Managing Metabolic Dysfunction-associated Steatotic Liver... : Preventive Medicine: Research & Reviews (original) (raw)
Introduction
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD) and later renamed metabolic dysfunction-associated fatty liver disease (MAFLD), is a major liver disorder characterised by the accumulation of fat in the liver in the absence of significant alcohol consumption.[1-3]
Globally, the prevalence of MASLD is rising steadily, with an estimated 32.4% of the population affected.[4] The prevalence varies significantly across regions, from 24.2% in Southeast Asia to 42.6% in North Africa and the Middle East.[4-6] The delayed diagnosis and limited management in resource-constrained settings, especially at the primary care level, have significant implications for public health and for low- and- middle-income countries.[7] These challenges often result in missed opportunities for early intervention, allowing the disease to progress unchecked with a heavy economic burden on both individuals and society at large.[8] Without early detection, patients are at a higher risk of developing cardiovascular disease, diabetes, and other metabolic complications.[9] Hence, addressing MASLD at the primary care level is not only a matter of improving individual health outcomes, but also of preventing a broader public health challenge.[9,10] This review article aims to provide essential information about MASLD that can help physicians in primary care and clinicians of different settings in prevention, early diagnosis and control of the disease.
History of Non-alcoholic Fatty Liver Disease, MASLD, and Change in Nomenclature
The term NAFLD was first introduced in 1986 to describe liver pathology in individuals consuming minimal or no alcohol at all.[10] The liver changes in NAFLD were found to resemble those seen in alcohol-related liver damage, but the absence of significant alcohol consumption and other liver diseases was key to its diagnosis. Thus, NAFLD was primarily defined as a disease of exclusion.[11] Over the next four decades, as the global burden of fatty liver diseases increased dramatically, extensive research revealed that the NAFLD was not a singular condition; but rather a spectrum of disorders linked to metabolic dysfunction, obesity and insulin resistance.[12] This growing evidence underscored the complexity of its pathogenesis and the need for a more inclusive framework.
Studies showed that even moderate alcohol consumption could contribute to liver steatosis, challenging the distinction between alcoholic and non-alcoholic liver diseases. Moreover, the self-reported nature of alcohol consumption data often led to underestimation due to social stigma, introducing a bias that further complicated diagnoses.[13] The exclusion of concurrent liver conditions, such as Hepatitis B and C, was also problematic, as these diseases could have a synergistic effect on the development of hepatic steatosis. These limitations called for a shift in the terminology and diagnostic approach, moving the focus from exclusion to the underlying metabolic causes.[14]
To address these challenges, international experts initiated a consensus-driven process in 2020, proposing the term MAFLD.[15] This new terminology introduced criteria that broadened the diagnostic scope beyond alcohol consumption and excluded other liver diseases. By removing the stigmatisation linked to alcohol, MAFLD provided a more comprehensive understanding of the disease’s aetiology and pathophysiology.[15]
Building on this concept, the term further evolved into Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) to better align with the metabolic focus and highlight the steatotic nature of the condition.[16] This shift has redefined how clinicians and researchers approach liver diseases, emphasising metabolic health and its broader implications for patient care. The natural history of MASLD and risk factors for fibrosis are depicted in Figure 1.[17]
Natural history of metabolic dysfunction-associated steatotic liver disease. MASH: Metabolic dysfunction-associated steatotic hepatitis, HCC: Hepatocellular carcinoma[ 16 ]
Epidemiology of MASLD in India
In India, the prevalence of MASLD is estimated at 38.6% in adults and 35.4% in children.[6] This translates to roughly one in every three individuals in India being affected by MASLD.[6] MASLD is a significant public health issue in India.[1] The prevalence of MASLD in India is estimated to be around 21.8% (14.1%–48.2%), with notable regional differences influenced by dietary patterns, socioeconomic factors and genetic predispositions.[18] The disease burden is further compounded by the fact that many individuals remain undiagnosed until later stages when liver fibrosis has already developed, leading to complications such as cirrhosis, liver failure or hepatocellular carcinoma (HCC).[19] Urbanisation and lifestyle changes, such as increased consumption of processed foods and reduced physical activity, have contributed significantly to the rising prevalence.[20] These shifts, combined with the growing burden of metabolic syndrome, have placed MASLD among the most pressing health challenges in India.[20]
Gender differences in MASLD epidemiology are also striking. Men tend to have a higher prevalence of MASLD compared to premenopausal women, likely due to the protective role of oestrogen in women.[21] However, this trend reverses in older age groups, where postmenopausal women are more affected, attributed to the hormonal changes after menopause. These patterns highlight the complex interplay between metabolic health, lifestyle factors and hormonal influences in shaping MASLD risk.[21] Understanding the epidemiology of MASLD in India is critical for designing effective prevention and management strategies.[22]
Pathogenesis
Liver cells (hepatocytes) are responsible for lipid metabolism in the body. Macrophages present in the liver called Kupffer cells are activated in response to inflammation and secrete certain inflammatory cytokines. There are certain types of cells called ’hepatic stellate cells’ which get activated during inflammation by the inflammatory mediators and secrete increased collagen, resulting in fibrosis of the liver.[23] The exact pathogenesis of the development of MASLD is not established. Initially, ’the two-hit hypothesis’ was proposed where fat accumulation in hepatocytes as a first hit and the inflammatory process triggered act as a second hit.[24] Later, it was found that many genetic factors also play a role in the development and progression of the disease and multiple parallel hit theory was proposed.[25] Once liver fibrosis has developed, it may lead to further cascade of events such as liver cirrhosis, decompensated liver disease and HCC. Recent studies have shown that insulin resistance plays a major role in the initiation of the cascade of events by increasing the free fatty acids in the circulation, resulting in their accumulation in the liver.[26]
Risk Factors of MASLD
Since the fat accumulation in the liver is due to metabolic defects, the disease is not caused by a single factor but rather a complex interplay of multiple metabolic risk factors.[27] Some major risk factors are dietary habits (high calorie, high salt, low dietary fibres, ultra-processed food and trans-fat consumption) and a sedentary lifestyle. Over time, these factors contribute to overweight/obesity, central obesity (which is more prone to develop among Asians), type 2 diabetes mellitus (T2DM) (insulin resistance), metabolic syndrome, dyslipidaemia and arterial hypertension. Studies have demonstrated a positive association between MASLD and other NCDs.[28] Some non-modifiable risk factors such as age, sex (more common in men), family history of T2DM and other genetic and epigenetic factors also contribute to the pathogenesis of MASLD. MASLD has both hepatic (fibrosis, cirrhosis and carcinoma) and extrahepatic (cardiovascular diseases, other cancers, obstructive sleep apnoea, chronic kidney disease and polycystic ovarian disease) manifestations.[29] Notably, the risk factors for MASLD are exclusive to the disease but are common for all NCDs. The ICMR-INDIAB study estimates a high prevalence of these risk factors in India.[30] Furthermore, disease progression and mortality vary between individuals with and without T2DM [Figure 2].[6,10] The diagnostic criteria for MAFLD are given in Box 1.
Diabetes mellitus as a major contributor to progression and mortality of non-alcoholic fatty liver disease[ 6 , 10 ]
Diagnostic Criteria for Metabolic-associated Fatty Liver Disease
Although hepatic steatosis is essential to diagnose MASLD, ultrasonography, a key screening tool for hepatic steatosis, is often not available at the primary care level, making early diagnosis challenging. Alternative diagnostic scores, like fatty liver index (FLI), hepatic steatosis index (HSI), having the potential of detecting hepatic steatosis using biochemical and anthropometric parameters, can be considered viable options at the primary care level.[32,33]
Emerging Concept of MASLD
Based on the multi-society Delphi consensus led by three international liver organisations in 2023, new nomenclature and diagnostic criteria were suggested considering the nature, pathogenesis and aetiology of the disease. MASLD was proposed, and the criteria for diagnosis were given as the presence of liver steatosis along with any one of cardiometabolic criteria, such as overweight/obesity, T2DM, elevated blood pressure, elevated plasma triglycerides and elevated HDL levels: the cut-off values are same as mentioned above in criteria for MASLD in Box 1.[47] The consensus also took into consideration the amount of alcohol intake and gave a nomenclature of metabolic dysfunction and alcoholic liver disease to include the individuals who consume more than the threshold of NAFLD but less than the threshold of alcoholic liver disease (20–50 g/day and 30–60 g/day for women and men, respectively). Those consuming alcohol above this threshold are categorised into alcohol-related liver disease.[48-50]Figure 3 summarises the nomenclature suggested for the spectrum of diseases covered under steatotic liver disease. Studies have shown that insulin resistance has a strong association with MASLD, which is in turn significantly associated with cardiovascular events and mortality.[51,52]
Spectrum of diseases covered under steatotic liver disease as suggested by the Delphi consensus 2023[ 6 , 10 ]
How MASLD Diagnosis is Different from MAFLD
The diagnosis of MASLD differs from that of its predecessor, MAFLD, as it introduces a broader and more inclusive framework.[34] While both conditions emphasize the role of metabolic dysfunction as the primary driver of liver steatosis, MASLD adopts a refined approach to accommodate a wider range of contributing factors.[34]
MAFLD diagnosis required evidence of hepatic steatosis, either through imaging or biopsy, along with the presence of metabolic dysfunction. This dysfunction was typically defined by conditions such as obesity, type 2 diabetes, or metabolic syndrome. In addition, MAFLD excluded other causes of liver steatosis, such as significant alcohol intake or chronic viral hepatitis, to focus solely on metabolic origins.[35] MASLD simplifies the diagnostic process by prioritising the role of metabolic dysfunction without rigidly excluding other factors. It allows for the coexistence of mild alcohol intake or additional contributors like genetic predispositions, provided metabolic dysfunction is the primary driver of liver disease. This approach reduces ambiguity and ensures a more comprehensive understanding of liver steatosis in clinical practice.[34] MASLD’s diagnostic framework is more flexible and clinically applicable, addressing the limitations of MAFLD by emphasising inclusivity and simplifying the recognition of metabolic dysfunction as the central cause of liver steatosis.[36] This shift is expected to improve disease management, research, and public health strategies.[36]
Diagnostic and Screening for MASLD
Screening for MASLD primarily focuses on identifying individuals with hepatic steatosis and evaluating the risk of hepatic fibrosis. Liver biopsy is considered the gold standard for diagnosing MASLD, as it directly detects hepatic steatosis and assesses liver damage. However, it is an invasive procedure and not practical for widespread screening.[37] Ultrasonography is a commonly used and more accessible alternative for detecting liver fat, especially at the primary care level.[38]
Non-invasive diagnostic tools like vibration-controlled transient elastography (Fibroscan), computed tomography scans (using liver attenuation index) and magnetic resonance imaging-based techniques are highly accurate for quantifying liver fat and fibrosis. However, these advanced technologies are often unavailable in primary care settings due to cost and infrastructure limitations.[37]
To meet the need for simpler and more affordable screening methods, algorithm-based tools have been developed. These rely on biochemical markers instead of imaging. The Fatty Liver Index or FLI uses BMI, waist circumference, triglycerides and gamma-glutamyl transferase (GGT) levels to predict liver steatosis. Similarly, the HSI incorporates alanine transaminase (ALT), aspartate aminotransferase (AST), BMI, and diabetes status to assess the likelihood of steatosis. These tools provide practical alternatives for identifying MASLD in resource-constrained settings.[39]
Assessing Hepatic Fibrosis
Hepatic fibrosis is an essential prognostic marker in MASLD, as it indicates disease progression and the risk of complications like cirrhosis. The Fibrosis-4 (FIB-4) score is one of the most commonly used non-invasive tools for assessing fibrosis risk.[40] It is calculated using age, AST, ALT and platelet count. A low FIB-4 score indicates a minimal risk of advanced fibrosis, while higher scores necessitate further evaluation with imaging or specialized tests like Fibroscan.[40]
Guidelines for Screening
The American Association of Clinical Endocrinology released guidelines in 2022 for the diagnosis and management of MASLD (previously NAFLD).[41] These guidelines highlight high-risk groups that should undergo screening, stratify fibrosis risk using tools like the FIB-4 score and provide algorithms for disease management. Primary healthcare teams play a crucial role in managing patients with low fibrosis risk by promoting lifestyle modifications and regular follow-up, while those with higher risk are referred for specialised care.[41] A flow for screening is provided in Flowchart 1.[42]
Screening flow diagram of MASLD[ 42 ]
A focus on simple, non-invasive methods can improve detection rates and help reduce the burden of advanced liver disease.[37]
Challenges in Classifying MASLD
Studies have shown that the individuals with Lean NAFLD have more visceral fat despite having normal BMI and they constitute 25.3% of the overall prevalence of NAFLD in India.[43] Lean NAFLD is broadly classified into type-1, which is due to visceral adiposity and insulin resistance, and type-2 is due to monogenic diseases with genetic abnormalities.[44] Studies have shown that individuals with lean NAFLD have higher chances of developing long-term severe liver diseases such as decompensated liver disease, liver failure, cirrhosis and HCC than the obese NAFLD individuals.[45]
Another challenge is the diagnosis of hepatic steatosis as it is subjective and observer-dependent, thereby interobserver variability is inevitable. Systematic reviews conducted on the diagnostic accuracy of ultrasonography showed that it has a sensitivity of 84.8% and specificity of 93.6%, but this varies between different studies.[38] Studies have shown that many physicians underestimate the significance of the disease and do not recognise the need for referral for the disease in isolation.[46] Moreover, being a chronic disease without any apparent symptoms, only the tip of the iceberg comes to notice, but the real hidden burden of the disease can be known only through valid, reliable, non-invasive and cost-effective universal screening methods.
Prevention and Management
Since MASLD is multifactorial and most of the predisposing risk factors are metabolic in nature, prevention and management of MASLD mainly focus on dietary changes and lifestyle modifications like weight loss (at least 3%–5% to improve liver steatosis and >7% to improve steatohepatitis) and structured exercise intervention (150–200 min/week of moderate-intensity physical activity in three to five sessions) as the first-line therapy.[53] Studies conducted on dietary modifications for preventing the progression of MAFLD recommend the Mediterranean diet, rich in antioxidants and has anti-inflammatory properties on the liver, avoiding processed foods and sugar-sweetened beverages, adequate intake of foods containing unsaturated fatty acids and dietary fibres and avoiding alcohol consumption.[54,55] The effect of lifestyle modification on MAFLD has been studied and found a significant improvement.[7,56] Studies have also proven a positive dose-response effect of weight reduction by diet and physical activity on features of NAFLD and this highlights the role of primary care physicians.[57]
Systematic reviews have shown that treatment with Vitamin E significantly reduces the level of biochemical markers such as AST and ALT and also reduces hepatic inflammation and fibrosis.[58] Placebo-controlled trial conducted on non-diabetic patients with NAFLD for finding the effect of the drug Pioglitazone showed that it resulted in a reduction of hepatic steatosis and lobular inflammation by increasing adiponectin but has no effect on hepatic fibrosis and also it resulted in increased weight gain among the participants.[59,60] Systematic reviews have reported a significant cardiovascular disease risk reduction in people with insulin resistance, pre-diabetes and diabetes mellitus.[61] Studies on Statin treatment showed that there is a significant reduction in cardiovascular mortality among patients with MAFLD administered with statins.[62] Many other trials have been conducted to study the effect of anti-diabetic drugs in improving hepatic steatosis and among them Pioglitazone, glucagon-like peptide-1 (GLP-1) receptors agonists such as Liraglutide, Semaglutide and sodium-glucose cotransporter-2 (SGLT-2) inhibitors like Dapagliflozin, Canagliflozin have shown promising results and are currently recommended for use in MAFLD patients with type-2 diabetes mellitus.[42,63-68]
Why MASLD be Addressed at Primary Care?
MASLD is a multifactorial chronic disease with limited medical and surgical treatment modalities. It is better to approach the disease at primordial and primary stages, and primary care physician and facilities are the one who attend to many such patients and thus can play a major role in the prevention of MASLD as they are close to the community. Health education on the risk factors of MASLD, targeting young children and adolescents, like in schools and colleges, can help prevent the risk factors and thereby act as primordial prevention. Furthermore, secondary level of prevention is possible by early diagnosis of the disease by screening the high-risk groups and early referral for confirmation, thus preventing disease progression.[69]
Early Interventions to Prevent MASLD
Preventing MASLD should begin in childhood, focusing on promoting healthy habits early in life. Schools play a crucial role by introducing programmes that educate children on healthy eating, emphasizing the risks of processed and sugary foods. Structured physical education classes and community sports programmes encourage regular exercise, while school mid-day meal programmes can offer balanced, nutrient-dense meals. Raising parental awareness about healthy cooking practices further reinforces these efforts. Early screening for overweight or obese children is essential to address risk factors through lifestyle interventions, helping to install lifelong healthy behaviours and reduce MASLD risk in adulthood.[70]
Colleges also play a vital role in prevention by fostering lifelong health habits. Health campaigns and workshops can raise awareness about healthy diets, the risks of alcohol and the importance of regular physical activity. Fitness programmes, such as subsidised gym memberships or yoga sessions, encourage students to stay active. Regular health check-ups for metabolic disorders, especially for those with a family history of obesity or diabetes, provide early detection and intervention. These measures collectively promote awareness and prevention, reducing MASLD prevalence over time.[71]
Programmatic Approach towards Metabolic-associated Fatty Liver Disease
Due to the high prevalence of MASLD in India and modifiable nature of most risk factors, MASLD has been incorporated into the National Programme for Prevention and Control of non-communicable disease (NP-NCD) in 2023.[72] According to the operational guidelines must be referred by the medical officer to the higher centre or, if available, managed through teleconsultation with specialists. Currently, MASLD screening in pregnancy is not recommended as per existing guidelines. However, studies suggest a positive association between MASLD in the first trimester of pregnancy and the subsequent development of Gestational Diabetes Mellitus.[73] Hence, early diagnosis of MASLD at the primary care level using FLI and HSI algorithms and appropriate lifestyle modifications can prevent the incidence of GDM in pregnancy and thereby reducing the future risk of developing T2DM among the women.[74,75]
The National Programme for Prevention and Control of Cancer, Diabetes, Cardiovascular Diseases and Stroke (NPCDCS) includes MASLD under its broader category of NCDs.[76] The Ayushman Bharat Health and Wellness Centres (AB-HWCs) also provide comprehensive primary healthcare services, including prevention and management of MASLD. Furthermore, the government has initiated training programmes for healthcare providers on MASLD management at the primary care level.[77,78] Key milestones in this area are listed in Table 1.[77-79,80]
Key milestones in MASLD and programmatic interventions in India
Primary Healthcare Providers and MASLD Prevention and Control
Given the high prevalence of risk factors such as obesity, diabetes and hypertension in India, primary care physicians are uniquely positioned to intervene early.[81]
PHCPs can prioritise screening for MASLD among high-risk groups, [Tables 2 and 3].[42,80] Counselling on weight management, physical activity and balanced diet with low refined carbohydrates and unhealthy fats should be done at the primary care level. Promoting these changes can prevent progression to more severe conditions like non-alcoholic steatohepatitis (NASH) or cirrhosis.[82]
Fib-4 score and interpretation[ 80 ]
Fibro scan and interpretation[ 42 ]
For patients who are unable to achieve sufficient lifestyle changes or have progressed to NASH, pharmacological interventions may be necessary. Medications like GLP-1 receptor agonists and SGLT2 inhibitors, which target underlying issues such as insulin resistance and hyperglycaemia, have shown potential in controlling MASLD progression.[83] In addition, PHCPs can support in educating and raising awareness about MASLD within their communities.[84] This can be done through public health campaigns, patient education resources and local outreach efforts. Engaging communities in discussions about regular health check-ups and liver function tests for at-risk individuals is also essential.[84] When advanced liver disease is suspected, it is vital for PHCPs to refer patients to specialists like hepatologists or gastroenterologists. Regular follow-up care is equally important for monitoring disease progression, adapting treatments and ensuring adherence to lifestyle modifications.[85]
Policy interventions
Policy interventions play a pivotal role, alongside the active involvement of healthcare providers, in effectively addressing MASLD in India. One critical step is the integration of MASLD screening into national health programmes. Routine health check-ups under national health initiatives should include MASLD screening, especially for high-risk groups such as individuals with metabolic syndrome and diabetes. This integration will ensure early detection and timely intervention, reducing the burden of the disease.
Training and capacity building for primary care providers must be prioritised. A focused effort to equip primary healthcare workers with the latest MASLD screening and management guidelines is essential. By enhancing their knowledge and skills, these providers will be better prepared to address the growing prevalence of MASLD effectively and ensure quality care at the grassroots level. Ensuring affordable access to diagnostic and therapeutic tools is crucial. Policymakers need to make diagnostic tests, such as ultrasound and liver function tests, and medications for MASLD affordable and accessible to all individuals, particularly those in underserved rural areas. Improving affordability and accessibility will help bridge the healthcare gap and enable equitable management of MASLD across different population groups.
Addressing MASLD in India requires a multi-pronged approach, with primary healthcare providers playing a key role in early detection, prevention and management.[86] By implementing community-level health interventions, improving screening practices and ensuring the availability of necessary resources, India can make significant progress in combating this growing public health challenge.[87] The government’s ongoing efforts, along with global and local guidelines, provide a solid foundation for these interventions, but sustained investment in healthcare infrastructure, education, and policy reforms is essential for long-term success.[88]
Challenges and Way Forward
In the Indian context, Liver Function Tests and Platelet count are included in the essential package of services provided by the Indian Public Health Standards (IPHS) 2022 under Ayushman Bharat Health and Wellness centre.[78] Therefore, FIB-4 calculation can be performed with the available parameters for individuals at high risk of developing MAFLD and if found positive, further investigations and management can be initiated at earlier stages. Community participation, being one of the pillars of primary health care, should be encouraged as community-based health promotion interventions not only increase the coverage of intervention but also enhance motivation and intervention uptake among at-risk populations.[89,90] Strengthening these efforts will significantly improve MAFLD prevention and management outcomes in India.
Conclusion
There is a rising burden of MASLD and thus chronic liver diseases in India. There is a need for raising awareness and knowledge about the diagnosis and management of MASLD in primary care physicians. Alongside, maximum utilization of the available resources at the primary healthcare level (like screening NAFLD using FIB-4 score) should be done for early diagnosis and facilitate appropriate referral to higher centres, and the same can be included in the programme once all the primary health centres are adequately equipped as per Indian Public Health Standards. Clearly, there is a major role of primary care providers and facilities in tackling MASLD. The first step is educating and raising awareness about MASLD in them and getting early identification of health conditions.
Relevance to Preventive Medicine:
Early diagnosis of MAFLD at the primary care level will help prevent the progress of disease and reduce the complications and reduce the burden of MASLD in India.
Implications for Clinical Practice:
Screening of MASLD by clinicians among individuals with a high risk of developing the disease is important in the prevention and early management of the disease.
Author contributions
VR and AD developed the concept. VR and CL further contributed in literature search, and preparation of manuscript. VJ, AD, KKL and CL contributed in editing and review of the manuscript. CL did the final editing. All authors approved the final version of the manuscript. VR will act as gaurantor of this manuscript.
Data availability statement
All data that support the review are available from the references cited in the manuscript.
Use of AI/data statement
The authors declare that all the sections of the manuscript are written without the assistance of AI.
Financial support and sponsorship
Nil.
Conflicts of interest & Disclaimer
CL is the Editor in Chief of Preventive Medicine Research & Review. However, as per ethical publishing standards adopted and followed by the journal; CL was not involved at any stage of peer review or in the final decision making of this manuscript.
Handling Editor: Dr. Rajiv Jayadevan, Sunrise Hospital, Kochi, Kerala
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Keywords:
India; liver health; MASLD; prevention; primary care; family medicine
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