India’s Hidden Liver Crisis: Understanding Masld (Formerly Nafld) Through A Precision Lens

Metabolic-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is increasingly acknowledged as a major public health issue in India, affecting approximately 16%-32% (around 120 million) of the population. Indians are prone to developing MSALD at lower body mass indices due to a higher accumulation of visceral fat and increased insulin resistance. While obesity is a significant risk factor in many Western nations, the disease's variability (9%-53%) is noteworthy and shaped by genetic, metabolic, and environmental influences. The rise in urban living and diet changes have increased the disease's prevalence, affecting even those not considered overweight. This condition is marked by imbalances in lipids, oxidative stress, and dysfunction in the gut-liver axis, with contributions from genetic variants (PNPLA3, TM6SF2, MBOAT7) and epigenetic changes. Diagnosing MASLD is difficult, as most traditional methods (ultrasound, liver enzyme tests) are not precise, and non-invasive techniques (FLI, NFS, FibroScan) need validation tailored to the Indian demographic. As a result, alternative diagnostic approaches such as the Body Roundness Index (BRI) and assessments based on the microbiome should be developed in India to confront the increasing incidence of MASLD. Progress in precision medicine—encompassing genomics, metabolomics, and AI-supported risk assessment—should promote the earlier identification and treatment of this condition. Thus, lifestyle changes need to be integrated into public health strategies to prevent disease progression, while a holistic approach that includes personalized medicine, national screening programs, and collaborative research should be essential for managing MASLDs within the Indian healthcare system.

Non-alcoholic fatty liver disease (NAFLD), which is now referred to as metabolic-associated steatotic liver disease (MASLD), has become a silent epidemic that frequently advances undetected to more severe conditions such as cirrhosis and hepatocellular carcinoma (HCC) [1-3]. MASLD happens when fat builds up in the liver (more than 5% of hepatocytes) even when no alcohol is consumed. It is now seen as a spectrum that ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), with the possibility of progressing to fibrosis, cirrhosis, and liver failure [4-6]. This condition is increasingly affecting lower- and middle-income countries (LMICs), including India, where rapid urbanization, dietary changes, and related genetic factors are exacerbating what was once thought to be a disease associated with wealth [7-9]. Distinct metabolic phenotypes of MASLD are observed in epidemiological studies conducted in India when compared to those in Western countries [10,11]. While obesity is a significant contributor in the West, many Indians develop MASLD at lower BMIs (body mass index) due to higher visceral fat accumulation and increased insulin resistance (IR) [12-14]. MASLD is commonly found among Indians possessing metabolic risk factors; it has been reported in 55.5%-59.7% of diabetics, 64.6%-95% of overweight or obese individuals, and 73% of patients with metabolic syndrome (MS) [15]. Nonetheless, a community-based epidemiological investigation carried out in rural India found that the overall occurrence of MASLD is 8.7%, with 164 out of 1911 participants being diagnosed. Interestingly, in individuals with a BMI < 23>The underlying mechanisms of MASLD are not yet completely understood, despite its rising prevalence in the general population. The accumulation of lipids in the liver, previously thought to be just a passive effect of metabolic defects, is now acknowledged as a significant factor in causing damage to liver cells through processes like lipotoxicity, oxidative stress, mitochondrial dysfunction (MD), and endoplasmic reticulum (ER) stress [19-22]. These stressors trigger inflammation, which is a critical element in disease progression, with hepatic macrophages (Kupffer cells) and stellate cells serving as primary players in the fibrotic remodeling process [23, 24]. Additionally, there is increasing evidence that the gut-liver axis contributes to the pathogenesis of MASLD, as changes in bile acid metabolism and endotoxin signaling resulting from dysbiosis further worsen liver inflammation and IR [25-27]. 

Genetic and epigenetic components influence individuals' vulnerability to MASLD, particularly within the South Asian demographic [28-31]. Variants in key genes such as PNPLA3 (patatin-like phospholipase domain-containing protein 3) (I148M), TM6SF2 (transmembrane 6 superfamily member 2) (E167K), and MBOAT7 (membrane-bound O-acyltransferase domain-containing 7) have been linked to the likelihood of hepatic fat buildup and fibrosis, with a greater occurrence of PNPLA3 variants among Indian populations, regardless of obesity, adding complexity to the progression of the disease [32-34]. Besides genetic predisposition, epigenetic changes like DNA methylation and histone acetylation play a significant role in the advancement of the disease, as they modify the expression of metabolic and inflammatory genes based on dietary and environmental factors [35-38]. This review examines the mechanistic elements of MASLD, focusing on molecular triggers, metabolic changes, and genetic factors that are common in the Indian population. By investigating genomics, lipid metabolism, immune signaling, and interactions between the gut and liver, we seek to provide an in-depth understanding of how MASLD develops in this group and how these insights could lead to customized treatment strategies. Understanding additional mechanisms beyond the existing treatments for MASLD is crucial for fostering the development of innovative diagnostics and therapies designed for specific populations with unique metabolic characteristics.

MASLD in India: Diagnosis, Prevalence, Risk Factors, and Unique Metabolic Profiles

Diagnostic methods for MASLD are increasingly recognized as a significant metabolic disease in India [39]. These methods need to be precise and readily accessible, taking diagnostics to a new level today. Currently, certain modalities may offer benefits or drawbacks compared to others. Ultrasound (US) is the most favored screening technique, as it is inexpensive and user-friendly; however, it lacks sensitivity for detecting mild steatosis and fibrosis [40, 41]. Likewise, liver enzyme levels, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT), serve merely as surrogate markers and may remain normal in many individuals, even when there is a substantial fat accumulation in the liver, which restricts their diagnostic utility [42, 43]. Given these considerations and based on these evaluations, several other non-invasive biomarker-based indices, such as the Fatty Liver Index (FLI), MASLD Fibrosis Score (NFS), and Fibrosis-4 (FIB-4) index, can assist in determining disease severity and identifying individuals at risk for fibrogenesis [44, 45]. Imaging modalities such as transient elastography (FibroScan), MRI-proton density fat fraction (MRI-PDFF), and magnetic resonance elastography (MRE) offer advanced and more precise methods for assessing liver fat levels and fibrosis [46, 47]. However, their use is still limited due to issues with cost and accessibility. Emerging metabolite-based biomarkers, including 20-carboxy arachidonic acid (20-COOH AA) and 13,14-dihydro-15-keto-prostaglandin D2 (dhk PGD2), are showing significant diagnostic accuracy in detecting MASLD [48, 49]. Furthermore, employing three-dimensional magnetic resonance elastography (3D-MRE), the FM-fibro index alongside liver stiffness measurement (FM-fibro LSM index), and evaluations driven by machine learning algorithms (MLA) enhance the differentiation of liver fibrosis stages with the advancements we have discussed [50,51]. Nonetheless, large cohort trials must be conducted to establish their clinical relevance. While liver biopsy remains the definitive method for diagnosing non-alcoholic steatohepatitis (NASH) and assessing fibrosis, its invasive nature, high cost, and potential for sampling error limit its routine use [52]. Consequently, there is a growing preference for non-invasive imaging and biomarker strategies, particularly for early identification and risk assessment in high-risk populations, such as individuals with T2D and metabolic syndrome (MS). It is essential to establish standardized, population-specific screening guidelines to enhance the diagnosis of MASLD and prevent disease progression in India [53,54].

Regional Disparities and Urban-Rural Trends

The prevalence of MASLD differs significantly across various regions of India, influenced by genetic factors, eating habits, and socioeconomic status (SES) [7, 55-57]. Higher rates of MASLD are observed in urban areas, attributed to sedentary lifestyles and diets rich in calories as opposed to rural areas. However, in rural communities, the shift towards increased consumption of processed foods and reduced physical activity may result in a rapid rise in metabolic complications. The differences in MASLD prevalence between urban and rural locations can be understood through variations in dietary practices, levels of physical activity, and environmental exposures [58, 59]. Urban residents tend to consume calorie-dense processed foods while working in sedentary settings. In contrast, rural residents may follow traditional diets, yet they may be missing out on essential nutrients and lack access to medical care. This may make them susceptible to factors that affect metabolism relating to MASLD [60,61]. Additionally, local environmental factors may contribute to a unique metabolic profile that could either increase risk or provide protection against MASLD. Grasping these differences is essential for developing effective, targeted interventions addressing both lifestyle-related and epigenetically inherited metabolic risks to improve public health [62,63]. A systematic review and meta-analysis on the prevalence of MASLD in India indicated a wide range, varying from 9% to 53%, with significant regional differences. A study conducted in North India revealed that the urban prevalence of MASLD in Delhi was 49.8%. In contrast, rural Ballabhgarh showed a lower prevalence rate of 28.1%, highlighting the impact of urbanization on metabolic health [7, 58]. The community-based cross-sectional study involved participants aged 30 to 60 years, excluding those with alcohol dependence (>140 g/week), a history of cirrhosis, HCC, or viral hepatitis, bedridden individuals, and pregnant women. Alarmingly high prevalence rates of MASLD are also reported in southern India. Indeed, population-based studies in coastal South India have indicated an overall prevalence of 49.8%. Moreover, it was found that urban residents face an even greater risk of developing MASLD, with an adjusted odds ratio (OR) of 1.21 (P = 0.048), regardless of gender, BMI, diabetes, and MS considerations. Consequently, these findings underscore the need for a timely and comprehensive longitudinal study to monitor the progression of the disease and emphasize prevention strategies, which may vary by region. A focused public health initiative to address the increasing burden of MASLD in India could be developed by integrating metabolic markers, epigenetic factors, and environmental influences.

The Lean MASLD Phenomenon: Beyond Obesity

Research on lean MASLD in the Indian population and the obesity paradox in chronic liver disease highlights the shortcomings of using BMI as a risk indicator [64-66]. Individuals with a normal BMI in India can still develop lean MASLD, primarily due to the accumulation of visceral fat, IR, and the presence of ectopic fat. At the same time, the obesity paradox [66] suggests that having a slight excess of body fat might be advantageous in severe liver disease, potentially by providing energy reserves or modulating inflammation. These observations underline the intricate role of body fat in liver disease, where lean individuals might face health challenges from visceral fat, while moderate amounts of body fat may enhance survival in advanced cases. These insights suggest the necessity for different approaches in screening and risk assessment, concentrating on metabolic and genetic markers instead of relying only on measurements like BMI [67, 68]. This perspective aligns with the traditional view that not all body fat is harmful, highlighting the importance of tailored strategies in effectively managing the condition. In this context, the Body Roundness Index (BRI) should be included in health evaluations, especially in India, where MASLD is becoming a significant public health concern [69, 70]. Unlike BMI, which does not consider where fat is distributed, BRI includes waist circumference to offer a more accurate measurement of visceral fat—an important factor in MASLD. Research indicates that MASLD is increasing in India, even among individuals with a normal BMI, due to central obesity and genetic factors [8-10, 13, 14]. Given that visceral fat is a better indicator of liver fat accumulation than overall body weight, adding BRI to clinical practices will enhance early detection, enable targeted interventions, and ultimately reduce liver-related health issues [71, 72].

Metabolic and Lifestyle Risk Factors

The metabolic characteristics of India play a crucial role in the prevalence of MASLD, as they are closely linked to the key elements of MS, including IR, dyslipidemia, hypertension, and central obesity, even among individuals with a normal BMI [73,74]. These metabolic abnormalities foster a lipotoxic and pro-inflammatory environment, leading to increased liver fat accumulation and disease advancement [75, 76]. Rapid changes in diet and lifestyle driven by urbanization and economic development have further elevated the risk of MASLD. A growing reliance on ultra-processed foods that are high in refined carbohydrates and unhealthy fats, along with a decline in traditional, fiber-rich diets, has exacerbated metabolic dysfunction [77,78]. Specific dietary patterns associated with MASLD show higher consumption of non-vegetarian diets (35% vs. 23%, P = 0.002), regular fried food intake (35% vs. 9%, P = 0.000), frequent consumption of spicy foods (51% vs. 15%, P = 0.001), and tea (55% vs. 39%, P = 0.001) [79]. Urbanization and sedentary habits have emerged as significant metabolic factors contributing to MASLD. With improved work environments, there is a decline in physical activity and an increase in stress, shifting from physically demanding jobs to predominantly desk-bound roles [80,81]. This transition has led to reduced daily energy expenditure, promoting the accumulation of visceral fat and prolonged IR. Such changes in metabolic trends highlight the necessity for immediate public health initiatives, which should prioritize lifestyle modifications, early screening programs, and culturally relevant dietary guidelines to address the rising incidence of MASLD in India. Importantly, the diverse cultural traditions in India have significantly shaped regional eating habits, which influence metabolic and epigenetic profiles that may impact the development of an MASLD phenotype over time [82,83]. Traditional diets composed of various whole foods consumed in rural settings create different metabolic profiles. However, this protective effect may be diminished by the increasing trend toward universal diets due to urbanization, alongside a rise in the consumption of high-fat and high-sugar processed foods, which could make individuals more susceptible to metabolic disorders. Chronic dietary patterns can induce epigenetic modifications, such as DNA methylation and histone alterations, which may change the expression of genes involved in lipid metabolism, insulin responsiveness, and inflammation [84, 85]. Epigenetic alterations shaped by dietary habits across generations could lead to population-specific susceptibilities to MASLD [86, 87]. For instance, pregnant rodents fed a diet high in fat and sugar experience epigenetic changes in the fetal liver [88, 89]. The offspring exhibited changes in the metabolism of liver lipids that increased their risk of developing MASLD in later life. These changes were associated with modifications in DNA methylation and histone proteins of genes related to lipogenesis and inflammation, suggesting that a mother’s diet can alter the epigenome in a way that affects disease vulnerability in future generations [90, 91]. There are additional animal and human studies linking diet to epigenetic changes, but these fall beyond the scope of this discussion.  Hence, understanding how the cultural diversity in diets and their metabolic effects interact with evolving modern diets will be crucial for creating personalized nutrition plans and targeted strategies to address MASLD in India over time.

Metabolic and Molecular Mechanisms of Hepatic Lipid Dysregulation in MASLD 

The liver plays a vital role in lipid metabolism, managing the synthesis, storage, breakdown, and distribution of lipids to ensure a proper lipid balance [92, 93]. Various tissues use lipids for energy while preventing excessive accumulation. The liver is responsible for synthesizing fatty acids from scratch, controlling the intake of lipids from food and the blood, and overseeing their distribution to other tissues for either storage in fat cells or use through β-oxidation [94, 95]. Four interrelated metabolic pathways govern the lipid equilibrium in the liver: (1) absorption of lipids from the bloodstream, (2) production of fats through de novo synthesis, (3) breakdown of fatty acids, and (4) the creation and secretion of triglyceride-rich very low-density lipoproteins (VLDLs) [96]. The free fatty acids (FFAs) and circulating lipoproteins are derived from either dietary intake or adipose tissue (AT). Excess carbohydrates are converted into fatty acids through a process known as de novo lipogenesis, which uses acetyl-CoA and malonyl-CoA as intermediates and depends significantly on enzymes including fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) [97, 98]. The process of fatty acid oxidation (FAO)—which mainly takes place in mitochondria and peroxisomes—produces ATP and ketone bodies [99]. The formation and secretion of VLDLs then facilitate the transport of surplus lipids into the bloodstream, helping to avert metabolic overload in hepatocytes. The pathway to metabolic imbalance is characterized by the accumulation of lipids in liver cells and the onset of MASLD [100]. IR causes the liver to increase de novo lipogenesis, primarily influenced by the activities of sterol regulatory element-binding protein-1c (SREBP-1c) and enhanced functions of fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) [101, 102]. This leads to the generation of more FFAs than the liver can metabolize and export, causing fat to build up within its cells. Dysfunctional AT increases lipolysis, resulting in the release of FFAs into the bloodstream [103,104]. When the FFAs are taken up by the liver, they can produce toxic lipid intermediates such as ceramides and diacylglycerols (DAGs), which initiate a cascade of MD, ER stress, and inflammation via the JNK (c-Jun N-terminal kinase) and NF-κB (Nuclear Factor-kappa B) signaling pathways [105,106]. This cellular damage further harms liver parenchymal cells, facilitating the transition from simple steatosis to NASH [107,108]. Lower levels of adiponectin released by AT, resulting from metabolic dysregulation, diminish insulin sensitivity and its anti-inflammatory role [109,110]. The levels of pro-inflammatory cytokines, such as TNF-α (Tumor Necrosis Factor Alpha) and IL-6 (interleukin-6), increase, thereby promoting liver inflammation and fibrosis. This establishes a detrimental cycle of excessive lipid accumulation, the presence of harmful saturated lipids, and chronic inflammation, which exacerbates the advancement of MASLD [111,112]. Consequently, these findings highlight the urgent need for the development of therapeutic approaches that focus on metabolic pathways to impede disease progression. 

Gut-Liver Axis and Dysbiosis, and NAFLD

Emerging evidence suggests that the gut microbiome significantly influences the development and progression of MASLD by affecting the gut-liver axis, which facilitates bidirectional communication between the gut and liver through portal circulation, bile duct, and systemic circulation [113,114]. Dysbiosis, or microbial imbalance, interferes with communication between the gut and liver and heightens intestinal permeability, allowing many harmful microbial byproducts to reach the liver [115,116]. This effect particularly targets tight junction proteins, including occludin, claudin-1, and ZO-1 (Zonula Occludens-1), thereby compromising the gut barrier—this is attributed to decreased mucus production as well as tight junction dysfunction, which impairs the intestines' defense mechanisms [117,118]. As a result, pathogenic bacterial byproducts can translocate into portal circulation and exacerbate the effects of MASLD [119, 120]. Additionally, the gut microbiome plays a crucial role in maintaining metabolic balance by regulating bile acid metabolism, insulin sensitivity, and immune responses [121,122]. Bile acids, which are generated from cholesterol in the liver, facilitate lipid digestion and serve as metabolic signaling molecules [123]. Gut bacteria alter the composition of bile acids through processes like deconjugation, dehydroxylation, and arabinose epimerization, leading to various effects on host metabolism and insulin sensitivity [124,125]. Bacteroides and Clostridium bacteria are known to deconjugate primary bile acids, thereby reducing the level at which they are reabsorbed [126, 127]. The conversion of primary bile acids into secondary ones by bacteria such as Clostridium and Eubacterium results in varying signaling capabilities. Bile-acid-regulated receptors, namely the farnesoid X receptor (FXR) and the Takeda G-protein-coupled receptor 5 (TGR5), influence lipid metabolism, glucose regulation, and inflammation [128,129]. Activation of FXR reduces liver fat production and enhances insulin sensitivity, while TGR5 activation boosts energy expenditure and lowers inflammation [130,131]. Dysbiosis can disturb bile acid balance and hinder FXR/TGR5 signaling, consequently leading to liver fat accumulation and IR [132, 133]. Patients with NASH exhibit increased bile acid production, and preclinical studies indicate that antibiotic treatment may affect the bile acid/intestinal FXR pathway, subsequently influencing fat buildup in the liver [134,135]. Furthermore, germ-free (GF) mice, which are resistant to obesity caused by diet, illustrate the microbiota's contribution to the progression of MASLD through FXR-dependent mechanisms [136, 137]. Dysbiosis leads to heightened intestinal permeability, which subsequently triggers metabolic endotoxemia and results in systemic inflammation [138,139]. The gut barrier typically prevents microbial products like lipopolysaccharides (LPS), peptidoglycans, and bacterial DNA from entering the bloodstream [140,141]. A counteraction to this is provided by beneficial bacterial metabolites, such as short-chain fatty acids (SCFAs), which contribute to maintaining barrier integrity and ensuring homeostasis within the gut [142, 143]. The main SCFAs—acetate, propionate, and butyrate—are produced through the fermentation of dietary fibers by bacteria and have a range of systemic effects [144, 145]. Butyrate helps maintain the integrity of the gut barrier, stimulates the differentiation of regulatory T cells (Tregs), and exhibits anti-inflammatory properties [146,147]. Propionate influences the metabolism of glucose in the liver by affecting gluconeogenesis and the accumulation of lipids, whereas acetate acts as an energy source but can also trigger lipogenesis in conditions of microbial imbalance [148,149]. On the other hand, harmful bacterial products like LPS can increase permeability and inflammation [139,140]. When LPS and other microbial elements enter the portal circulation, they activate TLR4 (Toll-like receptor 4) on hepatocytes and Kupffer cells, causing NF-κB signaling and the activation of inflammasomes, which leads to the secretion of proinflammatory cytokines such as TNF-α, IL-6, and IL-1β [150-152]. These cytokines contribute to hepatic IR, steatosis, and the advancement of NASH and cirrhosis. Approaches such as probiotics, prebiotics, dietary modifications, or bile acid therapy show promise in re-establishing the balance of microflora and ensuring gut-liver harmony [153,154]. A thorough understanding of these interactions is crucial for developing therapeutic strategies that may help in preventing or managing metabolic disorders. 

Challenges & Future Directions

MASLD in India presents a complex interaction of genetic, metabolic, and environmental factors, making its diagnosis and treatment challenging. The disease is frequently underdiagnosed due to its asymptomatic nature and the limited availability of noninvasive diagnostic methods. Currently, there are no established screening protocols tailored for the diverse Indian population. Genetic factors, such as variations in PNPLA3 or TM6SF2, combined with epigenetic changes influenced by diet and environmental and socioeconomic pressures, further complicate the disease's progression. The importance of the gut-liver relationship is also notable; however, the lack of microbiome studies conducted in India hinders the development of targeted therapies. As urbanization progresses, a diet high in carbohydrates and the presence of obesity alongside micronutrient deficiencies worsen metabolic issues, while socioeconomic inequalities prevent timely interventions. The burden of MASLD may be intensified in these communities due to another factor, specifically consanguineous marriages, which could lead to a higher inheritance of genetic variants that are detrimental to metabolic functioning, insulin sensitivity, and lipid accumulation in the liver. Additionally, the lack of longitudinal studies using multi-omics approaches complicates our understanding of how MASLD progresses to more severe conditions like NASH and HCC. A precision medicine strategy that combines genomics, microbiomics, and metabolomics is essential for early risk evaluation and tailored therapies [155-157]. Innovative non-invasive metabolic and epigenetic biomarkers for diagnostics have the potential to transform early detection while significantly lowering the reliance on liver biopsies [158, 159]. Microbiome-focused strategies, such as the use of probiotics and nutritional changes, should be evaluated scientifically within the Indian population. Predictive models powered by AI enhance the assessment of risk and treatment approaches [160, 161]. At a broader level, there is a need for national screening recommendations for MASLD, integration into primary healthcare, and public health campaigns promoting healthier lifestyles and diets. Addressing the rising incidence of MASLD in India will require an interdisciplinary research approach that integrates systems biology with healthcare and policy. There is an urgent need for a precision medicine approach that assesses risk and offers personalized therapies at initial stages, incorporating genomics, metabolomics, and microbiome analysis. New non-invasive metabolic and epigenetic biomarkers for diagnostics have the potential to dramatically improve early detection while significantly reducing the need for liver biopsies. Evaluating microbiome-focused approaches such as probiotics and dietary changes should take place within the Indian context. AI-driven predictive models can improve risk assessment and treatment strategies. Broadly, there should be a framework for national guidelines on MASLD screening, integration into primary healthcare, and public health efforts that advocate for healthier diets and lifestyles. Solutions will necessitate a systems biology-oriented interdisciplinary research and policy strategy that links research and healthcare to tackle the growing challenge of MASLD in India [162-164]. 

India faces a rising burden of MASLD, influenced by urbanization, metabolic shifts, and genetic predispositions. The high prevalence among both obese and lean individuals highlights the need for improved diagnostic strategies beyond BMI, such as the Body Roundness Index (BRI) and non-invasive biomarkers. Addressing regional dietary patterns, lifestyle changes, and socioeconomic disparities is crucial for effective prevention and management. Given the complex interplay between metabolic, genetic, and gut-liver axis factors, a precision medicine approach integrating genomics, metabolomics, and microbiome research holds promise for personalized interventions. Additionally, national screening guidelines, public health initiatives, and interdisciplinary research efforts are essential to mitigate MASLD’s growing impact on India’s healthcare system. 

Conflict of Interest

The authors do not have anything to declare. 

Acknowledgments

This research is supported by Bandhan, India. 

Author Contribution

Conceptualization and supervision: S. K. C.; Formal analysis: S. K. C.; Original draft preparation: S. K. C.; Writing—review and editing: S. K. C. and D. C.; Project administration: S. K. C.; Funding acquisition: S. K. C.