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Background & Aims: Iron has been proposed as influencing the progression of liver disease in subjects with non-alcoholic fatty liver disease (NAFLD). We have previously shown that, in the Hfe -/- mouse model of hemochromatosis, feeding of a high-calorie diet (HCD) leads to increased liver injury. In this study we investigated whether the feeding of an iron deficient/HCD to Hfe -/- mice influenced the development of NAFLD., Methods: Liver histology was assessed in Hfe -/- mice fed a standard iron-containing or iron-deficient diet plus or minus a HCD. Hepatic iron concentration, serum transferrin saturation and free fatty acid were measured. Expression of genes implicated in iron regulation and fatty liver disease was determined by quantitative real-time PCR (qRT-PCR)., Results: Standard iron/HCD-fed mice developed severe steatosis whereas NAS score was reduced in mice fed iron-deficient HCD. Mice fed iron-deficient HCD had lower liver weights, lower transferrin saturation and decreased ferroportin and hepcidin gene expression than HCD-fed mice. Serum non-esterified fatty acids were increased in iron-deficient HCD-fed mice compared with standard iron HCD. Expression analysis indicated that genes involved in fatty-acid binding and mTOR pathways were regulated by iron depletion., Conclusions: Our results indicate that decreasing iron intake attenuates the development of steatosis resulting from a high calorie diet. These results also suggest that human studies of agents that modify iron balance in patients with NAFLD should be revisited., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Metabolic (dysfunction)-associated fatty liver disease (MAFLD) is characterized by the accumulation of lipids in the liver (steatosis). In predisposed individuals, liver steatosis can progress to inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. The pathogenesis of MAFLD is complex and incompletely understood, involving various steatogenic, pro-inflammatory, and fibrogenic processes. Hyperactivation of the innate immune system through hepatic toll-like receptors (TLRs) contributes to the pathogenesis of MAFLD. Products of intestinal microbiota and danger signals from damaged hepatocytes constitute key ligands of TLRs that promote MAFLD. Most TLRs promote development and progression of MAFLD by induction of pro-inflammatory and pro-fibrogenic cytokines. Several nutraceutical and therapeutic agents improve MAFLD partly through the inhibition of hepatic TLRs. Herein, we review the available literature on hepatic TLR expression and signaling; crosstalk between gut microbiota and hepatic TLRs; and the contribution of TLRs to the pathogenesis of MAFLD. We also highlight implications for therapeutic approaches for MAFLD based on modulation of TLR signaling., Competing Interests: Conflict of interest The authors declare no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background & Aims: Ultrasound-guided attenuation parameter (UGAP) is recently developed for noninvasive evaluation of steatosis. However, reports on its usefulness in clinical practice are limited. This prospective multicenter study analyzed the diagnostic accuracy of grading steatosis with reference to magnetic resonance imaging-based proton density fat fraction (MRI-PDFF), a noninvasive method with high accuracy, in a large cohort., Methods: Altogether, 1010 patients with chronic liver disease who underwent MRI-PDFF and UGAP were recruited and prospectively enrolled from 6 Japanese liver centers. Linearity was evaluated using intraclass correlation coefficients between MRI-PDFF and UGAP values. Bias, defined as the mean difference between MRI-PDFF and UGAP values, was assessed by Bland-Altman analysis. UGAP cutoffs for pairwise MRI-PDFF-based steatosis grade were determined using area under the receiver-operating characteristic curve (AUROC) analyses., Results: UGAP values were shown to be normally distributed. However, because PDFF values were not normally distributed, they were log-transformed (MRI-logPDFF). UGAP values significantly correlated with MRI-logPDFF (intraclass correlation coefficient = 0.768). Additionally, Bland-Altman analysis showed good agreement between MRI-logPDFF and UGAP with a mean bias of 0.0002% and a narrow range of agreement (95% confidence interval [CI], -0.015 to 0.015). The AUROCs for distinguishing steatosis grade ≥1 (MRI-PDFF ≥5.2%), ≥2 (MRI-PDFF ≥11.3%), and 3 (MRI-PDFF ≥17.1%) were 0.910 (95% CI, 0.891-0.928), 0.912 (95% CI, 0.894-0.929), and 0.894 (95% CI, 0.873-0.916), respectively., Conclusions: UGAP has excellent diagnostic accuracy for grading steatosis with reference to MRI-PDFF. Additionally, UGAP has good linearity and negligible bias, suggesting that UGAP has excellent technical performance characteristics that can be widely used in clinical trials and patient care. (UMIN Clinical Trials Registry, Number: UMIN000041196)., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Although the red pepper and its seeds have been studied for metabolic diseases, the effects and potential mechanisms of red pepper seed extract (RPS) on hepatic lipid accumulation are not yet completely understood. This study aimed to evaluate the inhibitory effect of RPS on hepatic lipid accumulation via autophagy. C57BL/6 mice were fed a high-fat diet (HFD) or a HFD supplemented with RPS. RPS treatment inhibited hepatic lipid accumulation by suppressing lipogenesis, inducing hepatic autophagic flux, and activating AMPK in HFD-fed mice. To investigate the effect of RPS on an oleic acid (OA)-induced hepatic steatosis cell model, HepG2 cells were incubated in a high-glucose medium and OA, followed by RPS treatment. RPS treatment decreased OA-induced lipid accumulation and reduced the expression of lipogenesis-associated proteins. Autophagic flux dramatically increased in the RPS-treated group. RPS phosphorylated AMPK in a dose-dependent manner, thereby dephosphorylated mTOR. Autophagy inhibition with 3-methyladenine (3-MA) antagonized RPS-induced suppression of lipogenesis-related protein expressions. Moreover, the knockdown of endogenous AMPK also antagonized the RPS-induced regulation of lipid accumulation and autophagy. Our findings provide new insights into the beneficial effects of RPS on hepatic lipid accumulation through the AMPK-dependent autophagy-mediated downregulation of lipogenesis.

Background: The impact of hepatic steatosis on liver stiffness measurement (LSM) in both chronic hepatitis B(CHB) and metabolic-associated fatty liver disease (MAFLD) remains controversial., Aims: To determine whether LSM is affected by hepatic steatosis in CHB-MAFLD., Methods: Hepatic steatosis and liver fibrosis were assessed by histological and noninvasively methods. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the diagnostic performance of LSM., Results: The prevalence of MAFLD in CHB patients (n = 436)was 47.5% (n = 207). For patients with low amounts of fibrosis (F0-1 and F0-2), the median LSM was 8.8 kPa and 9.2 kPa in patients with moderate- severe steatosis,which was significantly higher than that in patients with none-mild steatosis (P < 0.05) . The positive predictive value(PPV) was lower for LSM identifying significant fibrosis (F ≥ 2) as well as severe fibrosis (F ≥ 3) in group which controlled attenuation parameter(CAP) ≥ 268 dB/m than its counterpart(68.2% vs 84.6% and 24.3% vs 45.0%). The AUROC of LSM detected F ≥ 2 was 0.833 at a cutoff of 8.8 kPa and 0.873 at a cutoff of 7.0 kPa in patients with CAP ≥ 268 and CAP < 268, respectively., Conclusions: The presence of moderate-severe steatosis, detected by histology or CAP, should be taken into account to avoid overestimation of LSM., Competing Interests: Declaration of Competing Interest Jia Li designed the study. Jie Liu, Ma Ying,Ping Han and Jing Wang conducted the study, collected the data, and drafted the manuscript. Yong-gang Liu and Rui- fang Shi department of Pathology. Jia Li finalized the manuscript. The authors have no conflicts of interest to disclose., (Copyright © 2022 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Background: No study has examined whether serum uric acid/creatinine (sUA/Cr) is associated with the newly defined metabolic-associated fatty liver disease (MAFLDs). Furthermore, studies on other factors influencing their relationship have not been conducted. Aim: To investigate the relationship between sUA/Cr and newly defined MAFLD, and to identify any factors that affect this relationship. Methods: We retrospectively reviewed the data of patients who underwent abdominal computed tomography (CT) at the Hospital Health Promotion Center. Participants were divided into the healthy (no evidence of liver disease; n  = 707), MAFLD+non-heavy drinking (steatosis diagnosed by CT and drinking <140 and 70 grams/week for men and women, respectively; n  = 291), and MAFLD+heavy drinking (fatty liver diagnosed by CT and drinking >140 and 70 grams/week for men and women, respectively; n  = 61) groups. The relationship between sUA/Cr and MAFLD among the three groups were compared using multivariate logistic regression. Results: After adjusting for age, it was observed that when the sUA/Cr ratio increased by 1, the risk of MAFLD increased by 1.205 times the risk in the normal group. After adjusting for age, an increase by 1 in the sUA/Cr ratio increased the probability of non-heavy drinking+MAFLD and heavy drinking+MAFLD by 1.302 and 1.556 times, respectively, compared with healthy individuals. For those who smoked, the probability of heavy drinking+MAFLD was 9.901 times higher compared with healthy individuals. Conclusion: The newly defined MAFLD is related to sUA/Cr. The amount of alcohol consumption and smoking influenced the association between sUA/Cr and MAFLD.

ABSTRACT: Background and Aim: Non-alcohol fatty liver disease (NAFLD) is a metabolic disorder that represents the hepatic manifestation of systemic process, and is a strong risk factor for diabetes Meletus, whereas the presence of DM increases the severity of NAFLD/NASH and its progression. Data on the impact of diabetes on NASH phenotype is sparse from northern India. We studied and compared the clinical profile of NALFD in the presence and absence of DM and the effect of diabetes on NASH. Methods: We did a cross-sectional analysis of data from NAFLD patients (n = 90) who were divided into diabetic and non-diabetic cohorts and their respective demographic, biochemical, imaging and histological features were recorded and compared. Results: Out of 90 patients, 53.3% were females with a mean age of 44 ± 12 years. The mean BMI and WHR of the study cohort were 28.9 ± 3.4 and 1.01 ± 0.15, respectively. The current study showed that 35.8% were diabetics. The mean age and WHR were 52 ± 11 years vs 40 ± 10 years and 1.1 ± 0.17 vs 0.99 ± 0.09, respectively, in diabetic and non-diabetic NAFLD patients. Non-invasive fibrosis scores, including BARD (2.8 vs 1.73), FIB-4 (3.4 vs 2.2) and NFS (0.97 vs −1.13), were significantly higher in diabetic NAFLD compared to non-diabetic NAFLD (P < 0.03). The histological grade of steatosis and fibrosis as depicted by the mean NAS score (5.7 ± 1.2 vs 4.63 ± 0.8) was higher in diabetic NAFLD vs non-diabetic NAFLD; however, only the fibrosis stage was statistically significant between the groups (P < 0.001). Conclusion: Despite the small no of cases, we should conclude that there is a bidirectional relationship between NAFLD and DM where the progression of one increases the rate of progression of other. Diabetic patients have higher risk of NASH and hence increased risk of liver related mortality and should be screened early for NAFLD/NASH. [ABSTRACT FROM AUTHOR]

Background: The ritonavir-boosted protease inhibitor (PI/r) use has been associated with several metabolic abnormalities, and the non-alcoholic fatty liver disease (NAFLD) is becoming a very frequent comorbidity among HIV-infected patients. Methods: We performed an observational, prospective study of HIV-infected patients with NAFLD, receiving one PI/r plus two nucleoside analogues, who switched from the PI/r to raltegravir or were treated only with lifestyle modification, maintaining antiretroviral therapy unchanged. Changes in liver steatosis after 12 months were evaluated by transient elastography and measurement of controlled attenuation parameter (CAP). Results: As a whole, 61 patients (46 males; median age, 55.4 years) were enrolled, and 32 of them have been switched from PI/r to raltegravir. At baseline, median CAP was 259 dB/m, 28 (45.9%) subjects had a moderate-to-severe hepatic steatosis (CAP ≥260 dB/m), and 19 patients (31.1%) had elevated aminotransferases. Type-2 diabetes mellitus was present in 5 persons, and chronic HCV coinfection in 4. At month 12, the median decrease in CAP values was -27 dB/m in patients switched to raltegravir and -11 dB/m in those with unchanged cART ( p  = .021). The number of patients with CAP ≥260 dB/m decreased from 16 to 6 (-62.5%) in patients switched to raltegravir and from 12 to 8 (-33.3%) in the other group ( p  = .037). Conclusion: After 12 months, HIV-infected patients with NAFLD switching from a PI/r to raltegravir showed a significantly greater decrease in the hepatic steatosis degreee in comparison with those with unchanged cART and treated only with lifestyle modification.

Objective: To systematically review studies about the diagnostic accuracy of magnetic resonance imaging proton density fat fraction (MRI-PDFF) in the classification of hepatic steatosis grade in patients with non-alcoholic fatty liver disease (NAFLD)., Methods: Areas under the summary receiver operating characteristic curves (AUROC), sensitivity, specificity, overall diagnostic odds ratio (DOR), diagnostic score, positive likelihood ratio (+LR), and negative likelihood ratio (-LR) for MRI-PDFF in classification of steatosis grades 0 vs. 1-3, 0-1 vs. 2-3, and 0-2 vs. 3 were compared and analyzed., Results: A total of 6 studies were included in this meta-analysis (n = 635). The summary AUROC values of MRI-PDFF for classifying steatosis grades 0 vs. 1-3, 0-1 vs. 2-3, and 0-2 vs. 3 were 0.98, 0.91, and 0.90, respectively. Pooled sensitivity and specificity of MRI-PDFF for classifying steatosis grades 0 vs. 1-3, 0-1 vs. 2-3, and 0-2 vs. 3 were 0.93 and 0.94, 0.74 and 0.90, and 0.74 and 0.87, respectively. Summary +LR and -LR of MRI-PDFF for classifying steatosis grades 0 vs. 1-3, 0-1 vs. 2-3, and 0-2 vs. 3 were 16.21 (95%CI, 4.72-55.67) and 0.08 (95%CI, 0.04-0.15), 7.19 (95%CI, 5.04-10.26) and 0.29 (95%CI, 0.22-0.38), and 5.89 (95%CI, 4.27-8.13) and 0.29 (95%CI, 0.21-0.41), respectively., Conclusions: Our meta-analysis suggests that MRI-PDFF has excellent diagnostic value for assessment of hepatic fat content and classification of histologic steatosis in patients with NAFLD., Key Points: • MRI-PDFF has significant diagnostic value for hepatic steatosis in patients with NAFLD. • MRI-PDFF may be used to classify grade of hepatic steatosis with high sensitivity and specificity.

Drug-induced steatosis (DIS) and drug-induced steatohepatitis (DISH) are two of several types of drug-induced liver injury (DILI). They can be caused by various drugs and may present as acute, potentially lethal disorders or as chronic slowly progressive liver injury. Despite the fact that they are distinct disorders, the slow progressive forms of DIS and DISH are often confused with or misdiagnosed as non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), which are much more common and, by definition, not caused by drugs. Currently the only way to identify DIS is via imaging studies or a liver biopsy, while DISH can be identified only through liver biopsy. In addition, diagnosis of either DIS or DISH requires an exhaustive clinical evaluation and comprehensive causality assessment to rule out other possible causes and determine the association with the suspected drug. Furthermore, it is difficult, using existing methods, to monitor the progression of DIS and DISH and to determine the underlying mechanism. Therefore, there is a great unmet need for non-invasive biomarkers that will be able to identify the development of DIS or DISH during drug development and to monitor for progression or regression of the disorder during treatment or following drug discontinuation. Recent developments in the fields of NAFLD and NASH have introduced several novel biomarkers that show promise for the diagnosis, monitoring, and severity assessment of these common diseases. Given the significant overlap in possible underlying mechanisms and histological pattern between NAFLD/NASH and DIS/DISH, these postulated NAFLD and NASH biomarkers may have a potential application to DIS and DISH. This article reviews the existing medical literature and other publically available information pertaining to novel serum biomarkers for NAFLD and NASH, and explores the concurrent identification of these biomarkers for DIS and DISH.

Background and Purpose: Nonalcoholic fatty liver disease (NAFLD) is a worldwide health problem with high prevalence and morbidity associated with obesity, insulin resistance, type 2 diabetes mellitus (T2DM), and dyslipidemia. Luteolin is a natural flavonoid with various activities. We aimed to investigate whether luteolin can alleviate NAFLD and its possible mechanism. Materials and Methods: A mouse model with NAFLD was induced by Western diet (WD) and carbon tetrachloride (CCl4) injection. Twenty-four mice were distributed into three groups randomly: Normal diet group (CON, n = 8), NAFLD group (NAF, n = 8), and luteolin group (LUT, n = 8). NAFLD model was induced by feeding mice in NAF and LUT groups with WD and injecting CCl4. CON group were fed with a normal diet in the same period. The LUT group was administered orally with luteolin (20 mg/kg) every day, starting from the 1st day of the 5th week for 8 weeks, while the CON group was treated with a vehicle. Throughout the experiment, body weight, lipid profile, glucose tolerance test, and the hepatic expressions of CD36/FABP1/LC3B/Bcl-2 were measured beside the histopathological examination. Results: Luteolin treatment effectively prevents the body from weight gain in mice with NAFLD (NAF vs. LUT: 36.0 g vs. 32.4 g, p < 0.05). Serum total cholesterol and triglyceride levels are both significantly increased in the NAF group (p < 0.01) and reduced to some extent in the LUT group (p < 0.05). Oral glucose tolerance test (OGTT) test results show that luteolin could improve the impaired glucose tolerance and downregulate the elevated fasting blood glucose in mice with NAFLD (p < 0.05). Histopathological results demonstrate luteolin reduces hepatic steatosis and hepatic fibrosis in NAFLD mice. The possible mechanisms may include that luteolin decreases hepatic CD36 and FABP1 expression, and increases levels of autophagy marker LC3B and antiapoptotic protein Bcl-2. Conclusion: Luteolin could reduce hepatic steatosis and fibrosis, hyperglycemia, body weight, and serum lipid levels in NAFLD mice, which exhibits huge potential in the treatment of metabolic disorders related to NAFLD. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is a liver disease causing different progressive pathological changes. Trimethylamine N-oxide (TMAO), a product of gut microbiota metabolism, is a specific agonist of the protein kinase R-like endoplasmic reticulum kinase (PERK) pathway, one of the endoplasmic reticulum stress (ERS) pathways. TMAO has been associated with the occurrence and development of NAFLD based on the results of previous studies, but whether the simple consumption of TMAO can directly induce NAFLD and its underlying mechanism remain unclear. To investigate this question, we constructed an animal model in which adult male zebrafish were fed a controlled diet containing 1 % or 3 % TMAO for 20 weeks. Eventually, we observed that TMAO caused lipid accumulation, inflammatory infiltration, liver injury and liver fibrosis in zebrafish livers; meanwhile, the PERK signaling pathway was activated in the zebrafish livers. This finding was further confirmed in HepG2 cells and hepatic stellate cells models. In conclusion, this study found that TMAO directly induced different pathological states of NAFLD in zebrafish liver, and the activation of PERK pathway is an important mechanism, which may provide crucial strategies for the diagnosis and treatment of NAFLD. • Hepatic steatosis caused by TMAO mainly occurred at the initial stage of the lesion. • TMAO provoked NASH and promoted liver fibrotic pathological changes in zebrafish. • The activation of PERK pathway was involved in TMAO-induced NAFLD. [ABSTRACT FROM AUTHOR]

Background: Current dietary guidelines generally treat all types of vegetables the same. However, whether specific vegetables are more beneficial or deleterious for preventing chronic liver disease (CLD) remains uncertain., Methods: We investigated the associations between starchy and non-starchy vegetables and the odds of hepatic steatosis and fibrosis in a US nationwide cross-sectional study. Diet was assessed by the 24-h dietary recalls. Hepatic steatosis and fibrosis were defined based on vibration-controlled transient elastography (TE). Multiple logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs)., Results: Among 4170 participants with reliable TE test, 1436 were diagnosed with steatosis, 255 with advanced fibrosis. Increased intake of total starchy vegetables was associated with higher odds of steatosis (OR per 1-SD increment 1.11, 95% CI 1.01-1.24) and advanced fibrosis (OR = 1.39, 95% CI 1.15-1.69). Similar positive associations were observed for potatoes. Conversely, intakes of total non-starchy (OR = 0.82, 95% CI 0.71-0.95) and dark-green vegetables (OR = 0.89, 95% CI 0.82-0.97) were inversely associated with steatosis prevalence. Replacing 5% of energy from starchy vegetables (OR = 0.65, 95% CI 0.44-0.97) or potatoes (OR = 0.65, 95% CI 0.43-0.97) with equivalent energy from dark-green vegetables was associated with lower odds of steatosis., Conclusions: These findings support the recommendation to limit starchy vegetable intake and increase non-starchy vegetable intake in CLD prevention, and provide evidence for the potential health benefit from dietary substitution of non-starchy vegetables for starchy vegetables., (© 2022. Asian Pacific Association for the Study of the Liver.)

Accurate detection of liver steatosis is important for liver disease management. Ultrasound attenuation coefficient estimation (ACE) has great potential in quantifying liver fat content. The ACE methods commonly assume uniform tissue characteristics. However, in vivo tissues typically contain non-uniform structures, which may bias the attenuation estimation and lead to large standard deviations. Here we propose a series of non-uniform structure detection and removal (NSDR) methods to reduce the impact from non-uniform structures during ACE analysis. The effectiveness of NSDR was validated through phantom and in vivo studies. In a pilot clinical study, ACE with NSDR provided more robust in vivo performance as compared with ACE without NSDR, indicating its potential for in vivo applications., Competing Interests: Conflict of interest dislcosure The Mayo Clinic and two authors (P.G. and S.C.) have a potential financial interest related to the technology referenced in this article., (Copyright © 2022 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Excessive liver fat (steatosis) is now the most common cause of chronic liver disease worldwide and is an independent risk factor for cirrhosis and associated complications. Accurate and clinically useful diagnosis, risk stratification, prognostication, and therapy monitoring require accurate and reliable biomarker measurement at acceptable cost. This article describes a joint effort by the American Institute of Ultrasound in Medicine (AIUM) and the RSNA Quantitative Imaging Biomarkers Alliance (QIBA) to develop standards for clinical and technical validation of quantitative biomarkers for liver steatosis. The AIUM Liver Fat Quantification Task Force provides clinical guidance, while the RSNA QIBA Pulse-Echo Quantitative Ultrasound Biomarker Committee develops methods to measure biomarkers and reduce biomarker variability. In this article, the authors present the clinical need for quantitative imaging biomarkers of liver steatosis, review the current state of various imaging modalities, and describe the technical state of the art for three key liver steatosis pulse-echo quantitative US biomarkers: attenuation coefficient, backscatter coefficient, and speed of sound. Lastly, a perspective on current challenges and recommendations for clinical translation for each biomarker is offered., (© RSNA, 2022.)

Background US tools to quantify liver fat content have recently been made clinically available by different vendors, but comparative data on their accuracy are lacking. Purpose To compare the diagnostic performances of the attenuation parameters of US machines from three different manufacturers (vendors 1, 2, and 3) in participants who underwent liver fat quantification with the MRI-derived proton density fat fraction (PDFF). Materials and Methods From July 2020 to June 2021, consecutive participants with chronic liver disease were enrolled in this prospective single-center study and underwent MRI PDFF quantification (reference standard) and US on the same day. US was performed with two different machines from among three vendors assessed. Areas under the receiver operating characteristic curve (AUCs) for the staging of liver steatosis (MRI PDFF: ≥5.5% for grade ≥S1 and ≥15.5% for grade ≥S2) were calculated in test and validation samples and then compared between vendors in the study sample. Results A total of 534 participants (mean age, 60 years ± 13 [SD]; 320 men) were evaluated. Failure of measurements occurred in less than 1% of participants for all vendors. Correlation coefficients with the MRI PDFF were 0.71, 0.73, and 0.54 for the attenuation coefficients of vendors 1, 2, and 3, respectively. In the test sample, AUCs for diagnosis of steatosis grade S1 and higher and grade S2 and higher were 0.89 and 0.93 for vendor 1 attenuation, 0.88 and 0.92 for vendor 2 attenuation, and 0.79 and 0.79 for vendor 3 attenuation, respectively. In the validation sample, a threshold value of 0.65 for vendor 1 and 0.66 for vendor 2 yielded sensitivity of 77% and 84% and specificity of 78% and 85%, respectively, for diagnosis of grade S1 and higher. Vendor 2 attenuation had greater AUCs than vendor 3 attenuation ( P = .001 and P = .003) for diagnosis of grade S1 and higher and grade S2 and higher, respectively, and vender 2 had greater AUCs for attenuation than vendor 1 for diagnosis of grade S2 and higher ( P = .04). For all vendors, attenuation was not associated with liver stiffness (correlation coefficients <0.05). Conclusion To stage liver steatosis, attenuation coefficient accuracy varied among US devices across vendors when using MRI proton density fat fraction quantification as the reference standard, with some demonstrating excellent diagnostic performance and similar cutoff values. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Dubinsky in this issue.

Elevated intraocular pressure (EIOP) is a major risk factor for glaucoma. Both EIOP and fatty liver share metabolic risk factors, which implies a possible link between EIOP and fatty liver. We aimed to determine the association of fatty liver with EIOP and estimate the effect of fatty liver on EIOP directly and indirectly through insulin resistance. Data from 16,240 adults who underwent health examinations at a single center were analyzed. Multiple logistic regression analyses revealed that fully adjusted odds ratio (OR) and 95% confidence interval (CI) for EIOP in the fatty liver group compared to the non-fatty liver group were 1.36 and 1.08-1.71. Alcoholic liver disease was associated with EIOP in subgroup analysis (OR = 1.80, 95% CI: 1.27-2.56). There was a linear dose-response relationship between EIOP and the severity of fatty liver. Mediation analysis revealed that the total effect of fatty liver on intraocular pressure was 0.90 (0.81-0.99), with a direct effect of 0.81 (0.71-0.90) and an indirect effect of 0.09 (0.06-0.11) through insulin resistance. Fatty liver is independently associated with EIOP. It primarily has a direct effect on intraocular pressure. This suggests that evaluation of EIOP should be considered in patients with fatty liver.

Background: Metabolic associated fatty liver disease (MAFLD) is associated with complications and mortality in patients with coronavirus disease 2019 (COVID-19). However, there are no prognostic scores aimed to evaluate the risk of severe disease specifically in patients with MAFLD, despite its high prevalence. Lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase have been used as markers of liver damage. Therefore, we propose an index based on lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase for the prediction of complications and mortality in patients with MAFLD and COVID-19., Aim: To evaluate the prognostic performance of an index based on lactate dehydrogenase and transaminases (aspartate aminotransferase/alanine aminotransferase) in patients with COVID-19 and MAFLD [liver fibrosis and nutrition (LNF)-COVID-19 index]., Methods: In this retrospective cohort study, two cohorts from two different tertiary centers were included. The first was the derivation cohort to obtain the score cutoffs, and the second was the validation cohort. We included hospitalized patients with severe COVID-19 and MAFLD. Liver steatosis was evaluated by computed tomography scan. Area under the receiver operating characteristic (ROC) curve analysis and survival analysis were used., Results: In the derivation cohort, 44.6% had MAFLD; ROC curve analysis yielded a LFN-COVID-19 index > 1.67 as the best cutoff, with a sensitivity of 78%, specificity of 63%, negative predictive value of 91% and an area under the ROC curve of 0.77. In the multivariate analysis, the LFN-COVID-19 index > 1.67 was independently associated with the development of acute kidney injury (odds ratio: 1.8, 95% confidence interval: 1.3-2.5, P < 0.001), orotracheal intubation (odds ratio: 1.9, 95% confidence interval: 1.4-2.4, P < 0.001), and death (odds ratio: 2.86, 95% confidence interval: 1.6-4.5, P < 0.001) in both cohorts., Conclusion: LFN-COVID-19 index has a good performance to predict prognosis in patients with MAFLD and COVID-19, which could be useful for the MAFLD population., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Tracking liver polarity with noninvasive and dynamic imaging techniques is helpful to better understand the non-alcoholic fatty liver (NAFL). Herein, a novel near-infrared (NIR) fluorescent probe Cy-Mp is constructed using a "symmetry collapse" strategy. The structure modification leads to the conversion of locally excited state fluorescence to charge transfer state fluorescence. Cy-Mp emits at near-infrared (NIR) wavelengths with high photostability as well as a large Stokes shift. Cy-Mp exhibits a ratiometric response to polarity, providing more accurate analysis of intracellular polarity via the built-in internal reference correction. Most importantly, the in vivo studies indicate that Cy-Mp can accumulate in the liver and the decreased polarity in the liver of mice with NAFL is verified by the ratiometric imaging, implying the great potential of Cy-Mp in the diagnosis of NAFL.

Competing Interests: N. S. has participated in Scientific Advisory Boards of Allergan, Intercept Pharma, MSD, Pfizer, Novo Nordisk, Gilead, Genkyotex, Astra-Zeneca, Boehringer Ingelheim, Sanofi, and clinical trials of AstraZeneca, Boehringer Ingelheim, Sanofi, DSM Nutritional Products and Roche Diagnostics. M. R. has participated on Scientific Advisory Boards of BMS, Boehringer Ingelheim Pharma, Eli Lilly, Fishawack Group, Gilead Sci., Novo Nordisk, Poxel S.A. Sociéte, Prosciento Inc., Sanofi, Servier Lab., Target Pharmasolutions, Terra Firma and in clinical trials of Astra Zeneca, Boehringer Ingelheim, Nutricia/Danone and Novartis.

Non-alcoholic fatty liver disease (NAFLD), a major cause of chronic liver disease, is known to affect a quarter of the global adults. Natural history of NAFLD shows interindividual variation, traditionally it progresses from simple steatosis to steatohepatitis to fibrosis/cirrhosis and finally yet rarely to hepatocellular carcinoma. It is largely a lifestyle-related disease and is often labeled as the hepatic manifestation of metabolic syndrome. Both prevention and control of NAFLD include controlling risk factors (obesity, diabetes mellitus, hypertension and dyslipidemia), through lifestyle modification and medications. Drug therapy for NAFLD per se is still evolving and till date, no drugs are approved. It is clinically silent, especially in the early stages, and is a diagnosis of exclusion. Certain easily calculated indices can stratify cases into high or low risk for advanced fibrosis, thereby dictating appropriate monitoring and treatment measures. In addition to complications specific to liver disease in those who do progress to advanced fibrosis or cirrhosis, an increased risk of nonliver disease-related morbidity and mortality is also present. Challenges are manifold and include rising burden due to ever-growing epidemic of diabetes and obesity, low public awareness, fragmented healthcare, no approved drugs, and dearth of data on magnitude and epidemiology of the disease. The recent integration of NAFLD into the National Program for Prevention and Control of Non-Communicable Diseases (NPCDCS) by the Ministry of Health and Family Welfare of India is a welcome step in this direction as the contributory factors are mostly the same for all diseases and controlling any one or all of them will have a desired impact on the prevalence of all the diseases under this program. [ABSTRACT FROM AUTHOR]

Objective: To explore the clinical value of computed tomography (CT) liver-to-spleen (L/S) attenuation ratio in patients with non-alcoholic fatty liver disease (NAFLD) accompanied by atherosclerotic plaque (AP). Methods: This was a single-center, retrospective, observational study of patients who were diagnosed with NAFLD undergoing CT scans at Beijing Changping Hospital of Chinese Medicine from April 2020 to April 2022. Patients were grouped according to whether they had a diagnosis of AP or not. Healthy individuals without NAFLD undergoing CT scans during the same period were also included as a control group. The patients were matched for gender, age, and BMI in a 1:1:1 ratio. Correlations between the CT L/S attenuation ratio, liver function indicators, and blood lipid levels were assessed in the three groups. The predictive value of the CT L/S attenuation ratio was evaluated using the receiver operating characteristic (ROC) curve and the area under the curve (AUC) analyses. Results: Eighty-nine cases in each group. The three groups had significant differences in liver function and blood lipid levels (P<0.05). The CT L/S attenuation ratio in the NAFLD+AP and NAFLD groups was lower than that in the control group and was the lowest in the NAFLD+AP group (P<0.05). There was no significant correlation between the CT L/S attenuation ratio and liver function indicators (P>0.05), but it positively correlated with high-density lipoprotein (HDL) and negatively correlated with low-density lipoprotein (LDL), triglycerides (TG), and total cholesterol (TC) (P<0.05). The CT L/S attenuation ratio had a high predictive value for NAFLD patients with AP (AUC=0.859). Conclusions: The CT L/S attenuation ratio in NAFLD patients with AP is significantly reduced and is closely related to the levels of blood lipid indicators. The CT L/S attenuation ratio has a high predictive value for NAFLD patients with AP. [ABSTRACT FROM AUTHOR]

To study the effect of probiotics on diet-induced non-alcoholic fatty liver disease (NAFLD) in mice, the NAFLD mouse model was established by giving NAFLD model diet, simultaneously, with 100 µL probiotic mixture (Lactobacillus plantarum 1201 and Bifidobacterium animalis subsp. lactis SF) intervention by gavage for 12 weeks. The results showed that the combined intervention recovered liver function, alleviated oxidative stress, and regulated autophagy in NAFLD mice; significantly improved intestinal flora and reduced endotoxin production, thereby inhibited the LPS/NF-κB signaling pathway and alleviated the inflammatory response. In addition, the combined dual bacterial intervention also improved insulin resistance in mice and regulated the PI3K-Akt/AMPK signaling pathway, which in turn regulated lipid metabolism, thereby reduced lipid accumulation in the liver. [ABSTRACT FROM AUTHOR]

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is typically first suspected when the results of liver function tests, measured as part of routine testing, are abnormal. Most often observed biochemical pattern in hepatic steatosis due to NAFLD is of increased levels of transaminases, with alanine aminotransferase (ALT) levels exceeding those of aspartate aminotransferase (AST). This classical pattern is particularly useful in differentiating between hepatic steatosis from NAFLD.The pathophysiology of non-metabolic complication like atherosclerosis and cardiovascular disease (CVD) depends vastly on fatty acids (lipid) transportation and Deposition. AIM Estimation of the AST: ALT, Albumin: Globulin, and TG: HDL ratios, along with their comparison among the Alcoholic and Non-alcoholic fatty liver disease patient. Materials & Methods: A prospective observational cohort study was conducted in the department of Biochemistry at GBCM & KKBM Subharti hospital, Jhajra, Dehradun after obtaining the ethical clearance from the institutional ethical committee (IEC) with registration no GBCM/IEC/2023/07-03 dated 25/07/2023. Cases comprised of 120 Ultrasonographically confirmed fatty liver patients by Random sampling method. 5ml blood sample was collected in the serum separation test tube (SST) and results were analysed using SPSS v.20. and statistical p-value of

Introduction and Objectives: Hepatitis B virus (HBV) might be an etiological factor modulating fat distribution in steatotic livers. We aim to compare hepatic steatosis distribution patterns between NAFLD and FL&CHB patients with second-harmonic generation (SHG)/two-photon excited fluorescence (TPEF) method., Patients and Methods: 42 patients with NAFLD, 46 with FL&CHB and 55 without steatosis were enrolled in the study. Overall and regional steatosis in liver sections were quantified by SHG/TPEF method. The accuracy of which was validated by pathologist evaluation and magnetic resonance spectroscopy (MRS). Difference in degree of overall and regional steatosis between NAFLD and FL&CHB groups was analyzed by Mann-Whitney U test. Multivariable linear regression analysis was used to model factors contributing to steatosis distribution., Results: The hepatic steatosis measured by SHG/TPEF method was highly correlated with pathologist grading (r=0.83, p<0.001) and MRS measurement (r=0.82, p<0.001). The level of overall steatosis in FL&CHB group is significantly lower than that in NAFLD group (p<0.001). In NAFLD group, periportal region has significantly lower steatosis percentage than lobule region and overall region (p<0.001); while in FL&CHB group there is no difference among regions. The ratio of steatosis at periportal region to lobule region is significantly higher in FL&CHB group than that in NAFLD group (p<0.05). Multivariable linear regression analysis shows that HBV infection is the major contributing factor (β=0.322, p<0.01)., Conclusions: SHG/TPEF method is an accurate and objective method in hepatic steatosis quantification. By quantifying steatosis in different histological regions, we found steatosis distribution patterns are different between FL&CHB and NAFLD patients., (Copyright © 2019 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

(1) Background : The etiology of non-alcoholic fatty liver disease (NAFLD) is multifactorial. Dietary composition has been implicated as a factor modulating intestinal barrier and could affect disease severity. The aim of this study was to evaluate dietary intake and markers of intestinal permeability in patients with NAFLD. (2) Methods : We enrolled 63 patients with NAFLD and compared them to age-matched controls. (3) Results: body mass index (BMI) and leptin to adiponectin ratio-the latter being an indicator of abdominal fat accumulation-correlated with the degree of hepatic steatosis being accompanied with rising levels of fasting insulin. Furthermore, endotoxin plasma levels and markers of inflammation were significantly higher in NAFLD compared to controls and increased with the severity of hepatic steatosis. Despite comparable intake of total energy and macronutrients, intake of fiber was lower in all patients with NAFLD compared to controls and were negatively related to disease severity. (4) Conclusions: Taken together, results of the present study suggest that fiber intake in patients is negatively related to steatosis degree and bacterial endotoxin levels, further suggesting that dietary fiber intake may be a target in NAFLD treatment (NCT: 02366052 and 03482284)., Competing Interests: J.M.S. reports grants/research supports from Gilead Sciences and Yakult Europe B.V. Consultation fees from BMS, Boehringer Ingelheim, Genfit, Gilead Sciences, Intercept Pharmaceuticals, IQVIA, Madrigal, Novartis, Pfizer, Roche and participation in company sponsored lectures for Falk Foundation, Merck. IB reports research supports from Yakult Europe B.V. All other authors declare no conflict of interest.

BACKGROUND Metabolic dysfunction-associated fatty liver disease (MAFLD) is now the term used for hepatic steatosis in patients who are overweight or obese, have type 2 diabetes mellitus (T2DM), or evidence of metabolic dysregulation. The prevalence of MAFLD among morbidly obese subjects is 65-93%. Hepatic dendritic cells (hDCs) are antigen-presenting cells that induce T cell-mediated immunity. MAFLD pathogenesis involves numerous immune cell-mediated inflammatory processes, while the particular role of hDCs is yet to be well defined. This study aimed to identify hDCs in liver biopsies from 128 patients with MAFLD associated with obesity. MATERIAL AND METHODS In this cross-sectional study, 128 liver biopsies from 128 patients with MAFLD (diagnosed as presence of hepatic steatosis, plus T2DM, metabolic dysregulation or overweight/obesity) were collected and assessed for CD11c⁺ immunoreactivity degree (CD11c as dendritic cell biomarker), through antigen retrieval, reaction with CD11c antibodies (primary), and marking with diaminobenzidine chromogen. RESULTS Among the 128 patients with MAFLD, 64 (50%) had MAFLD and fibrosis and 72 (56.2%) positively expressed hDCs (CD11c⁺). Among morbidly obese patients, 49 (64.5%) positively expressed hDCs (CD11c⁺) in liver tissue; from patients with obesity grade I- grade II (GI-II), 18 (54.5%) positively expressed hDCs (CD11c⁺) in liver tissue; and from non-obese patients with MAFLD, 5 (26.3%) positively expressed hDCs (CD11c⁺) in liver tissue. CONCLUSIONS hDC expression increases significantly in morbidly obese patients with MAFLD compared with non-obese patients, independent of the degree of fibrosis, suggesting the role of adaptive changes within hDCs in the perpetuation of inflammatory insults in chronic liver diseases.

Background: Hepatic steatosis is a major cause of chronic liver disease. Two-dimensional (2D) ultrasound is the most widely used non-invasive tool for screening and monitoring, but associated diagnoses are highly subjective., Aim: To develop a scalable deep learning (DL) algorithm for quantitative scoring of liver steatosis from 2D ultrasound images., Methods: Using multi-view ultrasound data from 3310 patients, 19513 studies, and 228075 images from a retrospective cohort of patients received elastography, we trained a DL algorithm to diagnose steatosis stages (healthy, mild, moderate, or severe) from clinical ultrasound diagnoses. Performance was validated on two multi-scanner unblinded and blinded (initially to DL developer) histology-proven cohorts (147 and 112 patients) with histopathology fatty cell percentage diagnoses and a subset with FibroScan diagnoses. We also quantified reliability across scanners and viewpoints. Results were evaluated using Bland-Altman and receiver operating characteristic (ROC) analysis., Results: The DL algorithm demonstrated repeatable measurements with a moderate number of images (three for each viewpoint) and high agreement across three premium ultrasound scanners. High diagnostic performance was observed across all viewpoints: Areas under the curve of the ROC to classify mild, moderate, and severe steatosis grades were 0.85, 0.91, and 0.93, respectively. The DL algorithm outperformed or performed at least comparably to FibroScan control attenuation parameter (CAP) with statistically significant improvements for all levels on the unblinded histology-proven cohort and for "= severe" steatosis on the blinded histology-proven cohort., Conclusion: The DL algorithm provides a reliable quantitative steatosis assessment across view and scanners on two multi-scanner cohorts. Diagnostic performance was high with comparable or better performance than the CAP., Competing Interests: Conflict-of-interest statement: All authors declare no conflict of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: Gallstone disease (GSD) and non-alcoholic fatty liver disease (NAFLD) share common risk factors. NAFLD can progress to non-alcoholic steatohepatitis (NASH), which may lead to severe liver conditions. This study aimed to assess the prevalence of NASH and associated factors in patients with GSD and fatty liver undergoing cholecystectomy. Material and Methods: This prospective observational study was conducted from March 2021 to June 2023 and included 134 patients diagnosed with GSD and fatty liver based on preoperative ultrasound. Core liver biopsies were obtained during cholecystectomy. Preoperatively, clinical, anthropometric, demographic, biochemical variables, and FibroScan parameters were recorded. Results: NASH was found in 21 (15.67%) patients, while 50 (37.31%) patients had probable NASH, and 63 (47.01%) had non-NASH scores. Metabolic syndrome was present in 63.6% of the patients. Univariate analysis revealed significant differences in AST and ALT values between the NASH and nonNASH groups. In multivariate analysis, AST was statistically significant (p= 0.041). Mean controlled attenuation parameter in patients with non-NASH was 219.40 ± 60.44 dB/m, and in patients with NASH, it was 265.48 ± 63.47 dB/m (p= 0.006). Fibrosis was present in 33 of the 82 slides examined, with 17 patients having grade 2 and two patients with grade 3 fibrosis. Conclusion: The high prevalence of NASH among GSD patients highlights a significant public health issue, prompting consideration for liver biopsy in individuals with NAFLD and GSD undergoing laparoscopic cholecystectomy. [ABSTRACT FROM AUTHOR]

Fatty liver disease (FLD) is the most common chronic liver disease worldwide. The pathogenesis of this disease is closely related to obesity and insulin resistance. Ginger has hypolipidemic and antioxidant effects and acts as an insulin sensitizer. This study aims to evaluate the effect of ginger supplementation on the fatty liver. A comprehensive search of Medline/PubMed, Embase, Scopus, Web of Science/ISI, and Cochrane databases was conducted without time or language restrictions. Eighteen eligible studies were identified, including 17 in-vivo experiments in quantitative analysis and 3 clinical trials in qualitative analysis. The present study provides comprehensive evidence of the efficacy of ginger to improve the liver levels of cholesterol (-5.60 mg/g), triglycerides (TG, -4.28 mg/g), malondialdehyde (-3.16 nmol/mg), catalase (CAT) (3.35 nmol/mg), superoxide dismutase (SOD, 3.01 U/mg), serum levels of alanine aminotransferase (ALT, -2.85 U/L), aspartate aminotransferase (AST, -0.98 U/L), TG (-4.98 mg/dL), low-density lipoprotein (LDL, -3.94 mg/dL), total cholesterol (TC, -3.45 mg/dL), high-density lipoprotein (HDL, 1.27 mg/dL), and fasting blood sugar (FBS, -2.54 mg/dL). Ginger administration may reduce many clinical aspects of FLD by several mechanisms, including insulin-sensitive effects, stimulating the expression of antioxidant enzymes, reducing the generation of reactive oxygen species (ROS), having antidyslipidemic activities, and reducing hepatic fat content. However, future clinical trials are essential to investigate the clinical application of ginger in this area., (© 2022 John Wiley & Sons Ltd.)

Aims: We examined the associations between liver volume and other quantitative and qualitative markers of hepatic steatosis with all-cause mortality in the general population., Methods: We included 2769 German middle-aged individuals with a median follow-up of 8.9 years (23,898 person-years). Quantitative markers used were serum liver enzymes and FIB-4 score, while qualitative markers of hepatic steatosis included magnetic resonance imaging (MRI) measurements of liver fat content and total liver volume. Cox proportional hazards models, adjusted for confounding factors, were undertaken to investigate the associations of liver volume and other markers of hepatic steatosis with all-cause mortality., Results: A larger MRI-assessed liver volume was associated with a nearly three-fold increased risk of all-cause mortality (Hazard Ratio = 3.16; 95% confidence interval 1.88; 5.30), independent of age, sex, body mass index, food frequency score, alcohol consumption and education level. This association was consistent in all subgroups considered (men vs. women; presence or absence of overweight/obesity, metabolic syndrome or diabetes). Higher serum liver enzyme levels and FIB-4 score were also significantly associated with higher all-cause mortality in the total population and in all subgroups. No independent associations were found between other quantitative and qualitative markers of hepatic steatosis and the risk of all-cause mortality., Conclusions: We showed for the first time that larger liver volume was associated with a three-fold increase in long-term risk of all-cause mortality. This association remained significant after adjustment for age, sex, alcohol consumption, obesity and other coexisting metabolic disorders., (© 2022 The Authors. Liver International published by John Wiley & Sons Ltd.)

Objectives: To investigate the diagnostic performance of attenuation imaging (ATI) for the assessment of low-grade hepatic steatosis using liver biopsy as the reference standard., Methods: The study included 57 potential donor candidates for living liver transplantation who underwent ATI, transient elastography (TE), and liver biopsy for evaluation of hepatic steatosis between February 2020 and April 2020. The attenuation coefficient (AC) from ATI and the controlled attenuation parameter (CAP) from TE were measured for each participant in a random and blind manner. The histologic hepatic fat fraction (HFF) was graded (S0, < 5%; S1, 5-33%; S2, 33-66%; S3, > 66%). The accuracy of ATI for diagnosing hepatic steatosis was compared with that of CAP using ROC analysis. Correlations between AC and HFF were evaluated, and factors affecting AC were determined by linear regression analysis., Results: The median HFF was 3% (range: 0-35%), with 31 (54.4%), 24 (42.0%), and 2 (3.5%) participants being graded as S0, S1, and S2, respectively. The AUCs for the ROCs of AC and CAP for the detection of hepatic steatosis were 0.808 (95% CI: 0.682-0.900) and 0.829 (95% CI: 0.706-0.916), respectively, with the difference not being statistically significant (p = 0.762). AC showed 61.5% of sensitivity and 90.3% of specificity. AC was positively correlated with HFF (p < 0.001). HFF was the only factor significantly affecting AC., Conclusions: ATI showed moderate sensitivity and high specificity in the diagnosis and quantification of hepatic steatosis in low-grade steatosis without fibrosis. Only HFF significantly affected AC., Key Points: • Attenuation imaging showed moderate sensitivity and high specificity performance in the diagnosis and quantification of hepatic steatosis in low-grade steatosis without fibrosis. • The diagnostic performance of the attenuation coefficient by attenuation imaging did not significantly differ from that of the controlled attenuation parameter by transient elastography in quantifying low-grade steatosis. • The histopathologically determined hepatic fat fraction was the only factor significantly affecting the attenuation coefficient., (© 2021. European Society of Radiology.)