Severity Of Nonalcoholic Fatty Liver Disease Research Articles

Effects of garlic supplementation on non-alcoholic fatty liver disease: A systematic review and meta-analysis of randomized controlled trials

• The meta-analysis results showed that garlic powder could improve ALT, AST, LDL-c, TC and weight. • Preclinical trials indicated that treatment with garlic supplementation could ameliorate abnormal serum and liver lipid profiles. • Garlic supplementation are conducive to the prevention and treatment of NAFLD. This research was to estimate the curative effect of garlic supplement on non-alcoholic fatty liver disease (NAFLD), a total of and five clinical studies (randomized controlled trials (RCTs) and nine preclinical studies was included. The effect size of clinical trials was determined by standardized mean difference (SMD) with 95 % confidence interval (CI). Meta-analysis of enrolled 139 patients receiving garlic powder revealed a significant improvement of NAFLD, which include ALT: 95 % CI, −11.75 to − 6.24; P < 0.00001; AST: 95 % CI, −7.15 to − 2.91; P < 0.00001; LDL cholesterol: 95 % CI, −15.25 to − 4.70; P = 0.0002; Total cholesterol: 95 % CI, −20.54 to − 7.01; P < 0.0001. Preclinical studies have demonstrated that consumption of garlic supplements reduces incidence and severity of NAFLD and inhibits hepatic steatosis, oxidative stress, and inflammation. The results of this study show that garlic supplement is conductive to the prevention and treatment of NAFLD.

Causes and risk profiles of mortality among individuals with nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States and worldwide. Though nonalcoholic fatty liver per se may not be independently associated with an increased risk for all-cause mortality, it is associated with a number of harmful metabolic risk factors, such as type 2 diabetes mellitus, hyperlipidemia, obesity, a sedentary lifestyle, and an unhealthy diet. The fibrosis stage is a predictor of all-cause mortality in NAFLD. Mortality in individuals with NAFLD has been steadily increasing, and the most common cause-specific mortality for NAFLD is cardiovascular disease, followed by extra-hepatic cancer, liver-related mortality, and diabetes. High-risk profiles for mortality in NAFLD include PNPLA3 I148M polymorphism, low thyroid function and hypothyroidism, and sarcopenia. Achieving weight loss through adherence to a high-quality diet and sufficient physical activity is the most important predictor of improvement in NAFLD severity and the benefit of survival. Given the increasing health burden of NAFLD, future studies with more long-term mortality data may demonstrate an independent association between NAFLD and mortality.

TRIM59 promotes steatosis and ferroptosis in non-alcoholic fatty liver disease via enhancing GPX4 ubiquitination

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease around the world. However, no specific medicine has been approved for NAFLD treatment. Our study was conducted to explore the role and mechanism of TRIM59 in NAFLD, aiming to provide a novel target for NAFLD treatment. Here, the expression of TRIM family members was detected in 10 mild and severe NAFLD tissues as well as 10 normal tissues. TRIM59 expression was verified in 10 normal tissues and 25 mild and severe NAFLD tissues. Palmitic acid and high-fatty diet were used for the construction of NAFLD models. Oil Red O staining was used to detect the level of steatosis. The content of TNF-α, IL-6, and IL-8 was measured to reflect the level of inflammation. Lipid reactive oxygen species was estimated by flow cytometry. We found that TRIM59 was highly expressed in NAFLD tissues compared with normal liver tissues. The inhibition of TRIM59 could inhibit the steatosis and inflammation in NAFLD, whereas its overexpression exhibited reversed effects. The application of ferroptosis inhibitor, deferoxamine, could markedly ameliorate steatosis and inflammation, which was mediated by overexpressed TRIM59. Besides, TRIM59 was demonstrated to interact with GPX4 and promoted its ubiquitination. The overexpression of GPX4 could significantly reverse the pathogenic effects of TRIM59 in NAFLD. Additionally, the inhibition of TRIM59 appeared to be a promising strategy to ameliorate NAFLD in mice model. In summary, our study revealed that TRIM59 could promote steatosis and ferroptosis in NAFLD via enhancing GPX4 ubiquitination. TRIM59 could be a potential target for NAFLD treatment.

Dysglycemia in young women attenuates the protective effect against fatty liver disease.

Sexual dimorphism has been reported in non-alcoholic fatty liver disease (NAFLD), similar to the sex differences evident with cardiovascular disease. Type 2 diabetes mellitus (T2D) significantly increases the risk and severity of NAFLD, but there is scarce information on whether T2D or altered glucose metabolism can modify the prevalence of NAFLD in men and women of reproductive age. To investigate the relationship between age, sex and NAFLD in subjects with and without dysglycemia. We analyzed 2,790 patients. NAFLD was characterized using established diagnostic criteria: one or more positive results on the fatty liver index and hepatic ultrasound. Liver fibrosis (liver stiffness measurement [LSM] ≥8.0 kPa) was assessed by Fibroscan®. For analysis purposes, we included both T2D and prediabetes under the predefined condition of dysglycemia. The global prevalence of NAFLD was higher in men than in women (50% and 34%; P<0.001), and the prevalence increased with age in both sexes. Older women (≥ 50 years) had a higher prevalence than younger women (<50 years), both in the overall cohort and in non-dysglycemic subjects. In dysglycemic subjects, the prevalence of NAFLD was slightly higher in men (68% vs 61%, p=0.021); in younger subjects, there were no differences in the prevalence of NAFLD between men and women (68% vs 64%, respectively; p=0.635). We found an interaction between dysglycemia and female sex (odds ratio [OR] 1.6 95% confidence interval [CI] 1.0-2.4, p=0.030), and between and age ≥50 years (OR 0.6, 95% CI 0.3-1.0, p=0.046). The global prevalence of LSM ≥8.0 kPa was higher in men compared with women (8% vs 4%; p< 0.001). This prevalence increased with age, mainly in men. We did not find any association between liver fibrosis and age and gender. While the global prevalence of NAFLD is higher in men than in women across all ages, younger women with dysglycemia have a similar risk of developing NAFLD as men of a similar age. Therefore, the presence of dysglycemia may erase the protective effect of female sex against fatty liverdisease.

NAFLD prevalence and severity in overweight and obese populations

Being overweight or obese are among the main risk factors for developing non-alcoholic fatty liver disease (NAFLD), which is considered to be the most prevalent chronic liver disease worldwide. The most important driver of NAFLD is dysfunctional visceral adipose tissue.1 NAFLD developing in the absence of visceral fat accumulation is rare2 and probably represents a distinct entity. Despite BMI being a poor indicator for visceral adiposity, and increased visceral adiposity frequently being observed as an underlying factor in people with NAFLD who are considered lean,3 people who are overweight or obese are at high risk of developing NAFLD compared with lean people.

Review article: the role of HSD17B13 on global epidemiology, natural history, pathogenesis and treatment of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) occurs in around a quarter of the global population and is one of the leading causes of chronic liver disease. The phenotypic manifestation and the severity of NAFLD are influenced by an interplay of environmental and genetic factors. Recently, several inactivating variants in the novel 17-Beta hydroxysteroid dehydrogenase 13 (HSD17B13) gene have been found to be associated with a reduced risk of chronic liver diseases, including NAFLD. To review the existing literature on the epidemiology of HSD17B13 and discuss its role in the natural history, disease pathogenesis and treatment of NAFLD. We extensively searched relevant literature in PubMed, Google Scholar, clinicaltrials.gov and the reference list of articles included in the review. HSD17B13 is a liver-specific, lipid droplet (LD)-associated protein that has enzymatic pathways involving steroids, pro-inflammatory lipid mediators and retinol. The estimated prevalence of the best characterised HSD17B13 variant (rs72613567) ranges from 5% in Africa to 34% in East Asia. Loss-of-function variants in HSD17B13 are protective against the progression of NAFLD from simple steatosis to non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis and hepatocellular carcinoma. Emerging data from mechanistic and preclinical studies with RNA interference (RNAi) and small molecule agents indicate that inhibiting HSD17B13 activity may prevent NAFLD progression. The loss-of-function polymorphisms of the newly identified HSD17B13 gene mitigate the progression of NAFLD. It is important to understand the exact mechanism by which these variants exert a protective effect and implement the gathered knowledge in the treatment of NAFLD.

Nonalcoholic Fatty Liver Disease Is Related to Abnormal Corrected QT Interval and Left Ventricular Hypertrophy in Chinese Male Steelworkers.

Nonalcoholic fatty liver disease (NAFLD) has been associated with an increased risks of corrected QT (QTc) prolongation and left ventricular hypertrophy (LVH), both of which are associated with the development of cardiovascular disease. Rotating night shift work and a higher risk of incident NAFLD have been reported in male steelworkers. This study aimed to investigate the association of the severity of NAFLD with a prolonged QTc interval and LVH in a large cohort of Chinese male steelworkers. We examined baseline data of 2998 male steel workers aged 26 to 71 years at two plants. All workers at both plants received regular health assessments, including 12-lead ECG and echocardiography. Abdominal ultrasonography was performed to evaluate the severity of NAFLD. QTc prolongation was defined as follows: normal ≤ 430 ms, borderline 431-450 ms, and abnormal ≥ 451 ms. LVH was defined as a left ventricular mass index (LVMI) >131 g/m2. Associations of NAFLD with an abnormal QTc interval and LVH were examined using univariate and multivariate analyses. The QTc interval and the LVMI were significantly correlated with the NAFLD fibrosis score, and the severity of NAFLD was correlated with an abnormal QTc interval and LVH (p for trend < 0.05). Multivariate analysis showed that in comparison to the workers without NAFLD, the odds ratios of having an abnormal QTc interval and LVH were 2.54 (95% CI: 1.22-5.39, p = 0.013) times and 2.23 (95% CI: 1.02-5.01, p = 0.044) times higher in the workers with moderate/severe NAFLD. NAFLD may be closely associated with the risks of an abnormal QTc interval and LVH, suggesting that regular electrocardiogram and echocardiogram monitoring could be used to evaluate the risk of arrhythmia and LVH in male steelworkers with NAFLD.

Once-Weekly Subcutaneous Semaglutide Improves Fatty Liver Disease in Patients with Type 2 Diabetes: A 52-Week Prospective Real-Life Study.

Nonalcoholic fatty liver disease (NAFLD) is commonly observed in patients with type 2 diabetes (T2D). Semaglutide, a glucagon-like peptide 1 receptor agonist, may have a therapeutic role by targeting common mechanisms involved in the pathophysiology of T2D and NAFLD. The study aimed to assess the effectiveness of Semaglutide on NAFLD in patients with T2D. Forty-eight patients were treated with subcutaneous Semaglutide in add-on to metformin for 52 weeks. After the baseline visit (T0), follow-up was scheduled quarterly (T3, and T6) and then at 12 months of therapy (T12). During each visit, body composition was analyzed by phase-sensitive bio-impedance, and NAFLD was diagnosed and staged by Ultrasound (US) imaging. Surrogate biomarkers of NAFLD were also calculated and followed over time. A significant decrease in anthropometric and glucometabolic parameters, insulin resistance, liver enzymes, and laboratory indices of hepatic steatosis was observed during treatment. Similarly, fat mass and visceral adipose tissue (VAT) decreased over time more than skeletal muscle and free-fat mass. US-assessed VAT thickness and the 12-point steatosis score also declined at T3 up to T12. Liver steatosis improved in most patients (70%), showing a reduction by at least one class in the semiquantitative US staging. Besides glucose control and body composition improvements, Semaglutide was effective in ameliorating the clinical appearance and severity of NAFLD in T2D patients.

Race and Ethnicity in Non-Alcoholic Fatty Liver Disease (NAFLD): A Narrative Review.

Non-alcoholic fatty liver disease (NAFLD) is a significant public health concern worldwide with a complex etiology attributed to behavioural, environmental, and genetic causes. The worldwide prevalence of NAFLD is estimated to be 32.4% and constantly rising. Global data, however, indicate considerable heterogeneity among studies for both NAFLD prevalence and incidence. Identifying variables that affect the estimated epidemiological measures is essential to all stakeholders, including patients, researchers, healthcare providers, and policymakers. Besides helping with the research on disease etiology, it helps to identify individuals at risk of the disease, which in turn will outline the focus of the preventive measures and help to fittingly tailor individualized treatments, targeted prevention, screening, or treatment programs. Several studies suggest differences in the prevalence and severity of NAFLD by race or ethnicity, which may be linked to differences in lifestyle, diet, metabolic comorbidity profile, and genetic background, among others. Race/ethnicity research is essential as it can provide valuable information regarding biological and genetic differences among people with similar cultural, dietary, and geographical backgrounds. In this review, we examined the existing literature on race/ethnicity differences in susceptibility to NAFLD and discussed the contributing variables to such differences, including diet and physical activity, the comorbidity profile, and genetic susceptibility. We also reviewed the limitations of race/ethnicity studies in NAFLD.

Stellate cell expression of SPARC-related modular calcium-binding protein 2 is associated with human non-alcoholic fatty liver disease severity

Histological assessment of liver biopsies is the gold standard for diagnosis of non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease (NAFLD), despite its well-established limitations. Therefore, non-invasive biomarkers that can offer an integrated view of the liver are needed to improve diagnosis and reduce sampling bias. Hepatic stellate cells (HSCs) are central in the development of hepatic fibrosis, a hallmark of NASH. Secreted HSC-specific proteins may, therefore, reflect disease state in the NASH liver and serve as non-invasive diagnostic biomarkers. We performed RNA-sequencing on liver biopsies from a histologically characterised cohort of obese patients (n= 30, BMI >35kg/m2) to identify and evaluate HSC-specific genes encoding secreted proteins. Bioinformatics was used to identify potential biomarkers and their expression at single-cell resolution. We validated our findings using single-molecule fluorescence in situ hybridisation (smFISH) and ELISA to detect mRNA in liver tissue and protein levels in plasma, respectively. Hepatic expression of SPARC-related modular calcium-binding protein 2 (SMOC2) was increased in NASH compared to no-NAFLD (p.adj <0.001). Single-cell RNA-sequencing data indicated that SMOC2 was primarily expressed by HSCs, which was validated using smFISH. Finally, plasma SMOC2 was elevated in NASH compared to no-NAFLD (p <0.001), with a predictive accuracy of AUROC 0.88. Increased SMOC2 in plasma appears to reflect HSC activation, a key cellular event associated with NASH progression, and may serve as a non-invasive biomarker of NASH. Non-alcoholic fatty liver disease (NAFLD) and its progressive form, non-alcoholic steatohepatitis (NASH), are the most common forms of chronic liver diseases. Currently, liver biopsies are the gold standard for diagnosing NAFLD. Blood-based biomarkers to complement liver biopsies for diagnosis of NAFLD are required. We found that activated hepatic stellate cells, a cell type central to NAFLD pathogenesis, upregulate expression of the secreted protein SPARC-related modular calcium-binding protein 2 (SMOC2). SMOC2 was elevated in blood samples from patients with NASH and may hold promise as a blood-based biomarker for the diagnosis of NAFLD.

NAFLD in Polycystic Ovary Syndrome: Association with PNPLA3 and Metabolic Features.

The aim of this study was to determine the frequency of the rs738409 polymorphism in the patatin-like phospholipase domain containing 3 (PNPLA3) gene in patients with polycystic ovary syndrome (PCOS) and its impact on nonalcoholic fatty liver disease (NAFLD) risk and severity. We also evaluated other risk factors associated with NAFLD and advanced fibrosis. This was a cross-sectional study involving 163 patients with PCOS at a tertiary center. Genotyping for the PNPLA3 polymorphism was undertaken using a TaqMan assay. The degree of fibrosis was defined by transient elastography. The prevalence of NAFLD was 72.4%, and the polymorphism was heterozygous in 41.7% and homozygous in 8% of patients. Homeostasis model assessment of insulin resistance ≥ 2.5 was the main factor associated with the risk of developing NAFLD (OR = 4.313, p = 0.022), and its effect was amplified by the polymorphism (OR = 12.198, p = 0.017). Age &gt; 32 years also conferred a higher risk for NAFLD. HDL values ≥ 50 mg/dL conferred protection against the outcome. Metabolic syndrome (OR = 13.030, p = 0.020) and AST &gt; 32 U/L (OR = 9.039, p = 0.009) were independent risk factors for advanced fibrosis. In women with PCOS, metabolic characteristics are more relevant than PNPLA3 polymorphism regarding the risk for NAFLD and its advanced forms, but these factors can act synergistically, increasing disease risk.

A liver secretome gene signature-based approach for determining circulating biomarkers of NAFLD severity.

Non-invasive biomarkers of non-alcoholic fatty liver disease (NAFLD) supporting diagnosis and monitoring disease progression are urgently needed. The present study aimed to establish a bioinformatics pipeline capable of defining and validating NAFLD biomarker candidates based on paired hepatic global gene expression and plasma bioanalysis from individuals representing different stages of histologically confirmed NAFLD (no/mild, moderate, more advanced NAFLD). Liver secretome gene signatures were generated in a patient cohort of 26 severely obese individuals with the majority having no or mild fibrosis. To this end, global gene expression changes were compared between individuals with no/mild NAFLD and moderate/advanced NAFLD with subsequent filtering for candidate gene products with liver-selective expression and secretion. Four candidate genes, including LPA (lipoprotein A), IGFBP-1 (insulin-like growth factor-binding protein 1), SERPINF2 (serpin family F member 2) and MAT1A (methionine adenosyltransferase 1A), were differentially expressed in moderate/advanced NAFLD, which was confirmed in three independent RNA sequencing datasets from large, publicly available NAFLD studies. The corresponding gene products were quantified in plasma samples but could not discriminate among different grades of NAFLD based on NAFLD activity score. Conclusion: We demonstrate a novel approach based on the liver transcriptome allowing for identification of secreted hepatic gene products as potential circulating diagnostic biomarkers of NAFLD. Using this approach in larger NAFLD patient cohorts may yield potential circulating biomarkers for NAFLD severity.

Association of Bariatric Surgery With Cardiovascular Outcomes in Adults With Severe Obesity and Nonalcoholic Fatty Liver Disease

There are no approved treatments for nonalcoholic fatty liver disease (NAFLD) despite its association with obesity and increased risk of cardiovascular disease (CVD). To examine the association between bariatric surgery and CVD risk in individuals with severe obesity and NAFLD. This large, population-based retrospective cohort study obtained data from the MarketScan Commercial Claims and Encounters database from January 1, 2007, to December 31, 2017. Participants included insured adults aged 18 to 64 years with NAFLD and severe obesity (body mass index ≥40) without a history of bariatric surgery or CVD before NAFLD diagnosis. Baseline characteristics were balanced between individuals who underwent surgery (surgical group) and those who did not (nonsurgical group) using inverse probability of treatment weighting. Data were analyzed from March 2020 to April 2021. Bariatric surgery (Roux-en-Y gastric bypass, sleeve gastrectomy, and other bariatric procedures) vs nonsurgical care. The main outcome was the incidence of cardiovascular events (primary or secondary composite CVD outcomes). The primary composite outcome included myocardial infarction, heart failure, or ischemic stroke, and the secondary composite outcome included secondary ischemic heart events, transient ischemic attack, secondary cerebrovascular events, arterial embolism and thrombosis, or atherosclerosis. Cox proportional hazards regression models with inverse probability treatment weighting were used to examine the associations between bariatric surgery, modeled as time varying, and all outcomes. The study included 86 964 adults (mean [SD] age, 44.3 [10.9] years; 59 773 women [68.7%]). Of these individuals, 30 300 (34.8%) underwent bariatric surgery and 56 664 (65.2%) received nonsurgical care. All baseline covariates were balanced after applying inverse probability treatment weighting. In the surgical group, 1568 individuals experienced incident cardiovascular events compared with 7215 individuals in the nonsurgical group (incidence rate difference, 4.8 [95% CI, 4.5-5.0] per 100 person-years). At the end of the study, bariatric surgery was associated with a 49% lower risk of CVD (adjusted hazard ratio [aHR], 0.51; 95% CI, 0.48-0.54) compared with nonsurgical care. The risk of primary composite CVD outcomes was reduced by 47% (aHR, 0.53 [95% CI, 0.48-0.59), and the risk of secondary composite CVD outcomes decreased by 50% (aHR, 0.50; 95% CI, 0.46-0.53) in individuals with vs without surgery. Results of this study suggest that, compared with nonsurgical care, bariatric surgery was associated with significant reduction in CVD risk in individuals with severe obesity and NAFLD.

Binge drinking does not appear to have an adverse effect on non-alcoholic fatty liver disease: Findings from a study of four First Nations communities.

BACKGROUND: Binge drinking and non-alcoholic fatty liver disease (NAFLD) are common health problems throughout the world. However, the impact of binge drinking on NAFLD has yet to be described. The objective of this study was to document the extent of liver disease in community-based NAFLD patients who self-reported monthly binge drinking and compare the findings to NAFLD patients from the same communities who denied binge drinking (controls). METHODS: The study was undertaken in four Manitoba First Nations communities where the sale and consumption of alcoholic beverages are prohibited but visits to urban centres are common. Binge drinkers were retrospectively matched 1:2 by age, sex, and body mass index (BMI) with controls. NAFLD was diagnosed by ultrasonographic features of excess fat in the liver in individuals with no alternative, non-metabolic explanation for fatty infiltration of the liver. Hepatic inflammation and function were determined by standard liver biochemistry testing and fibrosis by FIB-4 levels and hepatic elastography. RESULTS: Of 546 NAFLD patients, 88 (16%) attested to binge drinking. The mean age of binge drinkers was 40 (SD 13) years; 51% were male; and the mean BMI was 34 (SD 7). Compared with controls, binge drinkers had similar liver biochemistry results (alanine and aspartate aminotransferases: 41 [SD 39] and 36 [SD 30] versus 36 [SD 36] and 31 [SD 27] U/L, p = 0.35 and p = 0.37, respectively), FIB-4 values (0.75 [SD 0.55] versus 0.72 [SD 0.44], p = 0.41, respectively), and hepatic elastrography (6.6 [SD 3.9] versus 6.2 [SD 2.9] kPa, p = 0.37, respectively) findings. CONCLUSIONS: In this study population, monthly binge drinking did not appear to impact the severity of NAFLD.

S1436 Hepatic Steatosis and Fibrosis in Patients With Gout Detected by Elastography

Introduction: Gout is associated with non-alcoholic fatty liver disease (NAFLD), but neither the frequency nor severity of NAFLD in gout is well described. Elastography is a well-established ultrasonic method to evaluate both steatosis and fibrosis in the liver but has not been applied to evaluate gout patients. Methods: We employed the FibroScan to evaluate patients with advanced gout at one center from 11/1/2016-11/12021. We assessed the Fibrosis score (kPA), which measures liver stiffness (E score), and the controlled attenuation parameter dB/m (CAP) score, which measures steatosis. In addition, we assessed the four-factor fibrosis (FIB-4) Index formula. Results: 47 gout patients (7 females, 14.9%; 40 males, 85.1%) were evaluated. The mean age was 59.8 years and the mean BMI was 30.95 kg/m2. Tophi were present in 11. Disease duration ranged from 0-49 years. Comorbidities included: dyslipidemia (86.7%), DM (31.1%), HTN (63.6%), CHF (12.8%), CAD (12.8%), CKD (19.15%), known liver disease (33.3%) and current alcohol use (46.8%). 53.7% had hyperuricemia and 54.4% had elevations in ALT/AST. Hepatic steatosis was found in 40 (85.1%), but was not significantly different in males or females (p=0.37) or those with CHF (p=0.87), CAD (p=0.94), HTN (p=0.17), DM (p=0.68), dyslipidemia (p=0.59) or the presence of known liver diseases (p=0.37). CAP was correlated with BMI (r=0.53, p=0.0001) but not age, serum urate (SU), glucose, triglycerides (TGs), ALT, AST, FIB-4, or Fibrosis scores. By Fibroscan, 9 (19.1%) had evidence of fibrosis (E score >7), including one with moderate and 8 with severe fibrosis (cirrhosis). Moderate or severe fibrosis was significantly associated with age (p=0.03), known liver disease (p=0.003), but not ancestry, gender, BMI, TGs, HDL, glucose, gout duration, CHF, CAD, HTN, dyslipidemia, or DM. SU was comparable in those with or without moderate or severe fibrosis (p=0.24). The Fib-4 score was significantly greater in those with severe or moderate fibrosis (3.77) versus those with no or mild fibrosis (1.59, p=0.0045). There was a significant correlation between the Fibrosis score and FIB-4 score (r2=0.24, p=0.0009), but not between the Fibrosis score and ALT (p=0.44) or AST(p=0.41). Conclusion: Hepatic steatosis and fibrosis are common in patients with gout, but not associated with typical gout co-morbidities. Screening for NAFLD with elastography should establish the actual frequency of NAFLD in gout and provide a means to manage this co-morbidity more effectively.

Evaluate the elasticity of carotid artery in the type 2 diabetes mellitus patients with nonalcoholic fatty liver disease by two-dimensional strain imaging.

To evaluate carotid elasticity by using two-dimensional strain imaging (2DSI) in type 2 diabetes mellitus (T2DM) patients with nonalcoholic fatty liver disease (NAFLD). 98 patients with T2DM diagnosed in our hospital were selected. All the patients were without carotid plaque, which were proved by carotid ultrasonography. According to the fatty liver classification standard, patients were divided into three groups. There were 35 cases without NAFLD in group A, 33 cases with mild NAFLD in group B and 30 cases with moderate to severe NAFLD in group C. By using two-dimensional and M-mode ultrasound to measure the left carotid intima-media thickness (IMT), common carotid arterial systolic diameter (Ds) and diastolic diameter (Dd). The systolic peak velocity was measured by spectral Doppler ultrasound. The systolic global peak circumferential strain (CS), early and late systolic global circumferential strain rate (CSr) were measured by 2DSI. The stiffness parameters β1 and β2 were calculated by M-mode ultrasound and 2DSI separately. Among three groups, the Ds, Dd and systolic peak velocity showed no significant difference (all P > .05). In group C, IMT and β1 were obviously increased than those of groups A and B (all P < .05). Compared groups A and B, there were no significant difference in IMT and β1 (all P > .05). β2 was higher in groups B and C than those in group A, CS, CSr were lower in groups B and C than those in group A (both P > .05). The carotid elasticity of T2DM patients with NAFLD can be evaluated by 2DSI.

Alterations of Central Liver Metabolism of Pediatric Patients with Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and is associated with overweight and insulin resistance (IR). Almost nothing is known about in vivo alterations of liver metabolism in NAFLD, especially in the early stages of non-alcoholic steatohepatitis (NASH). Here, we used a complex mathematical model of liver metabolism to quantify the central hepatic metabolic functions of 71 children with biopsy-proven NAFLD. For each patient, a personalized model variant was generated based on enzyme abundances determined by mass spectroscopy. Our analysis revealed statistically significant alterations in the hepatic carbohydrate, lipid, and ammonia metabolism, which increased with the degree of obesity and severity of NAFLD. Histologic features of NASH and IR displayed opposing associations with changes in carbohydrate and lipid metabolism but synergistically decreased urea synthesis in favor of the increased release of glutamine, a driver of liver fibrosis. Taken together, our study reveals already significant alterations in the NASH liver of pediatric patients, which, however, are differently modulated by the simultaneous presence of IR.

Nonalcoholic fatty liver disease and diabetes.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in the world and represents a clinical-histopathologic entity where the steatosis component may vary in degree and may or may not have fibrotic progression. The key concept of NAFLD pathogenesis is excessive triglyceride hepatic accumulation because of an imbalance between free fatty acid influx and efflux. Strong epidemiological, biochemical, and therapeutic evidence supports the premise that the primary pathophysiological derangement in most patients with NAFLD is insulin resistance; thus the association between diabetes and NAFLD is widely recognized in the literature. Since NAFLD is the hepatic manifestation of a metabolic disease, it is also associated with a higher cardio-vascular risk. Conventional B-mode ultrasound is widely adopted as a first-line imaging modality for hepatic steatosis, although magnetic resonance imaging represents the gold standard noninvasive modality for quantifying the amount of fat in these patients. Treatment of NAFLD patients depends on the disease severity, ranging from a more benign condition of nonalcoholic fatty liver to nonalcoholic steatohepatitis. Abstinence from alcohol, a Mediterranean diet, and modification of risk factors are recommended for patients suffering from NAFLD to avoid major cardiovascular events, as per all diabetic patients. In addition, weight loss induced by bariatric surgery seems to also be effective in improving liver features, together with the benefits for diabetes control or resolution, dyslipidemia, and hypertension. Finally, liver transplantation represents the ultimate treatment for severe nonalcoholic fatty liver disease and is growing rapidly as a main indication in Western countries. This review offers a comprehensive multidisciplinary approach to NAFLD, highlighting its connection with diabetes.

Systematic Review and Meta-Analysis of the Usefulness of Epicardial Fat Thickness as a Non-Invasive Marker of the Presence and Severity of Nonalcoholic Fatty Liver Disease.

We performed a systematic review and meta-analysis to assess the association between epicardial fat thickness (EFT) and nonalcoholic fatty liver disease (NAFLD). This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) and was based on a registered protocol (CRD 4201809 5493). We searched Medline and Embase until December 2021 for studies reporting on the association between EFT and NAFLD. Qualitative reviews, meta-analyses and meta-regressions were performed to explore this association. Effect sizes are reported as standardized mean differences. We included 12 studies, comprising 3610 individuals. EFT was evaluated with trans-thoracic echocardiography in nine studies, two studies using cardiac computed tomography and one study using magnetic resonance imaging (MRI). The presence of NAFLD was evaluated using transabdominal liver ultrasound in nine studies. Other studies used histology, magnetic resonance spectroscopy and MRI-derived proton density fat fraction. Liver biopsy was performed to assess the severity of NAFLD in four studies. The random-effects meta-analysis indicated that, as compared to control patients with lean livers, patients with NAFLD displayed significantly higher EFT (standardized mean difference 0.61, 95% confidence interval: 0.47–0.75, p < 0.0001, I2 = 72%). EFT was further significantly higher in patients with severe liver steatosis versus patients with mild–moderate liver steatosis (standardized mean difference 1.21 95% confidence interval: 0.26–2.16, p < 0.001, I2 S = 96%). Through the meta-regression analysis, we found that patients with increasingly higher blood levels of aspartate aminotransferase displayed an increasingly higher depth of association. The current meta-analysis suggests that EFT may represent a useful surrogate for assessing the presence and severity of NAFLD in a non-invasive manner.

Rare ATG7 genetic variants predispose patients to severe fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disorders and has a strong heritable component. The aim of this study was to identify new loci that contribute to severe NAFLD by examining rare variants. We performed whole-exome sequencing in individuals with NAFLD and advanced fibrosis or hepatocellular carcinoma (n= 301) and examined the enrichment of likely pathogenic rare variants vs. the general population. This was followed by validation at the gene level. In patients with severe NAFLD, we observed an enrichment of the p.P426L variant (rs143545741 C>T; odds ratio [OR] 5.26, 95% CI 2.1-12.6; p= 0.003) of autophagy-related 7 (ATG7), which we characterized as a loss-of-function, vs. the general population, and an enrichment in rare variants affecting the catalytic domain (OR 13.9; 95% CI 1.9-612; p= 0.002). In the UK Biobank cohort, loss-of-function ATG7 variants increased the risk of cirrhosis and hepatocellular carcinoma (OR 3.30; 95% CI 1.1-7.5 and OR 12.30, 95% CI 2.6-36, respectively; p <0.001 for both). The low-frequency loss-of-function p.V471A variant (rs36117895 T>C) was also associated with severe NAFLD in the clinical cohort (OR 1.7; 95% CI 1.2-2.5; p= 0.003), predisposed to hepatocellular ballooning (p= 0.007) evolving to fibrosis in the Liver biopsy cohort (n= 2,268), and was associated with liver injury in the UK Biobank (aspartate aminotransferase levels, p <0.001), with a larger effect in severely obese individuals in whom it was linked to hepatocellular carcinoma (p= 0.009). ATG7 protein localized to periportal hepatocytes, particularly in the presence of ballooning. In the Liver Transcriptomic cohort (n= 125), ATG7 expression correlated with suppression of the TNFα pathway, which was conversely upregulated in p.V471A carriers. We identified rare and low-frequency ATG7 loss-of-function variants that promote NAFLD progression by impairing autophagy and facilitating ballooning and inflammation. We found that rare mutations in agene called autophagy-related 7 (ATG7) increase the risk of developing severe liver disease in individuals with dysmetabolism. These mutations cause an alteration in protein function and impairment of self-renewal of cellular content, leading to liver damage and inflammation.