health in risk stratification, although further prospective studies are needed to clarify its independent prognostic value and determine whether targeted interventions improve clinical outcomes.

Future research should prioritize phenotype-specific strategies for L-MAFLD. Emerging therapies targeting bile acid signaling, lipid metabolism, inflammation, and fibrogenesis may offer additional treatment options. However, their efficacy and safety in lean populations require dedicated evaluation.

Future management frameworks should integrate fibrosis stage, genetic susceptibility, metabolic dysfunction, body composition, and extrahepatic risk. Preserving muscle mass and reducing cardiometabolic risk should be considered alongside the treatment of steatohepatitis. Prospective studies should also evaluate emerging biomarkers, including microbiome signatures and markers of biological aging, while distinguishing established mechanisms from exploratory hypotheses. Ultimately, precision medicine in L-MAFLD will require validated risk-stratification tools and treatments tailored to the biological and clinical characteristics of individual patients.

This review has several limitations. First, it is a narrative synthesis rather than a systematic review or meta-analysis. The quantitative comparisons presented should therefore be interpreted in light of differences in study design, populations, and analytical methods. Second, many studies were conducted in selected populations, limiting the generalizability of their findings across ethnic and geographic groups. Retrospective cohort studies and cross-sectional analyses are also vulnerable to selection bias, residual confounding, and limitations in causal inference. Publication bias may further influence the apparent strength of reported associations.

Third, diagnostic definitions varied substantially across studies. Differences in BMI thresholds between ethnic groups, inconsistent use of waist circumference, and the application of NAFLD, MAFLD, or MASLD criteria complicate comparisons and limit the integration of findings into a unified framework. These distinctions are particularly important when interpreting evidence concerning lean phenotypes.

Finally, most therapeutic recommendations are extrapolated from broader MAFLD/MASLD populations, often with overweight or obesity. Their applicability to lean patients with different metabolic and body-composition profiles remains uncertain. Long-term prospective studies stratified by metabolic status and fibrosis stage are limited. Addressing these gaps will require harmonized phenotyping, dedicated clinical trials involving lean participants, and longitudinal studies across diverse ethnic and metabolic populations.

L-MAFLD should not be assumed to represent a benign form of fatty liver disease simply because BMI is normal. Evidence indicates that lean individuals can develop steatohepatitis, advanced fibrosis, and clinically important hepatic and extrahepatic complications. However, the magnitude and consistency of these risks vary across populations, and several reported associations remain susceptible to confounding and differences in diagnostic definitions.

Clinical assessment should extend beyond BMI to include fibrosis risk, glycemic status, blood pressure, lipid profiles, kidney function, and muscle health. FIB-4 and other appropriate NITs can support initial risk stratification, with elastography and selective liver biopsy used when indicated. Surveillance for cirrhosis-related complications and HCC should follow established risk-based recommendations. Cardiovascular and cancer screening should likewise reflect individual risk and applicable clinical guidelines.

A phenotype-informed approach should prioritize metabolic dysfunction, fibrosis severity, body composition, and extrahepatic risk rather than body weight alone. Future research must establish whether lean patients have distinct disease mechanisms, validate diagnostic and prognostic tools in this population, and determine the efficacy and safety of emerging therapies. Investigating genetic susceptibility, microbiome-related pathways, and biological aging may provide additional insights, but these mechanisms require further confirmation. Ultimately, improving outcomes in L-MAFLD will depend on better risk prediction and evidence-based, individualized management.