New trends on obesity and NAFLD in Asia

Nonalcoholic Fatty Liver Disease in Children: Where Are We?

Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, affecting approximately 25% of the world's population. Recently, because of the sedentary lifestyle and overnutrition resulting from urbanisation, the burden of NAFLD has rapidly increased in many Asian countries. Currently, the prevalence of NAFLD in Asia is approximately 30%, as is the case in many Western countries. In Asia, the prevalence and presentation of NAFLD vary widely across regions because of the substantial diversity in race, socioeconomic status and living environment. Furthermore, the dual aetiology of fatty liver, particularly with viral hepatitis in Asia, makes it complex and challenging to manage. Because Asians are likely to have central adiposity and insulin resistance, approximately 7%-20% of non-obese Asians with body mass indexes of less than 25kg/m2 are estimated to have NAFLD. Accumulating evidence indicates that NAFLD is associated with various extrahepatic comorbidities such as cardiovascular disease, chronic kidney disease, malignancy, in addition to liver-specific complications. Therefore, NAFLD should be managed as a multisystem disease in conjunction with metabolic syndrome. Lifestyle modification remains the basis of NAFLD management, but few patients can achieve adequate weight loss and maintain it long term. While various pharmacological agents are in phase 3 trials for steatohepatitis, Asian patients are underrepresented in most trials. This article reviews the epidemiological trends, clinical features, optimal assessment and current management practices for NAFLD in Asia.

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.

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.

398 Background: PD may increase the risk of development of NAFLD, a precursor for non-alcoholic steatohepatitis and cirrhosis. Studies have not clearly identified consistent RFs for NAFLD, but patients with post-PD NAFLD do not appear to have the traditional RFs for NAFLD such as metabolic syndrome. The primary objective of this study was to identify the incidence of and RFs for post-PD NAFLD. Methods: Retrospective chart review was done on 425 patients who underwent PD for a cancer diagnosis at our institution from 2007 to 2017 and had at least 6 months of postoperative follow up. Cox proportional hazards model was used to examine multiple potential pre-operative RFs for NAFLD including body mass index (BMI), estimated surgical blood loss, LFTs, hemoglobin, albumin, age, sex, comorbidities, and tobacco use as predictors of time to develop post-PD NAFLD. Patients without post-PD NAFLD were considered censored at the time of last follow-up. The proportional hazard assumptions were validated. Post-PD NAFLD was identified by review of radiology reports. Results: Sixty (14.1%) of the 425 patients had post-PD NAFLD. The male to female ratio was 236:189 and median follow up time was 1 year. Median age was 65 years with median time to NAFLD development of 7 months. Multivariate Cox Proportional Hazard model identified higher BMI and female sex as RFs for the development of post-PD NAFLD. Each 1-point increase in BMI implied an 8.43% increase in the hazard of fatty liver (HR = 1.083, 95% CI: 1.032-1.136; p=0.001). Females had 89.7% higher hazard of fatty liver compared to males (HR = 1.897, 95% CI: 1.084 - 3.319; p=0.025). There was no statistically significant association between post-PD NAFLD and other pre-operative characteristics studied. Conclusions: Female sex and higher BMI may be RFs for the development of NAFLD post-PD. No other pre-operative RFs were identified. In conclusion, patients with higher BMI and female gender may need closer monitoring for earlier detection and management of NAFLD. [Table: see text]

The growing burden of non-alcoholic fatty liver disease (NAFLD) parallels the increasing prevalence of obesity in Asia. The overall prevalence of NAFLD in Asia is now estimated to be 29.6% and may have surpassed that in Western populations. NAFLD increases with increasing age and is closely associated with metabolic syndrome. Ethnic differences exist in the prevalence of NAFLD, but the underlying factors are unclear. There were initial concerns about lean NAFLD being associated with more severe liver disease and increased mortality, but subsequent studies suggested otherwise. Only some NAFLD patients progress to develop advanced liver fibrosis and cirrhosis, while the liver status remains unchanged in the majority; fibrosis stage is the most important predictor of disease-specific mortality in NAFLD. Surveillance for hepatocellular carcinoma (HCC) remains a challenge due to undiagnosed cirrhosis and the development of HCC in non-cirrhotic NAFLD patients. Diabetes mellitus shares a bidirectional relationship with NAFLD; NAFLD is highly prevalent among patients with diabetes mellitus, and diabetes mellitus is associated with more severe NAFLD. Chronic hepatitis B (CHB) is a major cause of chronic liver disease in Asia; NAFLD and CHB are increasingly observed together because of the increasing prevalence of NAFLD. Despite studies reporting favorable virologic outcome in CHB patients with NAFLD, NAFLD has been found to be independently associated with fibrosis progression and poorer prognosis in CHB patients. Therefore, NAFLD in CHB patients should be given more attention.

The incidence of obesity is increasing in Asia, with implications on gastrointestinal (GI) and liver diseases. The Gut and Obesity in Asia Workgroup comprises regional experts with the aim of studying relationship between obesity and the GI and liver diseases in Asia. Through literature review and the modified Delphi process, consensus statements examining the impact of obesity on esophageal, gastric, pancreatic, colorectal, and liver diseases, exploring relationship between gut microbiome and obesity, and assessing obesity therapies have been produced by the Gut and Obesity in Asia Workgroup. Sixteen experts participated with 9/15 statements having strong consensus (>80% agreement). The prevalence of obesity in Asia is increasing (100% percentage agreement in brackets), and this increased prevalence of obesity will result in a greater burden of obesity-related GI and liver diseases (93.8%). There was consensus that obesity increases the risk of gastric cancer (75%) and colorectal neoplasia (87.5%). Obesity was also associated with Barrett's esophagus and esophageal adenocarcinoma (66.7%) and pancreatic cancer (66.7%) in Asia. The prevalence of non-alcoholic fatty liver disease (NAFLD) in Asia is on the rise (100%), and the risk of NAFLD in Asia (100%) is increased by obesity. Obesity is a risk factor for the development of hepatocellular carcinoma (93.8%). Regarding therapy, it was agreed that bariatric surgery was an effective treatment modality for obesity (93.8%) but there was less agreement on its benefit for NAFLD (62.5%). These experts' consensus on obesity and GI diseases in Asia forms the basis for further research, and its translation into addressing this emerging issue.

Watch a video presentation of this article Watch an interview with the author Nonalcoholic fatty liver disease (NAFLD) affects about 20% to 30% of the global population and increases the risk for hepatic and extrahepatic complications, including cardiovascular disease, diabetes, and some types of cancer.1 Although NAFLD is strongly associated with obesity, not all obese subjects will experience development of disease; conversely, a significant proportion of patients will have a normal body mass index (BMI) and are commonly referred to as having "lean NAFLD," or NAFLD in a lean person. Lean NAFLD is defined as disease that develops in subjects with a normal BMI based on ethnic-specific cutoffs of 25 kg/m2 in Caucasian patients and 23 kg/m2 in Asian patients. A limitation of this definition is that it relies solely on BMI, an imperfect index of body fat topography, and fails to identify body fatness in nearly half of adults. Notably, visceral adiposity is more strongly implicated in the predisposition to NAFLD development irrespective of BMI. Similarly, there is a lack of incorporation of concepts surrounding metabolic health in the current definition, with nearly a third of lean individuals likely being metabolically unhealthy (Fig. 1). Lean NAFLD prevalence rates range from 5% to 26%, but 5% to 45% in Asians and 5% to 20% in European populations1 (Fig. 2). In China, of 6905 subjects with a BMI < 25 kg/m2, 7.27% had ultrasonographic evidence of hepatic steatosis, whereas in another study of 2000 Chinese subjects with BMI < 24 kg/m2, 18% had NAFLD. In Hong Kong, the prevalence rate of NAFLD based on proton magnetic resonance spectroscopy (1H-MRS) spectroscopy was 19% in subjects with a BMI < 25 kg/m2. Other countries in Asia demonstrate a similar prevalence of BMI-based lean NAFLD (Japan: 15.2% in 3271 nonobese subjects; India [urban West Bengal]: 5% in those with BMI < 25 kg/m2 based on ultrasonography and subsequent computed tomographic validation; Korea: 12.6% in 29,994 health check nonobese participants). In western populations, the Dallas Heart Study revealed a prevalence rate of hepatic steatosis by 1H-MRS that ranged from 11% in African Americans to 20% in Caucasians and 26% in Hispanics with a BMI < 30 kg/m2. Similarly, a large study including subjects from Australia and Italy suggested that the prevalence rate of NAFLD was 20% in those of Caucasian descent with a BMI < 25 kg/m2.2 Data on the true population prevalence and ethnicity-based variations in lean NAFLD prevalence are still limited. By definition, patients with lean NAFLD have a lower BMI, but they also have a lower waist circumference and a more favorable metabolic profile with lower levels of dyslipidemia, diabetes, hypertension, glycemia, and homeostasis model assessment insulin resistance index compared with their obese counterparts. In cross-sectional studies, lean patients also have less hepatic inflammation and fibrosis. Despite the favorable phenotype, however,2, 3 lean patients with NAFLD may have a worse outcome and accelerated disease progression,4, 5 although one study in Chinese patients with shorter follow-up (4 years) suggested that nonobese patients may have a better prognosis, although this was not significant.3 As would be expected from the underlying metabolic abnormalities, lean NAFLD is associated with an increased risk for incident diabetes and cardiovascular disease compared with those without NAFLD.6 The pathophysiological pathways underlying the development and progression of NAFLD in lean subjects are not entirely clear. However, emerging evidence indicates that lean NAFLD is a distinct entity shaped by the dynamic interaction of genetic predisposition, metabolic dysregulation, the gut microbiota, and the enterohepatic circulation. Comparing lean and nonlean patients with NAFLD, the prevalence of the PNPLA3 (G) allele was reported to be higher in lean individuals in some but not all reports.7, 8 An increased prevalence of the TM6SF2 (T)2 and IFNL3/IFNL4 (C) allele among lean patients has also been demonstrated.9, 10 Lean patients with NAFLD tend to have a distinct metabolic and gut microbiota profile with higher concentrations of lysine that is implicated in visceral fat accumulation.7 In another study, patients were reported to have increased bile acids and farnesoid X receptor (FXR) activity (measured by fibroblast growth factors 15/19), implying that they have better metabolic adaptation and are perhaps relatively obese resistant. Notably, this adaptation attenuates with progression of disease2 (Fig. 3). Intriguingly, pilot data suggest that patients with lean NAFLD may have a distinct gut microbiota profile with enrichment of species implicated in the generation of liver fat.2 No specific guidelines exist for the management of lean as opposed to nonlean NAFLD. The current recommendations of the American Association for the Study of Liver Disease and the European Association for the Study of the Liver are weight loss alone or accompanied by increased physical activity for all patients with NAFLD. Although weight loss might intuitively appear to be less beneficial in lean patients, there are demonstrable effects of lifestyle intervention even in this subgroup.11 High fructose and cholesterol intake has been reported in patients with lean NAFLD, and it would seem appropriate to recommend reducing intake of these nutrients, while encouraging adoption of a Mediterranean-type diet. The latter also has beneficial effects on cardiovascular disease and visceral fat accumulation.12 Similarly, emerging evidence indicates that exercise can reduce liver fat independent of weight loss.13 Lean patients with NAFLD are underrepresented in ongoing clinical trials; thus, the impact of current investigational agents on lean disease is unclear. Of interest, inhibition of ileal bile acid uptake led to resolution of steatohepatitis in a mouse model,2 whereas liraglutide, a glucagon-like peptide-1 analogue, improved liver histology in lean patients.14 A significant proportion of patients with NAFLD are lean; however, this entity remains poorly characterized and understood. Although these patients demonstrate distinct pathophysiological mechanisms culminating in similar liver histology to obese patients, individuals with lean NAFLD remain at risk for development of hepatic and extrahepatic complications. Targeted studies are required to further clarify lean NAFLD pathogenesis and to develop appropriate management approaches.

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.

Where are we in the search for noninvasive nonalcoholic steatohepatitis biomarkers?

Comments on ‘Low serum sex hormone binding globulin is associated with nonalcoholic fatty liver disease in type 2 diabetic patients’

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.

Magnitude of Nonalcoholic Fatty Liver Disease: Eastern Perspective

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide.1, 2 Non-alcoholic steatohepatitis (NASH), the more severe form of NAFLD characterized by inflammation, hepatocyte ballooning and fibrosis, is associated with increased mortality from liver-related complications. With better understanding of the pathogenesis of NAFLD, the original two-hit hypothesis of insulin resistance and oxidative stress has evolved into a multiple-parallel hits hypothesis.3 Lipotoxicity is now thought to play a central role in NASH (and the metabolic syndrome), whereas simple steatosis may reflect a protective mechanism in place to buffer toxic lipid species.4 Oxidized low-density lipoprotein (oxLDL) can be defined as a particle derived from circulating low-density lipoprotein (LDL) that has undergone oxidative changes. The concept of oxidative stress and oxLDL is well established in atherogenesis but has only been recognized recently in the pathogenesis of NASH.5 OxLDL is taken up by macrophages by way of scavenger receptors, which unlike the LDL receptor, is not downregulated when the cholesterol content of the macrophage increases. The excessive accumulation of cholesterol leads to foam cell formation and activation of pro-inflammatory pathways in atherogenesis. Kupffer cells are the liver's resident macrophage population. Similar to foam cell formation in atherogenesis, foamy Kupffer cells were found in a hyperlipidemic mouse model of NASH, and the omission of cholesterol from the diet prevented the formation of the foamy Kupffer cells and hepatic inflammation.6 In a separate study, the administration of oxLDL to mice fed with a high-fat diet also induced NASH, further confirming the role of oxLDL in the pathogenesis of NASH.7 Activated Kupffer cells secrete interleukin-1 and tumor necrosis factor-α; these pro-inflammatory cytokines in turn activate the sterol regulatory element-binding protein 2 (SREBP-2) in hepatocytes. Physiological activation of SREBP-2 under low cholesterol conditions promotes cholesterol synthesis and retention. However, SREBP-2 is inappropriately activated despite cholesterol overload in NASH. The excess free cholesterol interrupts with the function of mitochondria and endoplasmic reticulum, leading to hepatocyte injury and death. In addition, activated Kupffer cells also secrete transforming growth factor-β1 which activates hepatic stellate cells, thus promoting hepatic fibrosis.8 OxLDL may also directly activate hepatic stellate cells via the lectin-like oxLDL receptor-1 (Fig. 1a).9 Anti-oxLDL antibodies (oxLDL-ab) have been shown to correlate negatively with hepatic inflammation.10 However, its potential as a marker for NASH is limited by the fact that the levels may vary from person to person and from time to time and may be influenced by exposure to pathogen due to molecular mimicry.5 On the other hand, immunization to boost oxLDL-ab has been shown to be protective against atherosclerosis and recently against NASH in mouse models, and these deserves further study (Fig. 1b).10 In this issue of the Journal, Ampuero and colleagues explore the possibility of using oxLDL-ab as a biomarker for NAFLD/NASH.11 This cross-sectional study included 72 patients with biopsy-proven NAFLD, among whom 38 had body mass index above 30 kg/m2 and 26 had NASH. By multivariate analysis, the oxLDL-ab level was independently associated with severe steatosis, while the oxLDL-ab-to-high-density lipoprotein cholesterol (HDL-C) ratio was associated with NASH and advanced fibrosis. Interestingly, the association between oxLDL-ab-based biomarkers and histological severity was only observed in NAFLD patients with body mass index below 30 kg/m2. The findings by Ampuero and colleagues are exciting and also raise new questions. While non-invasive tests of liver fibrosis are relatively well developed, the diagnostic accuracy of existing NASH biomarkers is moderate at best. The most widely tested serum marker of cytokeratin-18 fragments, which reflect hepatocyte apoptosis, showed initial promising results but only modest accuracy for diagnosing NASH in subsequent validation studies.12 The lack of a robust NASH biomarker hinders drug development and makes routine management of NAFLD suboptimal. In the current study, while the oxLDL-ab/HDL-C ratio appeared markedly increased in non-obese patients with NASH, the findings were based on a relatively small number of patients, and formal c-statistics and external validation have not been performed.11 On another note, the use of NASH biomarkers to monitor patients and assess treatment response is an even bigger question. At present, most biomarker studies are of cross-sectional design. Whether the change in biomarkers over time reflects histological and clinical progression or response is largely unknown. Nonetheless, oxLDL can potentially be modified by lipid lowering agents and anti-oxidants. For instance, vitamin E reduces oxLDL uptake by aortic smooth muscle cells by down regulating CD36 scavenger receptor, the specific oxLDL receptor.13 It would be interesting to evaluate the serial oxLDL or oxLDL-ab levels against histological changes of NASH. Another intriguing question raised by the study of Ampuero and colleagues is why the association between oxLDL-ab and NAFLD severity was only observed in non-obese patients. NAFLD in non-obese patients has been well described in the Asian population and is recently found to be not uncommon in western countries as well.14 It should be noted, however, that a wide range of body mass index has been used to define obesity in different ethnic groups. In particular, Asians tend to develop central obesity and metabolic complications at a lower body mass index. This is the basis for using lower body mass index cutoffs in some populations, although the definition is not universally agreed. In any case, cutoffs are largely arbitrary. In reality, the higher the adiposity, the higher the prevalence of NAFLD and its associated metabolic diseases. Moreover, body mass index is an imperfect measure of adiposity. Because it is calculated from body weight and body height, it cannot distinguish between muscle and fat mass. Waist circumference may be a better reflection of central or visceral obesity and has been adopted by the Third Adult Treatment Panel of the National Cholesterol Education Program and the International Diabetes Federation as one of the criteria to diagnose metabolic syndrome. Overall, even in the non-obese population, higher body mass index and waist circumference is associated with NASH and liver fibrosis, suggesting this is but the spectrum of disease.15 Data interpretation for non-obese NAFLD in a liver biopsy cohort can be difficult. Unlike population studies, patients undergoing liver biopsy are highly selected. Typical indications for liver biopsy include uncertain diagnosis (i.e., to rule out alternative diagnoses), high likelihood of advanced disease (based on metabolic risk factors or prior assessment using non-invasive tests), and participation in drug trial. The indications for liver biopsy in obese and non-obese patients can be different. In the current study, non-obese patients with NASH or advanced fibrosis had even higher oxLDL-ab/HDL-C ratio than their obese counterparts.11 In our opinion, this finding has two possible explanations. First, the non-obese NASH patients in this study might have higher histological severity or more concomitant metabolic complications. Second, the treatment received by obese patients (e.g., lipid lowering drugs or vitamin E) may have affected oxLDL and the lipid profile. Either of these possibilities will have major bearing on the development of oxLDL-ab as a biomarker and should be evaluated in future studies. In conclusion, the study by Ampuero and colleagues provides new data to support the association between oxLDL-ab and NASH and opens the door to a potential new biomarker. Before this marker can be adopted in clinical practice, bigger studies with longitudinal follow-up are required. Vincent Wong has served as an advisory board member for AbbVie, Gilead, Janssen, Otsuka, and Roche; a consultant for Merck and NovoMedica; and a speaker for Abbott, Echosens, Gilead, Novartis, and Roche. None of these represent significant and direct conflict with this editorial.

AGA Clinical Practice Update: Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Lean Individuals: Expert Review