The Chromatin Accessibility Landscape of Nonalcoholic Fatty Liver Disease Progression

Common Genetic Variants and Nonalcoholic Fatty Liver Disease

nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum ranging from simple steatosis to steatohepatitis (NASH), increasing fibrosis and eventually, cirrhosis ([22][1]). Importantly, NASH accompanied by fibrosis and severe inflammation is the most relevant predictor for disease progression

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the United States and, indeed, worldwide. It has become a global public health issue. In the United States, the prevalence in the general population is estimated at approximately 20%, while that in the morbidly obese population at approximately 75-92% and in the pediatric population at approximately 13-14%. The progressive form of NAFLD, nonalcoholic steatohepatitis, is estimated at approximately 3-5%, with approximately 3-5% of these having progressed to cirrhosis. Thus, the numbers of individuals at risk for end-stage liver disease and development of primary liver cancer is large. NAFLD is an independent risk factor for cardiovascular disease, leads to increased all-cause mortality, and to increased liver-related mortality. This review focuses on recent advances in our understanding of the NAFLD disease spectrum, including etiology, diagnosis, treatment, and genetic and environmental risk factors and suggests future directions for research in this important area.

We explored the role of the adiponutrin (PNPLA3) nonsynonymous-rs738409 single nucleotide polymorphism (SNP) in genetic susceptibility to nonalcoholic fatty liver disease (NAFLD) and whether this SNP contributes to the severity of histological disease. Two hundred sixty-six individuals were evaluated in a case-control association study, which included 172 patients with features of NAFLD and 94 control subjects. The rs738409 G allele was significantly associated with NAFLD (P < 0.001; OR 2.8 95%, CI 1.5-5.2), independent of age, sex, body mass index (BMI), and Homeostasis Model Assessment (HOMA) index. When we tested the hypothesis of a relation between the SNP and the histological spectrum of NAFLD, a significant association was observed [chi2 19.9, degree of freedom (df): 2, P < 5 x 10(-5), adjusted for HOMA and BMI]. The degree of liver steatosis, as evaluated by liver biopsy, was significantly associated with the rs738409 G allele. Patients with CC genotype showed a lower steatosis score (14.9% +/- 3.9) in comparison with the CG genotype (26.3% +/- 3.5) and GG genotype (33.3% +/- 4.0) (P < 0.005). The proportion of the total variation attributed to rs738409 genotypes was 5.3% (beta 0.23 +/- 0.07; P < 0.002). Our data suggest that the rs738409 G allele is associated not only with fat accumulation in the liver but also with liver injury, possibly triggered by lipotoxicity.

Nonalcoholic fatty liver disease (NAFLD) is becoming a severe global public health problem, and can developed into fibrotic nonalcoholic steatohepatitis (NASH), but its risk factors have not been fully identified. The objective of this study was to investigate the association between the android-to-gynoid fat ratio (A/G ratio) and the prevalence of NAFLD. This cross-sectional study is based on the 2003-2006 and 2011-2018 cycles of the National Health and Nutrition Examination Survey and included 10,989 participants. Participants aged 20 and older without viral hepatitis or significant alcohol consumption were included. Dual-energy X-ray absorptiometry was used to assess body composition. NAFLD was diagnosed using the United States fatty liver index (US FLI). Multivariable logistic regression models were used to evaluate the association between the A/G ratio and NAFLD. The prevalence of NAFLD was 32.15% among the study population. Android percent fat and the A/G ratio were significantly higher in patients with NAFLD than in those without NAFLD [41.68% (0.25) vs. 32.80% (0.27), p < 0.001; 1.14 ± 0.01 vs. 0.94 ± 0.00, p < 0.001, respectively]. Logistic regression analysis showed that android percent fat was positively correlated to NAFLD (OR: 1.15, 95% CI: 1.11-1.18), while gynoid percent fat was negatively correlated to NAFLD (OR: 0.92, 95% CI: 0.90-0.94), and the A/G ratio was significantly associated with the prevalence of NAFLD (OR: 1.59, 95% CI: 1.38-1.82) and fibrotic NASH (OR: 2.01, 95% CI: 1.71-2.38). We also found that females had a notably diminished A/G ratio compared with males (0.91 vs. 1.12, p < 0.001). In addition, the female population proportion was negatively correlated with the A/G ratio, which may partly explain the lower prevalence of NAFLD in females. What is more, the OR value of the A/G ratio in the female subgroup was much higher than that in the male subgroup in all adjusted models. A/G ratio is significantly associated with NAFLD and fibrotic NASH. Women have a lower A/G ratio than men, which may explain the sex difference in NAFLD prevalence. Furthermore, with a higher A/G ratio, the association between females and NAFLD are greatly elevated.

Nonalcoholic Fatty Liver Disease in Children: Where Are We?

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Biomarkers in Fatty Liver Disease—Here is the Skinny

Associations of muscle mass and grip strength with severe NAFLD: A prospective study of 333,295 UK Biobank participants.

Fibroblast growth factor 21 as a biomarker for NAFLD: Integrating pathobiology into clinical practice

Defining severe NAFLD based on ICD codes in large cohorts: Balancing feasibility and limitations

Afamin is a member of the hepatokine that are strongly associated with various metabolic diseases. The relationship between afamin and nonalcoholic fatty liver disease (NAFLD) remains unclear. This study aimed to explore the correlation between serum afamin levels and NAFLD. We analyzed 88 NAFLD patients and 88 age- and sex-matched healthy controls who took their health examinations at the First Affiliated Hospital, Zhejiang University School of Medicine. The association was further confirmed in 22 biopsy-confirmed NAFLD patients and 36 healthy controls. Serum afamin levels were evaluated using an enzyme-linked immunosorbent assay (ELISA). NAFLD patients had significantly higher serum afamin levels than the healthy controls (14.79 ± 5.04 mg/L versus 10.83 ± 3.24 mg/L; P < 0.001). Serum afamin levels were positively correlated with metabolic parameters including the body mass index, waist circumference, systolic blood pressure, liver enzymes, and lipid profiles. A multiple regression analysis showed that serum afamin levels were independently related to the risk of NAFLD (OR: 1.289, 95% CI, 1.141–1.456; P < 0.001). The receiver operating characteristic (ROC) analysis showed that the area under curve (AUC) of serum afamin plus the BMI for detecting NAFLD was 0.878. In participants with liver biopsies, the serum afamin plus the BMI detected NAFLD with an AUC of 0.758. In conclusion, serum afamin levels were positively associated with prevalence and risk of NAFLD, and serum afamin plus the BMI had a high diagnostic performance for NAFLD. This study provides epidemiological evidence of afamin in NAFLD.

These recommendations are based on the following: (1) a formal review and analysis of the recently published world literature on the topic [Medline search up to June 2011]; (2) the American College of Physicians’ Manual for Assessing Health Practices and Designing Practice Guidelines; (3) guideline policies of the three societies approving this document; and (4) the experience of the authors and independent reviewers with regards to NAFLD. Intended for use by physicians and allied health professionals, these recommendations suggest preferred approaches to the diagnostic, therapeutic and preventive aspects of care. They are intended to be flexible and adjustable for individual patients. Specific recommendations are evidence-based wherever possible, and when such evidence is not available or inconsistent, recommendations are made based on the consensus opinion of the authors. To best characterize the evidence cited in support of the recommendations, the AASLD Practice Guidelines Committee has adopted the classification used by the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup with minor modifications (Table 1). The strength of recommendations in the GRADE system is classified as strong (1) or weak (2). The quality of evidence supporting strong or weak recommendations is designated by one of three levels: high (A), moderate (B) or low-quality (C). This is a practice guideline for clinicians rather than a review article and interested readers can refer to several comprehensive reviews published recently.

The increasing burden of non-alcoholic fatty liver disease: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the world. NAFLD encompasses a spectrum of liver disease, ranging from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). With the pandemic of obesity and type 2 diabetes mellitus (T2DM), there has been an exponential growth in the prevalence of NAFLD over the past two decades. The prevalence of NAFLD in most Asian countries, including China, is above 25% in the general adult population.[1] Furthermore, there is a developing childhood obesity pandemic, and a meta-analysis of 20,595 children in Asia generated a pooled NAFLD prevalence of 5.53%, which had increased by approximately 1.6-fold since 2010. The pooled prevalence of NAFLD in Asian children increased from those with normal weight (1.5%) to those who were overweight (16.7%) or obese (50.1%).[2] A recent study suggested that NAFLD is not uncommon in lean Chinese adults with a normal waist circumstance. Metabolic risk factors, rather than genetic factors, may play an important role in the development of lean NAFLD,[3] and the hepatic and extra-hepatic complications can also develop in lean patients, which reinforces the importance of considering metabolic phenotype in the assessment of NAFLD, rather than using body mass index-based approaches.[4] Renaming of NAFLD to MAFLD: A diagnosis of NAFLD is made on the basis of histological or imaging-derived evidence of steatosis, in the absence of a known etiology of fatty liver. With advances in knowledge of the pathogenesis of the condition, the "exclusive" term NAFLD no longer serves to precisely describe a highly heterogeneous disease. In 2020, the novel term of metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed in an attempt to create an "inclusive" diagnosis.[5] Zeng et al[6] performed a cross-sectional study of Chinese adults which showed that the prevalence of MAFLD is higher than that of NAFLD, and therefore the newly-defined label of MAFLD may better reflect the metabolic pathogenesis. Furthermore, a pathologic analysis of patients with MAFLD showed that a single metabolic defect can have a significant role in the development of fibrosis and that insulin resistance plays a key role in the progression of steatohepatitis and the development of significant fibrosis.[7] As Zheng et al discussed, by using the new terminology, "cryptogenic cirrhosis" and MAFLD can now be diagnosed in lean individuals using metabolic criteria, rather than being viewed as completely separate entities. The renaming of NAFLD to MAFLD may result in significant improvements in awareness, advocacy, research, and the clinical management of the condition.[8] Update on the pathogenesis of MAFLD: The pathogenesis of NAFLD/MAFLD is a multifactorial process, involving interactions among nutrition, metabolism, genetic predisposition, the gut microbiota, and environmental factors. Although a great deal of progress has been made in recent decades, the pathogenic mechanism of NAFLD/MAFLD has yet to be fully elucidated. In this issue of the Chinese Medical Journal (CMJ), Pan et al[9] give an overview of the role of hepatocyte nuclear factor 4α (HNF4α) in the pathogenesis of NAFLD. HNF4α has been shown to regulate bile acid, lipid, and glucose metabolism; and hepatic HNF4α expression is much lower in patients with NAFLD and mouse models of NASH. Furthermore, there is evidence that hepatic HNF4α plays a key role in the initiation and progression of NAFLD and may represent a therapeutic target for NAFLD.[9] Huang et al[10] presented a systematic review regarding the role of retinol-binding protein 4 (RBP4) in the development of NAFLD and its potential therapeutic application. RBP4 induces hepatic de novo lipogenesis, impairs fatty acid oxidation, increases insulin resistance, and promotes hepatic inflammation. Furthermore, a high plasma RBP4 concentration is associated with a high risk of NAFLD; and agents that reduce the circulating RBP4 concentration and/or hepatic RBP4 expression have a protective effect against NAFLD. These findings suggest that RBP4 could be targeted as a novel diagnostic marker or therapeutic target for NAFLD.[10] Jackson et al[11] summarized the essential physiology of bile acid and sphingolipid metabolism, because the dysregulation of both are potential contributors to NAFLD. Specifically, the dysregulation of bile acid and sphingolipid metabolism has been linked to hepatic steatosis, inflammation, and fibrosis, and the further exploration of the pathologic effects mediated by bile acids and sphingolipids may also lead to new diagnostic and therapeutic strategies for NAFLD. Hepatitis B and concurrent MAFLD: Concomitant NAFLD/MAFLD in patients with chronic hepatitis B (CHB) has become highly prevalent over the past two decades. However, the risks associated with the dual etiologies, outcomes, and mechanisms involved in the interaction between CHB and NAFLD have not been fully characterized. Tong et al[12] summarize the findings of recent clinical and basic research studies related to the potential interactions between CHB and NAFLD. The prevalence of hepatic steatosis in CHB has been reported to be 32.8% (95% CI, 28.9%–37.0%); and it is higher in men and patients with obesity. The presence of hepatic steatosis in patients with CHB is related to metabolic, rather than viral factors. Patients with both CHB and NAFLD are more likely to experience liver-related outcomes or death than those with CHB alone. Many studies have shown that steatosis is positively associated with the clearance of hepatitis B virus (HBV) surface antigen and a reduction in HBV DNA, and the prevalence and incidence of NAFLD in patients with CHB may be lower than in those without. In Chang and colleagues' multi-center, prospective study of 1000 treatment-naïve patients with biopsy-confirmed CHB, NASH was found in 182 patients (18.2%), 46% of these achieved resolution of NASH, and only 4% of the patients developed new-onset NASH after 72 weeks of entecavir treatment. Body mass at baseline and a slight weight change during follow-up were associated with the prevalence, incidence, and remission of NASH in patients with CHB.[13] Finally, steatosis is more prevalent in patients with CHB and is a common reason for abnormal circulating liver enzyme activities in infected patients with a low HBV-DNA load or a good response to infection. From MAFLD to HCC: Although viral hepatitis remains the most common etiology of liver cancer-related deaths, NAFLD is the most rapidly growing contributor to mortality and morbidity related to liver disease in the world. The global burden of HCC is increasing alongside the NAFLD pandemic. A recently published review in CMJ summarizes the characteristics of NAFLD-related HCC.[14] The incidence of NAFLD-related HCC is much higher in patients with severe steatohepatitis, advanced fibrosis, and cirrhosis than in individuals with NAFLD in general, and it is most likely to occur in older men with metabolic syndrome. The incidence of HCC in patients with NAFLD-related cirrhosis is lower than that in those with hepatitis C virus- or HBV-related cirrhosis. Compared with HCCs of other etiologies, NAFLD-related HCCs are generally large, well-differentiated, solitary lesions with a higher level of inflammatory infiltration, and they are less likely to metastasize extra-hepatically. Moreover, NAFLD-related HCC is more likely to develop in the absence of cirrhosis.[14] In a recent issue of CMJ, Rios et al reviewed the progression of MAFLD to HCC and stated that lipotoxicity, insulin resistance, oxidative stress, chronic inflammation, multiple gene mutations, and alterations to the fecal microbial composition are the most important factors determining hepatic carcinogenesis, whereas steatohepatitis and fibrosis are not essential for the development of HCC in obesity-related fatty liver disease.[15] Non-invasive diagnosis of MAFLD: Accumulating evidence suggests that non-invasive tests can be used to diagnose NAFLD, assess its severity, and predict its prognosis. In a recent issue of CMJ, Li et al review new developments in non-invasive testing for NAFLD, with respect to steatosis, steatohepatitis, and fibrosis.[16] For the identification of steatosis, ultrasonography remains the most common method, because of its wide availability and low cost, but magnetic resonance imaging-proton density fat fraction is currently the most accurate means of identifying hepatic steatosis, and transient elastography (TE) represents a promising technique for the evaluation of hepatic steatosis and fibrosis. Except for the widely used controlled attenuation parameter, ultrasonographic attenuation has been reported to have a low failure rate and shows moderate-to-high performance for the discrimination of degrees of steatosis in patients with chronic liver disease.[17] Various non-invasive algorithms, such as the fatty liver index (FLI) and hepatic steatosis index (HSI), have been used as screening tests for steatosis in epidemiologic studies. In Chen et al's study, both FLI and HSI were shown to be useful screening tools for NAFLD in adults with obstructive sleep apnea/hypopnea syndrome.[18] In patients with steatohepatitis, some circulating biomarkers correlate with the severity of NASH but show modest predictive accuracy. Regarding liver fibrosis, liver stiffness measurement (LSM) using TE is highly accurate and is widely used worldwide. Magnetic resonance elastography is marginally better than TE, but it is limited by its cost and availability. In contrast, simple fibrosis scores, such as the fibrosis-4 (FIB-4) index and the NAFLD fibrosis score, can be easily calculated and are recommended for use in primary care. These scores and LSM have sufficiently high negative predictive values to exclude advanced fibrosis. Recently, Shi et al found that the combination of the presence of a metabolic disorder and the FIB-4 index provides for a more accurate diagnosis of advanced fibrosis in patients with NAFLD.[19] Thus, as part of the redefinition of MAFLD, metabolic risk factors should be taken into account during diagnosis and management. Therapeutic approaches to MAFLD: In a recent issue of CMJ, Shi et al[20] discuss recent advances and provide a perspective regarding the treatment of MAFLD. Weight management through an appropriate diet and physical activity remains the most important component of the treatment of MAFLD. Weight loss through bariatric surgery may be an effective means of achieving significant improvements in patients with morbid obesity and MAFLD. Although numerous agents, including novel modulators of glucolipid metabolism, are being assessed in clinical trials, there is still no approved drug for the treatment of MAFLD. The nomenclature of MAFLD emphasizes the existence of concomitant metabolic disorders and obesity, and patients with MAFLD are therefore subject to both hepatic and other metabolic risks. Thus, drugs targeting underlying cardiometabolic risk factors are essential to improve the outcomes of patients with MAFLD. The screening of patients who are at a high risk of MAFLD and the provision of a comprehensive individual therapeutic program are critical. For example, patients with MAFLD and T2DM would benefit from the use of antidiabetic agents, patients with overweight or obesity would gain greater benefit from weight management, and those with metabolic syndrome require comprehensive individualized management. These therapeutic approaches might help identify the patients with MAFLD who are at the greatest risk of disease progression and facilitate more precise and appropriate management. Summary and prospects: The growing burden of NAFLD parallels the increasing prevalences of obesity and metabolic syndrome worldwide. Cardiometabolic risk factors have a bidirectional relationship with NAFLD. The majority of patients with NAFLD meet the diagnostic criteria for MAFLD, and this represents a more appropriate term. Further clinical studies of the changes created by the redefinition of NAFLD/MAFLD, including the epidemiologic character, prognosis, diagnosis, prevention, and treatment of the condition, are required. Currently, MAFLD and CHB are increasingly being diagnosed in the same individuals, and the pathophysiological interaction between MAFLD and HBV infection in patients is worthy of further exploration. The long-term outcomes of MAFLD are related to the severity of metabolic dysfunction and liver fibrosis, rather than obesity. Metabolic syndrome and T2DM are the most important risk factors for MAFLD-related cirrhosis and HCC. A lack of awareness regarding the factors underlying MAFLD-related HCC may lead to delay in its diagnosis. The further development and validation of non-invasive diagnostic techniques and clinical pathways will help clinicians assess the severity of MAFLD, categorize patients, and identify those requiring specific treatments. There is still no effective approved drug for MAFLD, but the in-depth study of pathologic mechanisms may provide new therapeutic targets. Measures to increase awareness and treat or prevent the associated cardiometabolic diseases are necessary to reduce the growing burden of MAFLD. Funding This study was supported by grants from the National Key Research and Development Program of China (No. 2021YFC2700802), the National Natural Science Foundation of China (Nos. 81900507 and 82170593). Conflicts of interest None.

Answer questions and earn CME Content available: Author Interview and Audio Recording India is the seventh largest and second most populous country in the world. It has a rapidly developing economy with an estimated gross domestic product of US $2.87 trillion. Easy access to calorie-dense food and sedentary lifestyle together with the modern epidemics of diabetes mellitus (DM) and obesity have catapulted nonalcoholic fatty liver disease (NAFLD) into a substantial public health problem in India as in other parts of the world. NAFLD has emerged as one of the leading causes of cirrhosis, hepatocellular carcinoma (HCC), and liver transplant in India.1 Given its enormous population, the burden of NAFLD in India is likely to be substantial, which may significantly impact the limited health care resources in the country. The prevalence of NAFLD among the general population in India ranges from 9% to 53%.1, 2 One of the caveats in interpreting epidemiological data on NAFLD from India is that many of the studies have been conducted in the hospital setting and are therefore liable to referral bias. Although differences in diagnostic techniques for NAFLD may partly account for the wide variation in reported prevalence, a possible rural-urban divide and geographical variation are evident from the available data (Fig. 1). Most studies from urban centers have reported a higher prevalence as compared with those that cater to a largely rural population. One of the earlier population-based studies from India that showed a prevalence rate of 8.7% in predominantly nonobese populations was from rural West Bengal (Table 1).1 More recently, a population-based study from coastal south India reported an overall NAFLD prevalence rate of 49.8%; urban domicile was found to be associated with a higher risk for NAFLD after adjusting for sex, body mass index (BMI), DM, and metabolic syndrome (adjusted odds ratio [OR], 1.21; P = 0.048).3 As a part of the ongoing community-based Prospective Urban Rural Epidemiology (PURE) cohort study in north India, prevalence of NAFLD was found to be higher in urban communities (53.7%) in comparison with rural communities (30.2%) (P < 0.001).4 Among the high-risk groups, prevalence has been reported to be higher among those with type 2 DM, prediabetes, obesity, and metabolic syndrome.1 One of the multicenter studies across 101 Indian cities estimated the prevalence rate of NAFLD as 56.5% (n = 522) among 924 patients with type 2 DM.5 Further worrisome are the recent data showing a high prevalence of NAFLD in obese Indian children. More important than the mere presence of fatty liver is the prevalence of progressive nonalcoholic steatohepatitis (NASH) with or without hepatic fibrosis that adds to the significant liver disease and extrahepatic disease burden. Even though earlier data had suggested a mild liver histology in Indian patients with NAFLD,1 a recent retrospective review of 1000 liver biopsy-proven patients with NAFLD showed histological NASH in more than 60% of patients and advanced fibrosis (≥F3) in 35% of patients.6 Further, an interim analysis of an ongoing real-life, multicentric observational study (Indian Consortium on NAFLD [ICON-D]) in approximately 3000 patients with NAFLD showed the presence of significant fibrosis in 19%, 21%, and 29% of patients as assessed by Fibrosis-4 (FIB-4), aspartate aminotransferase (AST)-to-platelet ratio index (APRI), and FibroScan, respectively.7 The presence of metabolic risk factors and data on explant pathology also suggest NAFLD to be the predominant cause of cryptogenic cirrhosis and cryptogenic HCC in India (Table 2). Similar to data from the West, a recent Indian study has also shown a trend of NASH as the increasing cause of HCC over the years.8 Data from India corroborate that NAFLD is associated with several extrahepatic conditions, such as cardiovascular disease, chronic kidney disease, polycystic ovarian syndrome, obstructive sleep apnoea, vitamin D deficiency, and hypothyroidism.1 NAFLD also has been shown to affect quality of life, particularly in overweight/obese patients with NAFLD. As in the rest of the world, both environmental and genetic factors have been shown to be involved in the pathogenesis of Indian patients with NAFLD. Globally, multiethnic studies have suggested that Indians are more predisposed to insulin resistance and its consequences, including NAFLD. Most of the data from India suggest the presence of insulin resistance in patients with NAFLD; however, a small study suggested occurrence of NAFLD without insulin resistance.9 Earlier data from India had suggested certain subtle differences between Indian patients with NAFLD and their Western counterparts, with Indian patients having lower BMI and fewer cases of morbid obesity, diabetes, hypertension, or metabolic syndrome.1 However, most patients (85%-90%) with NAFLD in India are still overweight or obese as per the Asia-Pacific cutoffs for BMI, and around 10% to 15% of the patients are "lean" with a normal BMI (<23 kg/m2) (Table 1). The interim results of the ongoing real-life study from India (ICON-D) in approximately 3500 patients (mean BMI, 27.6 ± 5.7 kg/m2) showed the presence of overweight (BMI, 23-24.9 kg/m2) in 16%, obesity (BMI ≥ 25 kg/m2) in 73%, and lean NAFLD (BMI < 23 kg/m2) in 10.6% of patients7 (Table 1). Overall, metabolic syndrome was present in 43%, and at least one metabolic risk factor was present in 93% of patients with NAFLD (the commonest being central obesity in 84%).7 Indian data in lean patients with NAFLD suggest that although their total body fat is comparable with lean individuals without NAFLD, they are metabolically unhealthy, with an expanded visceral adipose tissue mass similar to overweight or obese patients with NAFLD.1 In addition to metabolic risk factors, studies from India have also suggested the role of small intestinal bacterial overgrowth, endotoxemia, and toll-like receptor expression in the pathogenesis of NAFLD.10 Dietary constituents and cooking medium vary greatly in different geographic regions of India. A substantial proportion of Indians consume a purely vegetarian diet. The influence of diet on the risk for NAFLD is an underexplored area. A small study from the rural area of Maharashtra state suggested that the risk for NAFLD did not differ between those consuming vegetarian and mixed diets.11 Among the genetic studies, earlier Indian data had suggested the lack of association of NAFLD with HFE gene mutations.1 PNPLA3 and TM6SF2 gene polymorphisms have been shown to be closely associated with prevalence and severity of NAFLD in India. A recent exome-wide association study showed a novel association of nuclear polymorphism rs4788084 with hepatic fat content, which regulates the expression of IL-27, an immune-regulatory gene.12 A novel variant of phosphatidylethanolamine N-methyltransferase (involved in fatty acid metabolism), identified using whole-exome sequencing, was shown to confer a three times greater risk for NAFLD in lean individuals.13 There are some data that suggest that the genetic predisposition to NAFLD may vary according to ancestral ethnicity. A recent study found that the TM6SF2 variant (rs58542926) was significantly associated with NAFLD susceptibility in individuals from South Indian ethnicity (OR, 1.9; 95% confidence interval [CI]: 1.5-3), while the PNPLA3 variant (rs2281135) conferred a higher risk for NAFLD in those of North East Indian ancestry (OR, 2.7; 95% CI: 1.37-5.3).14 Concomitant variants in both genes were common in patients with NAFLD irrespective of ethnicity, and the authors concluded that the presence of an additional variant compounded the risk for NAFLD.14 The diagnosis and treatment of patients with NAFLD in India has largely been on the same lines as suggested by various international societies and Indian National Association for the Study of the Liver.1 However, because of the limitations in resources, separate guidelines have been suggested for the management and referral of patients from primary health care level to secondary and tertiary care levels.15, 16 Among the various noninvasive scores, APRI has been found to be more accurate than FIB-4 in ruling out significant fibrosis in the community setting. True to the concept of population-based differences, different cutoffs for the Indian population have been suggested for controlled attenuation parameter, FIB-4, and FibroScan-AST scores for the assessment of hepatic steatosis, hepatic fibrosis, and NASH.17, 18 The large real-life data from the country suggest that in clinical practice, liver biopsy is not a well-accepted modality for determining disease severity, and the practice of liver biopsy in NAFLD in India may be restricted to only tertiary care centers.7 Lifestyle interventions are the primary modality for the management of NAFLD and have been shown to improve biochemical and histological outcomes in Indian patients.1 A study with paired liver biopsies in 58 morbidly obese patients showed improvement in all histological parameters of NAFLD, including steatosis, ballooning, lobular inflammation, NAFLD Activity Score, and fibrosis, at 1-year follow-up after bariatric surgery.19 Of various endoscopic bariatric therapies, only a small amount of data for eight patients described the utility of intragastric balloon for inducing weight loss in morbidly obese patients with cirrhosis (4-cryptogenic cirrhosis) on the transplant wait list.20 Pharmacotherapy in patients with NASH was earlier restricted to the use of vitamin E and pioglitazone.1 However, based on the recent data, the drug controller general of India has approved the use of saroglitazar, a dual peroxisome proliferator-activated receptor α/γ agonist, in a dosage of 4 mg/day for use in patients with NASH with F1-3 fibrosis.21 Although not recommended, the data on the use of vitamin D supplementation, high-potency multistrain probiotic, glucagon-like peptide-1 (GLP-1) agonists, and sodium-glucose co-transporter-2 (SGLT-2) inhibitors also have been encouraging in Indian patients with NAFLD. NASH-related decompensated cirrhosis and HCC are leading indications for liver transplant in India; however, there is a paucity of Indian data on transplant outcomes in patients with NASH. Given the high prevalence of NAFLD among the general population in India, donor steatosis in the living donor liver transplantation program is also a vexing problem.22 With NAFLD being a lifestyle disease, efforts for prevention and control are required not only at the individual and family level but also at the government and administrative level. The recent integration of NAFLD into the National Program on Prevention and Control of Cancer, Diabetes, Cardiovascular disease and Stroke by the Ministry of Health and Family Welfare of India is an encouraging step in this direction.16 In fact, India has become the first country to include NAFLD in one of its national programs. NAFLD has emerged as a major public health issue in India that is responsible for significant burden of hepatic and extrahepatic disease. Education of healthy lifestyle to children and adolescents in schools and colleges may be the need of the hour. Efforts are also required to change the perception of both physicians and the public toward this ongoing silent pandemic. Although much progress has been witnessed in the last one or two decades in NAFLD research in India, a lot more needs to be done.