Metabolic dysfunction-associated steatotic liver disease in India: A growing public health imperative and call to action

Introduction Metabolic dysfunction-associated steatotic liver (MASLD), previously called nonalcoholic fatty liver disease (NAFLD), is emerging as a global health crisis representing the fastest-growing contributor to liver morbidity and mortality worldwide. Its prevalence has seen a dramatic increase, rising from 25.3% in 1990–2006 to 38.0% in 2016–2019.[1] A consistent rise in mortality and disability adjusted life years (DALYs) over the past three decades has also been observed across various regions covered in the Global Burden of Disease study 2021.[2] MASLD includes a spectrum ranging from simple hepatic steatosis also called metabolic dysfunction-associated steatotic liver (MASL), metabolic dysfunction-associated steatohepatitis (MASH) which is characterized by inflammation and hepatocyte damage, and fibrosis, which can progress to cirrhosis and hepatocellular carcinoma. However, it is important to realize that MASLD is much more than just a hepatic disease. Apart from the metabolic syndrome risk factors, which are sine qua non for the diagnosis of MASLD, MASLD is also associated with a number of extrahepatic conditions, including polycystic ovarian syndrome, obstructive sleep apnea, coronary artery disease, chronic kidney disease, thyroid dysfunction, and osteoporosis. Indeed, the most common cause of mortality in patients with MASLD is cardiovascular disease.[3] Clarification of Nomenclature After much debate regarding the nomenclature, the terms steatotic liver disease (SLD), MASLD, and MASH were recommended instead of fatty liver, NAFLD, and NASH by a Delphi consensus of international experts.[4] This new terminology has been endorsed by more than 70 liver societies across the globe, including the Indian National Association for the Study of the Liver (INASL).[5] The new terminology avoids stigmatizing terms like “fatty” and lays stress on the fact that metabolic dysfunction and insulin resistance are the fundamental pathophysiologic drivers of the disease. For the practicing clinician, a few points are noteworthy. MASLD requires the presence of at least one of five metabolic risk factors in the presence of hepatic steatosis in a person without significant alcohol intake, i.e. <2 drinks/day (<20 g/day or 140 g/week) in females and <3 drinks/day (<30 g/day or 210 g/week) in males, respectively. Thus, unlike NAFLD, MASLD is not a disease of exclusion. Other etiologies of liver disease, like chronic viral hepatitis, can coexist with MASLD. Patients with hepatic steatosis and significant but moderate alcohol consumption (males: <60 g/day or <420 g/week and females: <50g/day or 350 g/week are categorized as MetALD if they have at-least one cardiometabolic risk factor. However, patients with higher alcohol consumption and metabolic risk factors are categorized as having alcohol-related liver disease with metabolic dysfunction.[4,5] Reassuringly, several large studies, including Indian studies, have corroborated that there is almost universal overlap among patients with NAFLD and MASLD with similar performance of diagnostic tests.[6] Thus, guidelines and concepts governing the management of patients with NAFLD are also applicable to patients identified with the new MASLD criteria.[5,7] Alarming Epidemiology and Disease Burden of Metabolic Dysfunction-associated Steatotic Liver in India The pooled prevalence among Indian adults has been estimated to be 38.6% in a meta-analysis of 54 Indian studies.[8] A recent study of 7764 Indian adults in 27 Indian cities reported an age-adjusted MASLD prevalence of 36.3% with significant fibrosis in 6.3%.[9] Hospital-based data indicate a higher MASLD prevalence (40.8%) compared to community-based data (28.2%).[8] Regional variations and rural–urban differences have also been suggested. These differences may reflect dietary patterns, genetics, urbanization, and diagnostic infrastructure. The burden is much higher in at-risk groups. For instance, among patients with type 2 diabetes mellitus, the MASLD prevalence was found to be 68.2% in a multicentric cross-sectional study of 13,750 Indian adults.[10] While overweight and obesity are the most common risk factors for MASLD, around 15% of patients with MASLD have normal body weight, which is referred to as the “lean MASLD” phenotype. First reported from eastern India, this phenotype has now been recognized all across the world. Contrary to previous understanding, current data, including Indian data, suggest that these patients have largely similar severity of liver disease and clinical outcomes compared to nonlean patients.[11] Central obesity is a major risk factor governing MASLD severity in lean MASLD.[12] It is a matter of grave concern that MASLD is being increasingly recognized in the younger population. Among Indian children, the pooled prevalence is 35.4% and a striking 63.4% among obese children.[8] This early onset portends significant morbidity in adulthood, including increased risk for diabetes, hypertension, and cirrhosis, highlighting the need for early detection and interventional research. Data indicate that there has been a 141% increase in MASLD cases and a 169% rise in MASLD-related deaths from 1990 to 2021 in India, with the highest DALY rates being observed in the 55–69 age range.[13] The burden is anticipated to rise further in parallel with the ongoing epidemics of obesity and diabetes mellitus, sedentary lifestyle, easy access to calorie-dense foods, and increasing age of the population. Pathogenesis and Natural History: Key Takeaways A detailed description of the multifactorial and complex pathophysiology of MASLD is beyond the scope of this editorial. However, a few points of clinical relevance should be noted. While genetics, oxidative stress, gut dysbiosis, altered adipokines and cytokine levels, etc., have been implicated, at its core, MASLD is a state of metabolic dysregulation that is primarily driven by insulin resistance. However, a few studies from eastern India and Bangladesh have suggested the notable absence of insulin resistance in many of their patients. Second, the prevailing adiposopathy in MASLD and other insulin-resistant states, such as obesity and diabetes mellitus, is primarily driven by the visceral adipose tissue rather than the subcutaneous adipose tissue. Measures of central obesity (like waist circumference) are a better surrogate of visceral adipose tissue than body weight-based measures like Body Mass Index. Third, the natural history of MASLD progression is dynamic, and the key determinant of outcomes is the degree of underlying fibrosis rather than the presence of MASH. Fortunately, most patients have a slow progression of fibrosis, although around 20%–30% patients can have a relatively rapid progression to advanced fibrosis in 7–10 years. Finally, while MASLD is highly prevalent in the community, a substantial proportion will not develop clinically significant liver disease. Thus, risk stratification is paramount to avoid further overburdening the already constrained healthcare resources of the country.[4] Screening, Diagnosis, Risk Stratification, and Referral [Figure 1]Figure 1: Simplified, comprehensive algorithm for screening, diagnosis, risk stratification, referral, and management of metabolic dysfunction-associated steatotic liverPatients with obesity (including central obesity), diabetes mellitus, metabolic syndrome, or deranged liver function parameters should be screened for MASLD. USG abdomen is the most commonly used and recommended screening modality despite its low sensitivity for mild hepatic steatosis. Where available, the more accurate controlled attenuation parameter value available with FibroScan is also being used for the detection of hepatic steatosis. Magnetic resonance imaging (MRI)-based imaging is costly, not widely available, and is primarily used as a research tool. However, it should be acknowledged that MR-Proton density fat fraction (PDFF) is currently the best noninvasive measure of hepatic steatosis, and improvement in MR-PDFF on follow-up is a good surrogate for histologic MASH resolution.[4,7] Risk stratification and referral decisions are primarily based on noninvasive assessment of underlying hepatic fibrosis. As a first test, a nonproprietary, widely validated, highly sensitive, blood-based test like FIB-4 is best suited in the community setting. While proprietary blood-based tests like enhanced liver fibrosis tests have also been suggested by some societies, these tests entail added cost without providing extra information and are not widely available. On the other hand, FIB-4 can be calculated from freely available online calculators and incorporates age, serum AST, serum ALT, and platelet count. These values are easily available as part of the routine evaluation of any patient with liver disease. Patients with FIB-4 <1 or 1.3 can be managed at the primary center with lifestyle modifications and management of coexisting metabolic comorbidities and do not need referral to higher centers or specialist consultation [Figure 1].[4,5,7] Patients with FIB-4 >1.3 or 1 (where advanced or significant fibrosis cannot be excluded) should be referred to a higher center for a second-tier noninvasive corroboration of fibrosis stage using elastography. Patients with liver stiffness measurement (LSM) <8.2 kPa can be sent back to the primary center, while those with elevated LSM need specialist consultation for consideration of MASLD-specific pharmacotherapies and management of advanced liver disease/cirrhosis[4,5,7] [Figure 1]. Management It should be emphasized that cardiovascular events and malignancies are the most common causes of mortality in patients with MASLD, and thus, a holistic management should be pursued. Appropriate management of metabolic comorbidities such as diabetes mellitus, hypertension, dyslipidemia, and obesity cannot be overemphasized, and statins, if indicated, are safe even in the presence of raised transaminases. Alcohol use in any amount should be strongly discouraged.[4] MASLD is primarily a lifestyle disease, and the central pillar of management involves lifestyle modifications focusing on dietary modifications and physical activity to target weight loss of 7%–10% over 6 months.[4,7] Weight loss directly improves liver histology: 3%–5% weight loss helps hepatic steatosis, ≥7% improves MASH, and ≥10% for fibrosis. Aerobic activity such as brisk walking, running, swimming, or cycling for 30–45 min at least 5 days a week (200 min/week) is advised to achieve 60%–70% of maximal heart rate. Exercise alone can improve insulin resistance and possibly steatosis even in the absence of weight loss. Resistance training is complementary, helps build lean mass, and may be particularly useful in those unable to do partake in aerobic exercises. While promising, the impact of yoga on MASLD requires further research.[14] For diet, reducing daily calories by 30% or 500–1000 kcal is more important than the specific diet type. While the Mediterranean diet or its equivalent diets may help, patients are better counseled to reduce both carbohydrates and fats using local foods and tastes for long-term adherence. This involves reducing the intake of sugar, deep-fried foods, refined foods, and excessive butter and oil, while simultaneously increasing the consumption of fruits, vegetables, and legumes, and minimizing cereals and grains.[4,14] Coffee has been shown to be beneficial, but the common practice of sweetening it may be counterproductive. Intermittent fasting could be beneficial, but more evidence is needed, including long-term safety and the best approach (e.g., alternate day fasting, severely reduced caloric intake for 2 days followed by 5 days of normal consumption, daily intermittent fasting of 18 h, etc.,).[14] Despite the clear benefits of lifestyle modifications, adherence to long-term changes remains notoriously low. Patient-reported barriers include lack of time, insufficient information on NAFLD diagnosis and management, negative perceptions of prescribed exercise and diet, physical symptoms interfering with behavior, and the presence of comorbidities.[15] Community engagement, patient education, and counseling are crucial. Digitally supported, patient-centric approaches that integrate personalized diet, exercise, and cognitive behavioral therapy through mobile applications can also offer continuous, tailored support and help improve patient compliance. The sphere of MASLD-specific pharmacotherapy is rapidly evolving. For a long time, Vitamin E and pioglitazone were the only drugs recommended by expert societies, although they were never formally approved by drug regulatory agencies for the management of MASLD. Saroglitazar, a dual peroxisome proliferator-activated receptor agonist, has been approved by the Drug Controller General of India for noncirrhotic MASLD with moderate fibrosis, MASH, or dyslipidemia.[3] Based on the MAESTRO-NASH and ESSENCE-3 trials’ findings, the US-FDA has recently given accelerated approval to resmetirom (thyroid hormone receptor-β agonist) and semaglutide (glucagon-like peptide-1 agonist), which have now been recommended by the American Association for the Study of Liver Diseases (AASLD) in MASLD with moderate fibrosis (LSM: 8–15 kPa).[16,17] A number of other drugs are currently being evaluated in phase 2/3 trials. While the expanding field of MASLD-specific pharmacotherapy is exciting, it should be reemphasized that lifestyle modifications remain the core of MASLD management, and the majority of patients with MASLD do not merit pharmacotherapy. Public Health Implications and Policy Imperatives As a rapidly expanding global public health problem, MASLD is likely to overwhelm the available healthcare infrastructure in the near future. An effective approach to reducing the MASLD burden requires a multifaceted strategy. This should include health education, promotion of healthy behaviors, strategic economic measures, health service integration, early diagnosis strategies, and targeted public health interventions. Comprehensive educational programs, tailored for various age groups, are needed to raise public awareness about MASLD risk factors and control strategies. There is a need to address knowledge gaps among both patients and physicians. Promoting proper nutrition and regular exercise, with an emphasis on culturally and socially appropriate solutions, is vital. Policymakers should consider strategic economic measures, such as imposing higher tariffs on unhealthy products such as sugary soft drinks, high-fat, and ultraprocessed foods. Developing an integrated and coordinated healthcare system that enables access to services across different levels of care is also essential. Given the commonalities in the pathophysiology and risk factors, such policy initiatives will help comprehensively tackle not only MASLD but also other prevalent noncommunicable diseases (NCDs) such as obesity, type 2 diabetes mellitus, and hypertension. Tackling the menace is beyond the scope of the average physician, and strong policy initiatives at a government level are the need of the hour. Recognizing the escalating public health, the Ministry of Health and Family Welfare of India took a significant step in 2021 by integrating MASLD into the existing National Programme for Prevention and Control of Cancer, Diabetes, Cardiovascular Diseases, and Stroke (NPCDCS), now renamed as National Programme for Non-Communicable Diseases (NP-NCD). This landmark integration signifies a comprehensive approach, encompassing health promotion, risk classification, timely diagnosis, and rapid treatment across various levels of health care, from community to tertiary care. Despite this crucial policy integration, significant challenges persist with no clear measure of the extent of NP-NCD implementation for MASLD.[18] The specific facilitators and barriers to its effective execution remain undetermined, and crucial data fields like waist circumference remain missing in NCD registers.[18] Thus, while the policy mandate is a laudable first step, further granular attention to operational details, capacity building for frontline workers with robust monitoring and evaluation mechanisms at the local level is needed. Conclusion MASLD represents an escalating public health crisis worldwide and in India. The silent progression of MASLD, coupled with the challenges in resource-limited settings, necessitates a paradigm shift toward accessible, cost-effective noninvasive screening tools. Tiered risk stratification using noninvasive tests like FIB-4 and elastography helps in making referral and management decisions. While comprehensive lifestyle modifications remain the cornerstone of management, overcoming barriers to adherence is vital and may be aided by culturally appropriate community-based interventions and innovative digital health solutions. The role of MASLD-specific pharmacotherapy is limited and evolving. A concerted, multisectoral public health response, grounded in evidence-based strategies and tailored to the sociocultural and economic landscape, is urgently required to mitigate the growing burden of MASLD and other noncommunicable diseases. Ethical approval statement Formal ethical approval from Institutional Ethical Committee is not required as this is purely a literature review and now new data was synthesized.