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Purpose of Review: Patients with non-alcoholic fatty liver disease (NAFLD), often considered as the hepatic manifestation of the metabolic syndrome, represent a population at high cardiovascular risk and frequently suffer from atherogenic dyslipidemia. This article reviews the pathogenic interrelationship between NAFLD and dyslipidemia, elucidates underlying pathophysiological mechanisms and focuses on management approaches for dyslipidemic patients with NAFLD., Recent Findings: Atherogenic dyslipidemia in patients with NAFLD results from hepatic and peripheral insulin resistance along with associated alterations of hepatic glucose and lipoprotein metabolism, gut dysbiosis, and genetic factors. Since atherogenic dyslipidemia and NAFLD share a bi-directional relationship and are both major driving forces of atherosclerotic cardiovascular disease (ASCVD) development, early detection and adequate treatment are warranted. Thus, integrative screening and management programs are urgently needed. A stepwise approach for dyslipidemic patients with NAFLD includes (i) characterization of dyslipidemia phenotype, (ii) individual risk stratification, (iii) definition of treatment targets, (iv) lifestyle modification, and (v) pharmacotherapy if indicated., (© 2022. The Author(s).)

Background: Liver diseases and cardiovascular diseases are closely associated. Noninvasive tests (NITs), such as the FIB-4 score, have been recommended by different guidelines to rule out advanced fibrosis and estimate the risk of liver-related outcomes in patients with chronic liver diseases (CLDs). However, the association of an elevated FIB-4 score with the development of myocardial infarction and/or stroke/transient ischemic attack (TIA) is unknown., Methods: By using the Disease Analyzer database (IQVIA), which compiles diagnoses, laboratory values as well as basic medical and demographic data of over 7.5 million patients followed in general practices in Germany, we identified 68 921 patients with available lab values for FIB-4 score calculation between 2005 and 2019. Patients with an FIB-4 score of less than 1.3 were matched 1:1 to patients with an FIB-4 score of at least 1.3 by age, sex and yearly consultation frequency., Results: In regression analysis, the incidence rate ratio (IRR) of myocardial infarction was similar among patients with an FIB-4 score of at least 1.3 compared with patients with a low FIB-4 score of less than 1.3, regardless of whether patients with or without preexisting liver disease were analyzed. Moreover, there was no significant increase in the IRR of stroke/TIA between patients with a high or low FIB-4 score, both in the general population and patients with CLD., Conclusion: Our study suggests that the FIB-4 score is not associated with cardiovascular events both in the general population as well as in patients with CLD., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Non-invasive tests such as the FIB-4 index (calculated on the basis of patients' age, AST/ALT levels and platelet count) have been recommended by different guidelines to rule out advanced fibrosis and stratify the risk of liver-related outcomes in patients with chronic liver diseases. An elevated FIB-4 index ≥1.3 is an independent predictor for liver cancer development among patients with NAFLD. However, the predictive value of an elevated FIB-4 index regarding (liver) cancer development among the general population is unknown., Methods: Using the Disease Analyzer database (IQVIA) which compiles diagnoses, laboratory values, and basic medical and demographic data for over 7.5 million patients followed in general practices in Germany, we identified 248,224 patients with available lab values for FIB-4 index calculation between 2005 and 2019. Patients with an average FIB-4 index of <1.3 were matched 1:1 to patients with a FIB-4 index of ≥1.3 by age and sex., Results: Within 10 years of the index date, the cumulative incidence of liver cancer was significantly higher in patients with a FIB-4 index ≥1.3 (0.25% versus 0.04%, p < 0.001). In a multivariate Cox-regression analysis, this association was found to be higher in patients with pre-existing liver disease (hazard ratio, HR: 10.54 versus 3.79). The risk of liver cancer development was most pronounced among men (HR: 9.40, p < 0.001) and patients ≤50 years of age (HR: 16.36, p < 0.001). A persistently high or increasing FIB-4 index over time was a strong predictor for liver cancer. Notably, the cumulative incidence of cancer in general was comparable among patients with a low/high FIB-4 index (15.7% versus 16.6%; p = 0.060)., Conclusion: Our data support the use of the FIB-4 index to estimate the risk of liver cancer development even in unselected patients without pre-existing liver disease. By contrast, the index does not appear to have any predictive value for other tumour sites., Competing Interests: Conflict of interest statement None declared., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Obesity, non-alcoholic fatty liver disease (NAFLD) and its more advanced form non-alcoholic steatohepatitis (NASH) are important causes of morbidity and mortality worldwide. Bile acid dysregulation is a pivotal part in their pathogenesis. The aim of this study was to evaluate the bile acid sequestrant colesevelam in a microbiome-humanized mouse model of diet-induced obesity and steatohepatitis., Methods: Germ-free C57BL/6 mice were associated with stool from patients with NASH and subjected to 20 weeks of Western diet feeding with and without colesevelam., Results: Colesevelam reduced Western diet-induced body and liver weight gain in microbiome-humanized mice compared with controls. It ameliorated Western diet-induced hepatic inflammation, steatosis, fibrosis and insulin resistance. Colesevelam increased de novo bile acid synthesis and decreased hepatic cholesterol content in microbiome-humanized mice fed a Western diet. It further induced the gene expression of the antimicrobials Reg3g and Reg3b in the distal small intestine and decreased plasma levels of LPS., Conclusions: Colesevelam ameliorates Western diet-induced steatohepatitis and obesity in microbiome-humanized mice., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Background & Aims: Studies investigating the gut-liver axis have largely focused on bacteria, whereas little is known about commensal fungi. We characterized fecal fungi in patients with non-alcoholic fatty liver disease (NAFLD) and investigated their role in a fecal microbiome-humanized mouse model of Western diet-induced steatohepatitis., Methods: We performed fungal internal transcribed spacer 2 sequencing using fecal samples from 78 patients with NAFLD, 16 controls and 73 patients with alcohol use disorder. Anti-Candida albicans (C. albicans) IgG was measured in blood samples from 17 controls and 79 patients with NAFLD. Songbird, a novel multinominal regression tool, was used to investigate mycobiome changes. Germ-free mice were colonized with feces from patients with non-alcoholic steatohepatitis (NASH), fed a Western diet for 20 weeks and treated with the antifungal amphotericin B., Results: The presence of non-obese NASH or F2-F4 fibrosis was associated with a distinct fecal mycobiome signature. Changes were characterized by an increased log-ratio for Mucor sp./Saccharomyces cerevisiae (S. cerevisiae) in patients with NASH and F2-F4 fibrosis. The C. albicans/S. cerevisiae log-ratio was significantly higher in non-obese patients with NASH when compared with non-obese patients with NAFL or controls. We observed a different fecal mycobiome composition in patients with NAFLD and advanced fibrosis compared to those with alcohol use disorder and advanced fibrosis. Plasma anti-C. albicans IgG was increased in patients with NAFLD and advanced fibrosis. Gnotobiotic mice, colonized with human NASH feces and treated with amphotericin B were protected from Western diet-induced steatohepatitis., Conclusions: Non-obese patients with NAFLD and more advanced disease have a different fecal mycobiome composition to those with mild disease. Antifungal treatment ameliorates diet-induced steatohepatitis in mice. Intestinal fungi could be an attractive target to attenuate NASH., Lay Summary: Non-alcoholic fatty liver disease is one of the most common chronic liver diseases and is associated with changes in the fecal bacterial microbiome. We show that patients with non-alcoholic fatty liver disease and more severe disease stages have a specific composition of fecal fungi and an increased systemic immune response to Candida albicans. In a fecal microbiome-humanized mouse model of Western diet-induced steatohepatitis, we show that treatment with antifungals reduces liver damage., Competing Interests: Conflicts of interest B.S. has been consulting for Ferring Research Institute, Gelesis, HOST Therabiomics, Intercept Pharmaceuticals, Mabwell Therapeutics, Patara Pharmaceuticals and Takeda. B.S.’s institution UC San Diego has received research support from Axial Biotherapeutics, BiomX, CymaBay Therapeutics, NGM Biopharmaceuticals, Prodigy Biotech and Synlogic Operating Company. B.S. is founder of Nterica Bio. UC San Diego has filed several patents with S.L. and B.S. as inventors related to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Published by Elsevier B.V.)

Background Aims: Nonalcoholic fatty liver disease (NAFLD) has emerged as the most prevalent chronic liver disease, with about one in four people being affected in most areas of the world. Due to its strong association with metabolic syndrome, NAFLD is associated with high morbidity and mortality. Recent data have suggested a pathophysiological association between NAFLD and thyroid disease, but most studies are explorative and results remained conflicting. Here, we aimed at evaluating a potential association between NAFLD and hypothyroidism as well as autoimmune thyroiditis primary care patients in Germany., Methods: Incidence rates of hypothyroidism and autoimmune thyroiditis were compared between a cohort of n = 40,583 patients with NAFLD and a cohort of equal size without NAFLD that was matched by sex, age, index year, obesity and diabetes within 10 years from the index date., Results: Within the 10 years observation period, incidence of hypothyroidism was significantly higher among patients with NAFLD compared to patients without NAFLD [hazard ratio: 1.53 (95% confidence interval, 1.43-1.64), P < 0.001]. Importantly, regression analysis revealed that the association was significant in both men and women patients as well as in patients from all age groups. Moreover, NAFLD patients showed a significantly higher incidence rate of autoimmune thyroiditis compared to patients without NAFLD [hazard ratio: 1.55 (95% confidence interval, 1.34-1.79), P < 0.001]. This association was most pronounced in patients >70 years., Conclusion: Our study provides strong evidence for a significant association between NAFLD and hypothyroidism as well as autoimmune thyroiditis in a large population-based cohort in Germany. This finding should trigger a particular awareness of thyroid diseases in this increasingly important patient group., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: Non-alcoholic fatty liver disease (NAFLD) is a global health burden. Risk factors for disease severity include older age, increased body mass index (BMI), diabetes, genetic variants, dietary factors and gut microbiota alterations. However, the interdependence of these factors and their individual impact on disease severity remain unknown., Methods: In this cross-sectional study, we performed 16S gene sequencing using fecal samples, collected dietary intake, PNPLA3 gene variants and clinical and liver histology parameters in a well-described cohort of 180 NAFLD patients. Principal component analyses were used for dimensionality reduction of dietary and microbiota data. Simple and multiple stepwise ordinal regression analyses were performed., Results: Complete data were available for 57 NAFLD patients. In the simple regression analysis, features associated with the metabolic syndrome had the highest importance regarding liver disease severity. In the multiple regression analysis, BMI was the most important factor associated with the fibrosis stage (OR per kg/m 2 : 1.23, 95% CI 1.10-1.37, P < .001). The PNPLA3 risk allele had the strongest association with the histological grade of steatosis (OR 5.32, 95% CI 1.56-18.11, P = .007), followed by specific dietary patterns. Low abundances of Faecalibacterium, Bacteroides and Prevotella and high abundances of Gemmiger were associated with the degree of inflammation, ballooning and stages of fibrosis, even after taking other cofactors into account., Conclusions: BMI had the strongest association with histological fibrosis, but PNPLA3 gene variants, gut bacterial features and dietary factors were all associated with different histology features, which underscore the multifactorial pathogenesis of NAFLD., (© 2021 The Authors. Liver International published by John Wiley & Sons Ltd.)

Non-alcoholic fatty liver DISEASE (NAFLD) is the most common chronic liver disease in Western countries and affects approximately 25% of the adult population. Since NAFLD is frequently associated with further metabolic comorbidities such as obesity, type 2 diabetes mellitus, or dyslipidemia, it is generally considered as the hepatic manifestation of the metabolic syndrome. In addition to its potential to cause liver-related morbidity and mortality, NAFLD is also associated with subclinical and clinical cardiovascular disease (CVD). Growing evidence indicates that patients with NAFLD are at substantial risk for the development of hypertension, coronary heart disease, cardiomyopathy, and cardiac arrhythmias, which clinically result in increased cardiovascular morbidity and mortality. The natural history of NAFLD is variable and the vast majority of patients will not progress from simple steatosis to fibrosis and end stage liver disease. However, patients with progressive forms of NAFLD, including non-alcoholic steatohepatitis (NASH) and/or advanced fibrosis, as well as NAFLD patients with concomitant types 2 diabetes are at highest risk for CVD. This review describes the underlying pathophysiological mechanisms linking NAFLD and CVD, discusses the role of NAFLD as a metabolic dysfunction associated cardiovascular risk factor, and focuses on common cardiovascular manifestations in NAFLD patients.

Background & Aims: Alterations in the gut microbiome have been associated with the severity of nonalcoholic fatty liver disease (NAFLD). Previous studies focused exclusively on the bacteria in the microbiome; we investigated changes in the viral microbiome (virome) in patients with NAFLD., Methods: In a prospective, cross-sectional, observational study, we extracted RNA and DNA virus-like particles from fecal samples from 73 patients with NAFLD: 29 patients had an NAFLD Activity Score (NAS) of 0-4, 44 patients had an NAS of 5-8 or liver cirrhosis (LCI), 37 patients had F0-F1 fibrosis, and 36 patients had F2-F4 fibrosis. As controls, 9 individuals without liver disease and 13 patients with mild primary biliary cholangitis were included in the analysis. We performed shotgun metagenomic sequencing of virus-like particles., Results: Patients with NAFLD and NAS 5-8/LCI had a significant decrease in intestinal viral diversity compared with patients with NAFLD and NAS 0-4 or control individuals. The presence of more advanced NAFLD was associated with a significant reduction in the proportion of bacteriophages compared with other intestinal viruses. Using multivariate logistic regression analysis with leave-1-out cross validation, we developed a model, including a viral diversity index and simple clinical variables, that identified patients with NAS 5-8/LCI with an area under the curve of 0.95 (95% confidence interval, 0.91-0.99) and F2-F4 fibrosis with an area under the curve of 0.88 (95% confidence interval, 0.80-0.95). Addition of data on viral diversity significantly improved multivariate models, including those based on only clinical parameters or bacterial diversity., Conclusions: In a study of fecal viromes from patients with NAFLD and control individuals, we associated histologic markers of NAFLD severity with significant decreases in viral diversity and proportion of bacteriophages. We developed a model based on fecal viral diversity and clinical data that identifies patients with severe NAFLD and fibrosis more accurately than models based only on clinical or bacterial data., (Published by Elsevier Inc.)

Maternal exercise (ME) during pregnancy has been shown to improve metabolic health in offspring and confers protection against the development of non-alcoholic fatty liver disease (NAFLD). However, its underlying mechanism are still poorly understood, and it remains unclear whether protective effects on hepatic metabolism are already seen in the offspring early life. This study aimed at determining the effects of ME during pregnancy on offspring body composition and development of NAFLD while focusing on proteomic-based analysis of the hepatic energy metabolism during developmental organ programming in early life. Under an obesogenic high-fat diet (HFD), male offspring of exercised C57BL/6J-mouse dams were protected from body weight gain and NAFLD in adulthood (postnatal day (P) 112). This was associated with a significant activation of hepatic AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor alpha (PPARα) and PPAR coactivator-1 alpha (PGC1α) signaling with reduced hepatic lipogenesis and increased hepatic β-oxidation at organ programming peak in early life (P21). Concomitant proteomic analysis revealed a characteristic hepatic expression pattern in offspring as a result of ME with the most prominent impact on Cholesterol 7 alpha-hydroxylase (CYP7A1). Thus, ME may offer protection against offspring HFD-induced NAFLD by shaping hepatic proteomics signature and metabolism in early life. The results highlight the potential of exercise during pregnancy for preventing the early origins of NAFLD.

Parameters of patients' body composition have been suggested as prognostic markers in several clinical conditions including cancer and liver transplantation, but only limited data on its value in critical illness exist to date. In this study, we aimed at evaluating a potential prognostic value of the skeletal muscle mass and skeletal muscle myosteatosis of critically ill patients at admission to the ICU., Design: Exploratory observational cohort study., Setting: An urban, academic medical institution., Patients: One-hundred fifty-five patients treated for critical illness on a medical ICU., Interventions: None., Measurements and Main Results: We used routine CT scans to assess the patients' individual body composition. The skeletal muscle index as a surrogate for sarcopenia was defined as the total skeletal muscle area at the level of the third lumbar vertebra on axial CT scan, normalized for the patient's height. Myosteatosis was evaluated by assessing the mean skeletal muscle attenuation measured in Hounsfield unit at the same sectional plane. The skeletal muscle index and mean skeletal muscle attenuation at admission to the ICU were significantly higher in patients with long-term survival (180-day or 1-year mortality), while both parameters were comparable between short-term survivors and nonsurvivors (ICU mortality or 30-d mortality). Patients with a skeletal muscle index or mean skeletal muscle attenuation below our established ideal cutoff values (74.95 mm 2 /cm and 29 Hounsfield unit) showed a significantly reduced overall survival. These findings were confirmed in univariate and multivariate Cox regression analyses. Furthermore, myosteatosis significantly correlated with the time of mechanical ventilation, the duration of hospital stay, and the presence of sepsis., Conclusions: Our data suggest that sarcopenia and myosteatosis represent important prognostic factors in critically ill patients that can be easily obtained from routine CT scans. Both parameters at admission to the ICU yield important information on the patients' long-term outcome and might be used for early clinical decision-making in these patients., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Liver fibrosis is the major determinant of liver related complications in patients with non-alcoholic fatty liver disease (NAFLD). A gut microbiota signature has been explored to predict advanced fibrosis in NAFLD patients. The aim of this study was to validate and compare the diagnostic performance of gut microbiota-based approaches to simple non-invasive tools for the prediction of advanced fibrosis in NAFLD. 16S rRNA gene sequencing was performed in a cohort of 83 biopsy-proven NAFLD patients and 13 patients with non-invasively diagnosed NAFLD-cirrhosis. Random Forest models based on clinical data and sequencing results were compared with transient elastography, the NAFLD fibrosis score (NFS) and FIB-4 index. A Random Forest model containing clinical features and bacterial taxa achieved an area under the curve (AUC) of 0.87 which was only marginally superior to a model without microbiota features (AUC 0.85). The model that aimed to validate a published algorithm achieved an AUC of 0.71. AUC's for NFS and FIB-4 index were 0.86 and 0.85. Transient elastography performed best with an AUC of 0.93. Gut microbiota signatures might help to predict advanced fibrosis in NAFLD. However, transient elastography achieved the best diagnostic performance for the detection of NAFLD patients at risk for disease progression.

Aging, physical activity, bodyweight and diet are well established risk factors for cardiovascular disease. For all of these factors a great impact on the intestinal microbiome has been described. The current review will discuss available data regarding the role of the gut microbiome in regulating blood pressure, vascular function and its possible contribution to atherosclerosis and heart failure., Competing Interests: Die Autoren haben Reisekostenerstattungen und Vortragshonorare von der Hypertonie Akademie der Deutschen Gesellschaft für Hypertonie und Prävention erhalten., (© Georg Thieme Verlag KG Stuttgart · New York.)

Non-alcoholic fatty liver disease (NAFLD) is frequent among obese individuals with metabolic syndrome. Variants PNPLA3 p.I148M, TM6SF2 p.E167K and MBOAT7 rs641738 are associated with higher liver fat contents. Here we analyzed 63 biopsied non-obese, non-diabetic patients with NAFLD (39 men, age: 20-72 years) recruited within the German NAFLD CSG program. The frequencies of the PNPLA3, TM6SF2 and MBOAT7 polymorphisms were compared with the remaining patients in the NAFLD CSG cohort and with a control population (n = 174). Serum CK18-M30 was measured by ELISA. In non-obese NAFLD patients, the frequency of the PNPLA3 p.I148M allele (74.6%), but not of the TM6SF2 or MBOAT7 polymorphisms, was significantly (P < 0.05) higher as compared to the other patients in the NAFLD CSG cohort (54.9%) or controls (40.2%). The presence of the minor PNPLA3 p.I148M risk allele increased the risk of developing NAFLD (OR = 3.29, P < 0.001) and was associated with higher steatosis, fibrosis, and serum CK18-M30 levels (all P < 0.05). According to the population attributable fraction (PAF), 49.8% of NAFLD cases could be eliminated if the PNPLA3 mutation was absent. The MBOAT7 polymorphism was more frequent (P = 0.019) in patients with severe hepatic steatosis. In conclusion, PNPLA3, and to a lesser extent, MBOAT7 variants are associated with NAFLD risk and modulate liver injury in non-obese patients without diabetes.