Polycyclic aromatic hydrocarbons-induced suppression of the PPARα/ACAA1 axis drives hepatic steatosis: Integrating epidemiology, network toxicology, and experimental validation.

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.

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.

Prevalence of Elevated Alanine Aminotransferase Among US Adolescents and Associated Factors: NHANES 1999–2004

Non-alcoholic fatty liver diseases in patients with COVID-19: A retrospective study

Epidemiology of non-alcoholic fatty liver disease in China

Non-alcoholic fatty liver disease (NAFLD) is rapidly becoming the most common liver disease worldwide. The prevalence of NAFLD in the general population of Western countries is 20–30%. About 2–3% of the general population is estimated to have non-alcoholic steatohepatitis (NASH), which may progress to liver cirrhosis and hepatocarcinoma. As a rule, the prevalence of NAFLD is higher in males and increases with increasing age, and it is influenced by the diagnostic method and the characteristics of the population, especially lifestyle habits. Population-based studies provide better estimates of the prevalence of NAFLD as compared to autoptic and clinical studies, but few such studies have been performed to date. The diagnosis of NAFLD in population studies is usually obtained by ultrasonography, which is known to underestimate the prevalence of fatty liver. The Dallas Heart Study and the Dionysos Study reported that 30% of the adults in the USA and 25% in Italy have NAFLD. In these studies, 79% and 55% of patients with NAFLD had normal aminotransferase levels, showing that liver enzymes are not surrogate markers of NAFLD in the general population. Noninvasive markers such as the fatty liver index obtained from the Dionysos Study may be useful to screen for NAFLD in the general population. The most important risk factors for NAFLD are male gender, age, obesity, insulin resistance and the cardiometabolic alterations that define the metabolic syndrome. The prevalence of NAFLD is 80–90% in obese adults, 30–50% in patients with diabetes and up to 90% in patients with hyperlipidemia. The prevalence of NAFLD among children is 3–10%, rising up to 40–70% among obese children. Moreover, pediatric NAFLD increased from about 3% a decade ago to 5% today, with a male-to-female ratio of 2:1. The incidence and natural history of NAFLD are still not well defined, but it is recognized that the majority of individuals with NAFLD do not develop NASH. The incidence of NAFLD is probably increasing in Western countries, strictly linked to lifestyle habits.

Association between folate and non-alcoholic fatty liver disease among US adults: a nationwide cross-sectional analysis.

Background Cross-sectional studies have assessed the prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with inflammatory bowel disease (IBD). However, longitudinal studies are more suitable to capture dynamic changes. Our aim was to investigate the prevalence and progression of NAFLD in a cohort of IBD patients using validated non-invasive tools. The role of metabolic, disease-related and genetic factors as predictors of NAFLD was also assessed. Methods IBD patients without known chronic liver disease were enrolled between 2019 and 2021. NAFLD was defined as Hepatic Steatosis Index (HSI) ≥ 36 or controlled attenuation parameter (CAP) ≥288 dB/m. Demographic data, traditional risk factors for NAFLD, biochemical tests and disease features were retrospectively collected in a dedicated database at the time of IBD diagnosis (defined as baseline) and at the last follow-up visit. PNPLA3 rs738409 C>G and TM6F2 E167K C>T polymorphisms were also investigated. Univariate and multivariate logistic regression analysis were performed to identify risk factors for NAFLD at baseline and at the end of follow-up. Results 227 consecutive patients (mean age 46.1 ± 13.4 years, 48.7% males, 57% Crohn’s disease, mean disease duration 9.4 ±7.5 years) were enrolled. Laboratory data at the time of diagnosis were available for 64 patients. The mean HSI was 30.9 ± 4.9 and 8/64 eligible patients (12.5%) had NAFLD at baseline. Male sex (odds ratio [OR]: 5.6; 95% confidence interval [CI] 3.1–8.9; P = 0.02) and body mass index (BMI) (OR: 1.4, 95% CI 1.1–2.9; P = 0.0008) were significantly associated with NAFLD at baseline. 11/64 (17.1%) patients developed NAFLD, accounting for an incidence rate of 4.0/100 PY; this was predicted only by changes in BMI over time (OR: 13.6, 95% CI 4.8–19.5; P = 0.001). At the last follow-up visit, NAFLD was diagnosed in 31.2% (71/227) according to HSI and in 21.1% (48/227) according to CAP. Among 8 patients with NAFLD at baseline, HSI worsened in 6 patients (41.0 ± 3.3 vs 44.0 ± 5.2), while two patients had steatosis regression. At the end of follow-up, age (P = 0.01), BMI (P = 0.002) and previous surgery (P = 0.01) were independently associated with NAFLD. Conclusion Our study confirms that NAFLD is common in patients with IBD. Variables related to IBD were not associated with incident NAFLD. Age, BMI and previous surgery were independently associated with NAFLD progression, suggesting a pathogenetic role of gut microbiota and impairment in bile acids metabolism. Our results suggest the need for active surveillance for NAFLD in patients with IBD.

This cross-sectional study was performed to identify the factors associated with non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes mellitus (T2DM) patients in Nablus, Palestine, and decrease the burden of liver diseases. Patients with T2DM who visited primary healthcare clinics in Nablus from January to April 2022 were invited [n=508] to participate. A face-to-face interview was conducted, and medical reports were used to collect the pa-tient's details. The hepatic steatosis index (HSI) was calculated as an indicator of the possibil-ity of the presence of NAFLD. Ultrasound was used to diagnose fatty liver disease (FLD) as mild, moderate, and severe. 399 Patients completed participation, with a mean age of 56.1±10.4 years; 56.1% were males, 91.2% had an HSI score ≥36, and 8.8% had an HSI score of 30-36. Moreover, 3.8% were diagnosed with mild FLD, 42.1% with moderate FLD, and 3.8% with severe FLD. Compared to patients without fatty liver disease, severe FLD pa-tients were at higher risk of having increased cholesterol levels (OR=1.047), increased HSI (OR=1.32), and diabetic retinopathy (OR=7.074). Predictors for moderate FLD have in-creased cholesterol levels (OR=1.023), glycated hemoglobin (HbA1c) (OR=1.06), HSI (OR=1.21), and age (OR=1.071). Predictors for mild FLD have increased cholesterol levels (OR=1.02), HbA1c (OR=1.312), HSI (OR=1.102), and age (OR=1.047). Decreased levels of low-density lipoproteins were associated with decreased risk of mild (OR=0.982), moderate (OR=0.97), and severe (OR=0.955) FLD. Diabetes treatment regimen, the number of years diagnosed with diabetes, hypertension, high-density lipoprotein, and triglycerides levels were not associated with FLD. In conclusion, the prevalence of NAFLD among Palestinian T2DM patients was higher than the reported global prevalence. Several modifiable (weight, HbA1c, HSI score, total cholesterol, and low-density lipoprotein levels) and non-modifiable (age and diabetic retinopathy) factors were associated with NAFLD. This research recommends a screening program for the early detection of NAFLD among Palestinian people with diabetes using ultrasound.

NAFLD is a predictor of liver injury in COVID-19 hospitalized patients but not of mortality, disease severity on the presentation or progression – The debate continues

The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis

Nonalcoholic Fatty Liver Disease in Children: Where Are We?

Global prevalence, incidence, and outcomes of non-obese or lean non-alcoholic fatty liver disease: a systematic review and meta-analysis

The relationship between bisphenol A (BPA) and non-alcoholic fatty liver disease (NAFLD) is undefined. We studied the impact of BPA on NAFLD. We performed a cross-sectional analysis of data from the National Health and Nutrition Examination Survey (NHANES) 2005-2014 among adults in the United States (US). NAFLD was diagnosed using the hepatic steatosis index (HSI) and the US fatty liver index (USFLI) in the absence of other causes of chronic liver diseases. The first sample using HSI consisted of 7605 adults. The second sample using USFLI consisted of 3631 participants with availability of fasting data. Of the first 7605 participants (mean age 47years, 48.4% male), the prevalence of NAFLD and abnormally elevated alanine aminotransferase (ALT) levels was correlated with urinary BPA levels (P<0.05). Compared to the reference group with lowest quartile of urinary BPA levels, those with the third and fourth quartiles were 81% and 53% more likely to develop NAFLD defined by HSI. In a multivariate model, the ORs for NAFLD in the third and fourth quartiles were 1.69 (95% CI 1.39-2.04) and 1.44 (95% CI 1.19-1.76) respectively (P for trend <0.001). In the second sample using USFLI, high BPA levels (fourth quartile) remained an independent predictor of NAFLD (OR 1.44, 95% CI 1.05-1.98, P for trend=0.012). High levels of urinary BPA were associated with NAFLD in a nationally representative sample of adults in the US. The pathophysiology remains unclear and warrants further investigation.

Introduction: About 30% of all U.S. adults and 70-80% of those with Type 2 diabetes mellitus (T2DM) have non-alcoholic fatty liver disease (NAFLD). Atherosclerotic cardiovascular disease (CVD) is more common among NAFLD patients, albeit with limited evidence from large prospective studies. Hypothesis: American Indians (AI) with NAFLD would be more likely to develop carotid atherosclerosis given their high prevalence of obesity and T2DM. Methods: The Strong Heart Family Study (SHFS) is a population-based family study of CVD and its risk factors in AI. Participants (n=2786; 59.6% female, mean age 40.8 ±17.3 y) were recruited from 12 tribes in 3 regions: Arizona, North/South Dakota, and Oklahoma. Carotid ultrasound-assessed plaque and plaque score were obtained at the baseline examination in 2001-03, and again in surviving participants (n=2406) from 2006 to 2009. NAFLD prevalence was estimated using hepatic steatosis index (HSI). NAFLD fibrosis score was used to separate NAFLD patients with or without advanced fibrosis. HSI is calculated using serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), BMI, diabetes status, and sex, while the NAFLD fibrosis score is derived from age, BMI, diabetes status, ALT, AST, platelet count, and serum albumin. Plaque progression was defined as any increase in plaque score (0 to 8 carotid segments with plaque) from baseline to the second examination. Frailty model was used in data analyses to account for the relatedness among family members. Results: Mean BMI of participants was 31.3 ± 7.5 kg/m 2 , 19% had T2DM, 32.6% were hypertensive, and 36.3% were current smokers. NAFLD prevalence (HSI &gt; 36) was 78%, while 6% did not have NAFLD (HSI &lt; 30) and 16% participants were in an intermediate category (HSI 30-36). Among participants with NAFLD (n=2096), three fibrosis classes were defined by NAFLD fibrosis scores: 1 no to moderate fibrosis (61%, fibrosis score &lt; -1.455), 2 indeterminate (31%, -1.455 ≤ fibrosis score ≤ 0.676), and 3 cirrhosis or severe cirrhosis (8%, fibrosis score &gt; 0.676). About 31% of participants had carotid atherosclerosis (plaque score ≥ 1) at baseline. About 14% of the 2252 participants who had two carotid ultrasound evaluations had plaque progression and 19% of those without carotid atherosclerosis at baseline (n=1571) had incident plaque at the second visit. Compared to those with no to moderate fibrosis, those who had cirrhosis or severe cirrhosis had higher risks of plaque progression with a hazard ratio (HR, 95% CI) of 1.8 (1.1-2.9, P=0.026), and of incident plaque with a HR (95% CI) of 2.6 (1.5-4.6, P=0.0009), adjusted for sex, smoking, hypertension, albuminuria, LDL-C, and HDL-C. Similar results were found among participants with intermediate fibrosis scores. Conclusions: The prevalence of HSI-defined NAFLD is high in AI. NAFLD fibrosis score predicts both incident and progressive carotid atherosclerosis.