Severe Fatty Liver Disease Research Articles

Impact of rosuvastatin on metabolic syndrome patients with moderate to severe metabolic associated fatty liver disease without overt diabetes: A randomized clinical trial

ObjectiveThis investigation aimed to evaluate the efficacy and safety of rosuvastatin in treating moderate to severe metabolic associated fatty liver disease (MAFLD). MethodsThis prospective, open-label, randomized study included non-diabetic participants with metabolic syndrome and intrahepatocellular lipid (IHCL) levels >10 %, as determined by proton magnetic resonance spectroscopy (1H-MRS). The primary objective was the effect of a 52-week rosuvastatin treatment (10 mg/day) on IHCL content. Secondary objectives included the association between IHCL reduction and lipid metabolism parameters, along with safety indices such as glycemic control and hepatic and renal function. ResultsThirty-two participants completed the study. Rosuvastatin resulted in a significant absolute (△IHCL: 7.61 ± 4.51 vs. 1.54 ± 5.33, p = 0.002) and relative reduction in IHCL (△IHCL%: −42.28 ± 24.90 % vs. −8.91 ± 31.93 %, p = 0.003) compared to the control. Reduction in IHCL correlated significantly with decreases in low-density lipoprotein cholesterol (LDL-C) (r = 0.574, p < 0.01), apolipoprotein B (ApoB) (r = 0.660, p < 0.001), and free fatty acids (FFA) (r = 0.563, p = 0.005). No significant safety differences were observed between groups. ConclusionsRosuvastatin significantly reduced hepatic steatosis in individuals with moderate to severe MAFLD and metabolic syndrome over 52 weeks, while maintaining a favorable safety profile.

Treatment with 1.25% cholesterol enriched diet produces severe fatty liver disease characterized by advanced fibrosis and inflammation and impaired autophagy in mice

Nonalcoholic fatty liver disease (NAFLD) is reaching pandemic proportions due to overnutrition. The understanding of advanced stages that recapitulate the human pathology is of great importance to get a better mechanistic insight. We hypothesized that feeding of WT (C57BL) mice with a diet containing a high content of fat (21%), sugar (41.5%) and 1.25% of cholesterol (called from now on high fat, sucrose and cholesterol diet, HFSCD) will reproduce the characteristics of disease severity. Analysis of 16 weeks HFSCD-fed mice demonstrated increased liver weight and plasmatic liver damage markers compared with control diet (CD)-fed mice. HFSCD-fed mice developed greater hepatic triglyceride, cholesterol and NEFA content, inflammation and NAFLD activity score (NAS) indicating an advanced disease. HFSCD-fed mice displayed augmented hepatic total CD3+ T and Th9 lymphocytes, as well as reduced Th2 lymphocytes and CD206 anti-inflammatory macrophages. Moreover, T cells and anti-inflammatory macrophages correlated positively and inversely, respectively, with intrahepatic cholesterol content. Consistently, circulating cytotoxic CD8+ T lymphocytes, Th1, and B cell levels were elevated in HFSCD-fed WT mice. Hepatic and adipose tissue expression analysis demonstrated changes in fibrotic and metabolic genes related with cholesterol, triglycerides, and fatty acid synthesis in HFSCD-fed WT. These mice also exhibited reduced antioxidant capacity and autophagy and elevated ERK signaling pathway activation and CHOP levels. Our results indicate that the feeding with a cholesterol-enriched diet in WT mice produces an advanced NAFLD stage with fibrosis, characterized by deficient autophagy and ER stress along with inflammasome activation partially via ERK pathway activation.

To Treat or Not to Treat: A Twist in Paxlovid-Induced Liver Injury Amidst Severe Fatty Liver Disease

To Treat or Not to Treat: A Twist in Paxlovid-Induced Liver Injury Amidst Severe Fatty Liver Disease

Contrast-enhanced Computed Tomography Versus Contrast and Non-contrast Enhanced Computed Tomography for Detecting Blunt Abdominal Injury

Objective: This study aimed to compare the diagnostic ability of contrast-enhanced computed tomography (CECT) and CECT combined with non-contrast computed tomography (NCT) for intraabdominal organ injury in patients with blunt abdominal injury.Material and Methods: Overall, 195 adult patients having had blunt abdominal trauma underwent CT at this institution; from 2016 and 2021. All CT images were retrospectively reviewed by two radiologists. The efficacy of detection of organ injuries and the degree of intra-abdominal injury were recorded. The radiologists scored their diagnostic confidence for each CT image dataset on a five-point scale: inter-observer agreement was also calculated.Results: All included patients underwent CT for blunt abdominal trauma. The most common cause of injury was motorcycle accident (59.5%), with patients being predominantly male: the mean patient age was 44 years. Hemoperitoneum was the most common CT finding, with a significantly higher detection rate on CECT combined with NCT than on CECT alone. There was no statistically significant difference in the diagnostic efficacy of the detected organ injury nor other types of organ injuries between CECT alone and CECT combined with NCT. Nevertheless, the accuracy of CECT in detecting hemoperitoneum may diminish in patients with severe fatty liver disease; especially in the perihepatic region.Conclusion: CECT alone is a potential tool for detecting abdominal injuries in patients with blunt trauma. NCT provides no additional benefits in detecting organ injury; except in cases of severe fatty liver disease. NCT is recommended as an optional protocol; particularly for patients with obesity.

FRI652 Type 2 Diabetes Management: More GLP1 Agonists And Less Metformin?

Abstract Disclosure: F.J. Lopez Maldonado: None. R.A. Cota: None. Case presentation: A 41-year-old male patient with family history of T2DM in both parents and brother, personal history of mild alcohol consumption and a sedentary job (public accountant), and obesity since age 30 presented to the endocrinology clinic due to failure to lose weight after 1 year of treatment with a nutritionist. During his first visit, the was asymptomatic and had acanthosis nigricans, his blood pressure was measured at 142/92 mmHg, weight was 100.8 kg, waist circumference was 128 cm, and serum glucose was at 280 mg/dL with an HbA1c of 11.9%. Further laboratory tests showed elevated levels of triglycerides (310 mg/dL), LDL (139 mg/dL), AST (96 U/L), and ALT (65 U/L). Two days later, glucose and HbA1c were repeated with similar results. A liver ultrasound was ordered which revealed diffuse hyperechogenicity of the liver and severe fatty liver disease. The ASCVD risk score was 5.4%. The patient was diagnosed with T2DM, obesity, mixed dyslipidemia, and fatty liver disease. The patient received education, nutrition support, exercise, and pharmacotherapy management with stepped-dose oral semaglutide without metformin. The dose was increased monthly starting at 3 mg and reaching the target dose of 14 mg QD. After three months, the patient demonstrated significant improvements in various parameters such as blood pressure (−10/−8 mmHg), weight (−9.8 kg), waist circumference (−25 cm), serum glucose (−179 mg/dL), HbA1C (−5.7%), triglycerides (−154 mg/dL), LDL (−18 mg/dL), AST (−60 U/L), and ALT (−38 U/L), along with an increase in HDL (+6 mg/dL). After approximately 4 months on the target dose the patient showed further improvements in several parameters including ASCVD risk score (2.1%), blood pressure (−20/12 mmHg), weight (−14.8 kg), waist circumference (−30 cm), serum glucose (−183 mg/dL), HbA1C (−6%), LDL (−25 mg/dL), AST (−63 U/L), and ALT (−40 U/L), and HDL (+10 mg/dL), except for triglyceride levels (−130 mg/dL). Follow-up liver ultrasound showed significant improvement in fatty liver disease. Real-world experiences with newly introduced drugs should be reported, as they may have beneficial effects beyond the ones studied. Oral semaglutide, the first oral GLP-1 analog, has been shown to be non-inferior to other subcutaneous GLP-1 analogs. In this case, improvements were observed in glycemic control, weight loss, lipid levels, and a reduction in cardiovascular risk, as well as an improvement in fatty liver disease. Presentation: Friday, June 16, 2023

Criteria of Formation of Fatty Liver Disease in Individuals of Different Age Groups in the Long-Term Period after Minimally Invasive Cholecystectomy

INTRODUCTION: Despite the technical advance in medicine and the use of minimally invasive laparoscopic techniques, complications of cholecystectomy considerably reduce the quality of life of the operated patients. Development of the most common and severe complication fatty liver disease (FLD) is difficult to predict due to numerous factors that influence its formation.&#x0D; AIM: To identify prognostic criteria of formation of FLD in the long-term period after cholecystectomy and to scientifically substantiate their significance.&#x0D; MATERIALS AND METHODS: To identify prognostic criteria of formation of FLD in the long-term period after minimally invasive cholecystectomy, 330 patients (159 men and 171 women) who underwent surgical treatment, were examined. Anthropometric data, hemodynamic parameters were evaluated, autonomic index was calculated. US evaluation of choledoch and Elastography of the liver, magnetic resonance tomography of the liver and magnetic resonance cholangiopancreatography were performed. Using chromatography-mass-spectrometry, microbial markers of parietal microbiome of the intestine were determined.&#x0D; RESULTS: Parameters of body mass index indicate the interrelation between the formation of FLD and increased body mass in patients of older age. In the first group with FLD, sympathetic status prevailed, and in the control group of the same age, parasympathicotonia was predominating. At the older age, in the second and third subgroup, the autonomic regulation did not influence the formation of FLD. The choledoch diameter in men and women with FLD of the first age subgroup was greater relative to patients of the control group and of the preoperative period and also relative to older patients of the same group. In the long-term period after cholecystectomy in the group with fatty liver disease, the opportunistic microflora prevailed over essential one, and aerobic microflora over anaerobic one. Besides, increased amount of fungi and viruses was noted, as well as a change in the distribution of obligate microflora due to decrease in the content of eubacteria and predomination of lactobacteria over bifidobacteria in the parietal layer of the intestine. In the individuals of older age, reduction of the obligate and increase in the opportunistic microflora including aerobic one, was noted.&#x0D; CONCLUSIONS: Age, autonomic regulation and body mass have a significant influence on the formation of FLD in the long-term period after cholecystectomy. In the group of older patients, the influence of the autonomic regulation is lower, and increase in body mass is higher than in younger individuals.

The effect of obstructive sleep apnea on fatty liver disease may be obscured by alcohol consumption: An ordinal logistic regression analysis

BackgroundObstructive sleep apnea (OSA) is closely associated with non-alcoholic fatty liver disease (NAFLD). The current definition of NAFLD cannot exclude the involvement of alcohol consumption in the development of fatty liver disease (FLD), but alcohol can aggravate OSA and participate in steatosis. There is limited evidence on the relationship between OSA and alcohol and its effect on FLD severity. ObjectiveTo determine the effect of OSA on FLD severity based on ordinal responses, and its relationship with alcohol consumption, in order to develop strategies for the prevention and treatment of FLD. MethodsPatients with chief complaints of "snoring" who underwent polysomnography and abdominal ultrasound between January 2015 and October 2022 were selected. A total of 325 cases were divided into three groups according to abdominal ultrasound results: no FLD (n = 66), mild FLD (n = 116), and moderately severe FLD (n = 143) group. Patients were also categorized into alcoholic and nonalcoholic groups. Univariate analysis was used to examine the correlation between OSA and FLD severity. Multivariate ordinal logistic regression analysis was further used to identify the determinants of FLD severity and differences between the alcoholic and nonalcoholic groups. ResultsA higher proportion of moderately severe FLD was observed in the group with an apnea/hypopnea index (AHI) > 30 compared to the AHI<15 group in all participants and in the nonalcoholic population (all p < 0.05). There was no significant difference among these groups in the alcoholic population. Ordinal logistic regression analysis found that in all participants, age [OR = 0.966(0.947–0.986)], BMI [OR = 1.293 (1.205–1.394)], diabetes mellitus [OR = 1.932(1.132–3.343)], hyperlipidemia [OR = 2.432(1.355–4.464)], severe OSA [OR = 2.36(1.315–4.259)] (all p < 0.05) were the independent risk factors for more severe FLD. However, different risk factors applied according to alcohol consumption. In addition to age and BMI, the independent risk factors for the alcoholic group also included diabetes mellitus [OR = 3.323(1.494–7.834)] while in the non-alcoholic group risk factors included hyperlipidemia [OR = 4.094(1.639–11.137)], and severe OSA[OR = 2.956(1.334–6.664)] (all p < 0.05). ConclusionSevere OSA is an independent determinant for developing more severe NAFLD in nonalcoholic population, and alcohol consumption may obscure the effect of OSA on the progression of FLD.

Successful treatment with lomitapide in a patient with homozygous familial hypercholesterolemia and severe fatty liver disease

Introduction and Aims: Homozygous-familial hypercholesterolemia (Ho-FH) is a rare condition due to biallelic mutations in low-density lipoprotein-receptor (LDL-R) genes characterized by high level of LDL-cholesterol (LDL-c) and huge risk of premature atherosclerotic cardiovascular disease (ASCVD), determining low quality of life and life expectancy. Lomitapide represents a therapeutic option for Ho-FH, but caution should be observed when used in fatty liver disease (FLD) and hypertransaminasemia since it is associated with onset/worsening of liver steatosis. We present a case of safe lomitapide therapy in an adult Ho-FH patient with pre-existing FLD. Case presentation: A 39-year-old man with severe hypercholesterolemia since childhood (LDL-c 405 mg/dl) and premature coronary heart disease history, was referred to our Modena Lipid Clinic. He presented an overt metabolic syndrome, FLD with hypertransaminasemia and elastosonographic significant liver fibrosis. Lipid-lowering-therapy (LLT) included rosuvastatin 20 mg, ezetimibe and evolocumab 140 mg twice a month without reaching LDL-c goal. Genetic analysis revealed homozygous pathogenic LDL-R gene mutation. Evolocumab was increased up to 420 mg twice a month and LDL-apheresis was started with quality of life worsening. Therefore, lomitapide 5 mg daily and low-fat diet were started, obtaining weight loss and lipid profile improvement. However, liver enzymes elevation higher than 5-fold was observed, leading to lomitapide discontinuation and baseline liver enzymes values restoration. After one-month wash-out, lomitapide was gradually reintroduced up to 5 mg daily without significant hypertransaminasemia recurrence, leading to LDL-c target achievement and LDL-apheresis discontinuation. Adherence to low-fat diet and weight loss resulted in FLD and fibrosis improvement. Conclusion: Ho-FH requires complex, combined treatment. Metabolic comorbidities co-existence makes Ho-FH management more difficult. Lomitapide can be safely used in Ho-FH patients with FLD and hypertransaminasemia, but strict follow-up of liver disease and a multidisciplinary approach are needed. Before lomitapide introduction, low-fat diet should be started advantageously and weight stabilization should be obtained.

Fatty Liver & Diabetes Statistics in Korea: Nationwide Data 2009 to 2017.

This study investigated the changes of fatty liver disease prevalence in general Korean population. This study analyzed data from the Korean National Health Insurance Service from 2009 to 2017 that included individuals aged 20 years or older who had undergone a medical health examination. Fatty liver disease was assessed using the fatty liver index (FLI). The disease severity was defined by FLI cutoff, ≥30 as moderate, and ≥60 as severe fatty liver disease. The prevalence of Korean adults aged 20 years or over with fatty liver disease (FLI ≥60) increased from 13.3% in 2009 to 15.5% in 2017 (P for trend <0.001). The increase in fatty liver disease prevalence was prominent in men (from 20.5% to 24.2%) and the young age (20 to 39 years) group (from 12.8% to 16.4%) (P for interaction <0.001). The prevalence of fatty liver disease was the highest in type 2 diabetes mellitus (T2DM, 29.6%) population compared to that of prediabetes or normoglycemia (10.0% and 21.8%) in 2017. The prevalence of fatty liver disease had statistically increased in individuals with T2DM and prediabetes (P for trend <0.001). Its prevalence increased more steeply in the young-aged population with T2DM, from 42.2% in 2009 to 60.1% in 2017. When applying a lower FLI cutoff (≥30) similar results were observed. The prevalence of fatty liver disease in the Korean population has increased. Individuals who are young, male, and have T2DM are vulnerable to fatty liver disease.

Predictors of hepatic steatosis in living liver donors

Fatty liver disease (steatosis) is considered a risk factor in donor liver transplantation (LT). Macrosteatosis (&gt;50%) is associated with primary graft dysfunction and may reduce long-term recipient survival.Objective: to identify predictors of macrovesicular steatosis (&gt;50%) by analyzing donor characteristics.Materials and methods. The retrospective study included 525 potential liver donors between January 1, 2019 and December 31, 2020. Clinical and morphological characteristics of donors were studied using logistic regression and receiver operating characteristic (ROC) analysis. Threshold values of parameters demonstrating statistical significance in multivariate analysis as predictors of &gt;50% hepatic steatosis were obtained by ROC analysis based on calculation of the optimal cutoff point.Results. Diabetes mellitus (DM), cause of donor’s death (traumatic brain injury), alanine transaminase (ALT) &gt;90 units/L and aspartate transaminase (AST) &gt;110 units/L were predictors of &gt;50% steatosis, revealed by time-zero biopsy in the donor. Almost identical sensitivity and specificity indicators were determined in ROC analysis for liver enzymes – ALT and AST – which were 69.1 and 80.6; 72.2 and 81.1, respectively. Given the obtained values, we can say that with elevated levels of liver enzymes in the donor’s blood, there is a high degree of probability of liver parenchymal damage, but low sensitivity indicates possible multifactoriality of liver damage, and fatty liver disease may be one of the factors, but there may also be no damage to the liver parenchyma. At the same time, the rather high specificity revealed in ROC analysis for liver enzymes is a reliable sign of the absence of fatty liver disease at enzyme values less than the threshold.Conclusion. The thresholds established for ALT and AST and their corresponding levels of sensitivity and specificity indicate that these parameters have a relatively low predictive level in the context of the presence of severe fatty liver disease in a donor. This allows, nevertheless, to use models built on their basis as screening models in the primary evaluation of liver donors.

Multi-Channel Metabolomics Analysis Identifies Novel Metabolite Biomarkers for the Early Detection of Fatty Liver Disease in Dairy Cows.

Fatty liver disease, a type of metabolic disorder, frequently occurs in dairy cows during the parturition period, causing a high culling rate and, therefore, considerable economic losses in the dairy industry owing to the lack of effective diagnostic methods. Here, metabolite biomarkers were identified and validated for the diagnosis of metabolic disorders. A total of 58 participant cows, including severe fatty liver disease and normal control groups, in the discovery set (liver biopsy tested, n = 18), test set (suspected, n = 20) and verification set (liver biopsy tested, n = 20), were strictly recruited and a sample collected for their feces, urine, and serum. Non-targeted GC-MS-based metabolomics methods were used to characterize the metabolite profiles and to screen in the discovery set. Eventually, ten novel biomarkers involved in bile acid, amino acid, and fatty acid were identified and validated in the test set. Each of them had a higher diagnostic ability than the traditional serum biochemical indicators, with an average area under the receiver operating characteristic curve of 0.830 ± 0.0439 (n = 10) versus 0.377 ± 0.182 (n = 9). Especially, combined biomarker panels via different metabolic pipelines had much better diagnostic sensitivity and specificity than every single biomarker, suggesting their powerful utilization potentiality for the early detection of fatty liver disease. Intriguingly, the serum biomarkers were confirmed perfectly in the verification set. Moreover, common biological pathways were found to be underlying the pathogenesis of fatty liver syndrome in cattle via different metabolic pipelines. These newly-discovered and non-invasive metabolic biomarkers are meaningful in reducing the high culling rate of cows and, therefore, benefit the sustainable development of the dairy industry.

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.

SIRT6 controls hepatic lipogenesis by suppressing LXR, ChREBP, and SREBP1

Fatty liver disease is the most prevalent chronic liver disorder, which is manifested by hepatic triglyceride elevation, inflammation, and fibrosis. Sirtuin 6 (Sirt6), an NAD+-dependent deacetylase, has been implicated in hepatic glucose and lipid metabolism; however, the underlying mechanisms are incompletely understood. The aim of this study was to identify and characterize novel players and mechanisms that are responsible for the Sirt6-mediated metabolic regulation in the liver. We generated and characterized Sirt6 liver-specific knockout mice regarding its role in the development of fatty liver disease. We used cell models to validate the molecular alterations observed in the animal models. Biochemical and molecular biological approaches were used to illustrate protein-protein interactions and gene regulation. Our data show that Sirt6 liver-specific knockout mice develop more severe fatty liver disease than wild-type mice do on a Western diet. Hepatic Sirt6 deficiency leads to elevated levels and transcriptional activities of carbohydrate response element binding protein (ChREBP) and sterol regulatory element binding protein 1 (SREBP1). Mechanistically, our data reveal protein-protein interactions between Sirt6 and liver X receptor α (LXRα), ChREBP, or SREBP1c in hepatocytes. Moreover, Sirt6 suppresses transcriptional activities of LXRα, ChREBP, and SREBP1c through direct deacetylation. In conclusion, this work has identified a key mechanism that is responsible for the salutary function of Sirt6 in the inhibition of hepatic lipogenesis by suppressing LXR, ChREBP, and SREBP1.

Neonatal exposure to a wild-derived microbiome protects mice against diet-induced obesity.

Obesity and its consequences are among the greatest challenges in healthcare. The gut microbiome is recognized as a key factor in the pathogenesis of obesity. Using a mouse model, we show here that a wild-derived microbiome protects against excessive weight gain, severe fatty liver disease and metabolic syndrome during a 10-week course of high-fat diet. This phenotype is transferable only during the first weeks of life. In adult mice, neither transfer nor severe disturbance of the wild-type microbiome modifies the metabolic response to a high-fat diet. The protective phenotype is associated with increased secretion of metabolic hormones and increased energy expenditure through activation of brown adipose tissue. Thus, we identify a microbiome that protects against weight gain and its negative consequences through metabolic programming in early life. Translation of these results to humans may identify early-life therapeutics that protect against obesity.

Effects of Tamoxifen vs. Toremifene on fatty liver development and lipid profiles in breast Cancer

BackgroundTamoxifen (TAM) and Toremifene (TOR), two kinds of selective estrogen receptor modulators (SERMs), have equal efficacy in breast cancer patients. However, TAM has been proved to affect serum lipid profiles and cause fatty liver disease. The study aimed to compare the effects of TAM and TOR on fatty liver development and lipid profiles.MethodsThis study performed a retrospective analysis of 308 SERMs-treated early breast cancer patients who were matched 1:1 based on propensity scores. The follow-up period was 3 years. The primary outcomes were fatty liver detected by ultrasonography or computed tomography (CT), variation in fibrosis indexes, and serum lipid profiles change.ResultsThe cumulative incidence rate of new-onset fatty liver was higher in the TAM group than in the TOR group (113.2 vs. 67.2 per 1000 person-years, p < 0.001), and more severe fatty livers occurred in the TAM group (25.5 vs. 7.5 per 1000 person-years, p = 0.003). According to the Kaplan-Meier curves, TAM significantly increased the risk of new-onset fatty liver (25.97% vs. 17.53%, p = 0.0243) and the severe fatty liver (5.84% vs. 1.95%, p = 0.0429). TOR decreased the risk of new-onset fatty liver by 45% (hazard ratio = 0.55, p = 0.020) and showed lower fibrotic burden, independent of obesity, lipid, and liver enzyme levels. TOR increased triglycerides less than TAM, and TOR increased high-density lipoprotein cholesterol, while TAM did the opposite. No significant differences in total cholesterol and low-density lipoprotein cholesterol are observed between the two groups.ConclusionsTAM treatment is significantly associated with more severe fatty liver disease and liver fibrosis, while TOR is associated with an overall improvement in lipid profiles, which supports continuous monitoring of liver imaging and serum lipid levels during SERM treatment.

Rare and common ATG7 variants predispose to severe fatty liver disease

Background: Nonalcoholic fatty liver disease (NAFLD), most frequently associated with metabolic dysfunction, is the leading cause of liver disease and has a strong heritable component.

Experience of successfully treating a child with severe metabolic-associated fatty liver disease in 12 weeks using traditional Chinese medicine alone

Experience of successfully treating a child with severe metabolic-associated fatty liver disease in 12 weeks using traditional Chinese medicine alone

Rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis

Background & AimsA common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis.MethodsWe performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models.ResultsData from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI 0.02–0.05], pz = 4.8×10–5) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05–1.3], pz = 0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI 1.03–1.45], pz = 0.021) in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (pz = 0.002) and lower serum triglycerides (pz = 1.5×10–4). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD.ConclusionsOur study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent.Lay summaryFatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including ‘cirrhosis’). It is closely linked to obesity and diabetes, but some genes are also thought to be important. We did this study to see whether one specific change (‘variant’) in one gene (‘MBOAT7’) was linked to fatty liver disease. We took data from over 40 published studies and found that this variant near MBOAT7 is linked to more severe fatty liver disease. This means that drugs designed to work on MBOAT7 could be useful for treating fatty liver disease.

Ablation of miR-144 increases vimentin expression and atherosclerotic plaque formation

It has been suggested that miR-144 is pro-atherosclerotic via effects on reverse cholesterol transportation targeting the ATP binding cassette protein. This study used proteomic analysis to identify additional cardiovascular targets of miR-144, and subsequently examined the role of a newly identified regulator of atherosclerotic burden in miR-144 knockout mice receiving a high fat diet. To identify affected secretory proteins, miR-144 treated endothelial cell culture medium was subjected to proteomic analysis including two-dimensional gel separation, trypsin digestion, and nanospray liquid chromatography coupled to tandem mass spectrometry. We identified 5 gel spots representing 19 proteins that changed consistently across the biological replicates. One of these spots, was identified as vimentin. Atherosclerosis was induced in miR-144 knockout mice by high fat diet and vascular lesions were quantified by Oil Red-O staining of the serial sectioned aortic root and from en-face views of the aortic tree. Unexpectedly, high fat diet induced extensive atherosclerosis in miR-144 knockout mice and was accompanied by severe fatty liver disease compared with wild type littermates. Vimentin levels were reduced by miR-144 and increased by antagomiR-144 in cultured cardiac endothelial cells. Compared with wild type, ablation of the miR-144/451 cluster increased plasma vimentin, while vimentin levels were decreased in control mice injected with synthetic miR-144. Furthermore, increased vimentin expression was prominent in the commissural regions of the aortic root which are highly susceptible to atherosclerotic plaque formation. We conclude that miR-144 maybe a potential regulator of the development of atherosclerosis via changes in vimentin signaling.

1030 Screening for Steatosis and Fibrosis in a General Population With Fatty Liver Using Transient Elastography (Fibroscan)

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are increasingly common in the United States and the Western World. In the United States, NAFLD and NASH are estimated to affect 1/3 and 1/10 Americans, respectively putting large proportion of the U.S. population at risk of advanced liver disease, cirrhosis and liver cancer. Transient Elastography or Fibroscan was approved in the United States in 2013 by the FDA as a non-invasive diagnostic test for the detection of steatosis and fibrosis in a variety of liver diseases including NAFLD. Until recently, access to Fibroscan has been limited primarily to academic research centers and tertiary care hospitals with the true status of NAFLD in the community and general U.S. population largely unknown. In this study, we report the status of NAFLD in a suburban community practice as identified by Fibroscan. METHODS: In this retrospective study, steatosis and fibrosis scores were analyzed in 489 NAFLD patients that had a Fibroscan (Fibroscan Compact 530) in a community hospital from February to November 2018. All the patients were referred for Fibroscan by gastroenterologists due to a fatty liver found on prior imaging studies by abdominal ultrasounds and / or CT scans. Patients with significant alcohol use (more than 2 drinks a day) and chronic liver disease (hepatitis B, Hepatitis C, autoimmune liver diseases and etc) were excluded from the analysis. RESULTS: Number of patient (percentage %). 1. *Steatosis score : S0 = 46 (9.40%), S1 = 15 (3.06%), S2 = 37 (7.56%) and S3 = 391 (79.95%). 2.** Fibrosis score : F0-F1 = 205 (41.92%), F2 = 148 (30.26%), F3 = 68 (13.90%) and F4 = 68 (13.90%). *Steatosis scoring: S0 = no fat, S1 = mild fat, S2 = moderate fat, S3 = severe fat. **Fibrosis scoring: F0-F1 = none to minimal scarring, F2 = moderate scarring, F3 = severe scarring, F4 = advanced fibrosis / cirrhosis. CONCLUSION: In this general population with incidental fatty liver, an alarming number of patients of nearly 80% have severe fatty liver disease (S3) and nearly a third (27.80%) have severe to advanced fibrosis / cirrhosis. With the higher than expected significant abnormal findings from this observational study, we recommend Transient Elastography (Fibroscan) as a screening tool to all clinicians managing patients with fatty liver disease. To confirm the validity of advanced liver disease found on Fibroscan, a liver biopsy should be considered in patients with severe or advanced (S3/4) liver fibrosis.