Article: Prognostic value of non-alcoholic fatty liver disease in the elderly patients
Reviewed by: D. Beard
Authors: Tallarico V, Recinella G, Magalotti D, et al.
Published in: Aging Clin Exp Res 2020
Comment: There is very little information about NAFLD in the geriatric patients. V. Tallarico et al. (Division of Internal Medicine, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy) investigated the independent prognostic value of NAFLD on overall mortality in the elderly. 804 subjects were followed up for mortality for a median time of 12.6 years.
The presence of NAFLD seems to be associated to a lower mortality, and survival tends to increase with the increasing of steatosis grade, while it is decreased for the older subjects, in patients with hypertriglyceridemia and for diabetics. The variables BMI and HDL-cholesterol have no role in this study.
Article: Complications, morbidity and mortality of nonalcoholic fatty liver disease.
Reviewed by: C. D. Byrne
Authors: Mantovani A, Scorletti E, Mosca A, et al.
Published in: Metabolism. 2020
Comment: Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized public health problem, affecting up to a quarter of the world’s adult population. The burden of NAFLD is influenced by the epidemics of obesity and type 2 diabetes mellitus (T2DM) and the prevalence of these conditions is not expected to decrease in the forthcoming decades.
Consequently, the burden of NAFLD-related liver complications (non-alcoholic steatohepatitis [NASH], cirrhosis and hepatocellular carcinoma) and the need for life-saving liver transplantation are also expected to increase further in the near future. This narrative review provides an overview of the current literature on main complications, morbidity and mortality of this common and burdensome liver disease.
Article: Advanced fibrosis is associated with incident cardiovascular disease in patients with non-alcoholic fatty liver disease
Reviewed by: C. D. Byrne
Authors: Henson JB, Simon TG, Kaplan A, Osganian S, Masia R, Corey KE
Published in: Aliment Pharmacol Ther. 2020 Feb
Comment: Non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular disease. It is not well understood, however, which individuals with NAFLD are at highest risk for cardiovascular disease. This study aimed to determine the factors associated with incident cardiovascular events in a prospective cohort of individuals with biopsy-proven NAFLD without pre-existing cardiovascular disease. After a median follow-up time of 5.2 years, 26/285 (9.1%) individuals experienced an incident cardiovascular event. Advanced fibrosis (stage 3-4) on biopsy was a significant predictor of incident cardiovascular disease, and this persisted on multivariable analysis (SHR 2.86, 95% CI 1.36-6.04) after considering relevant covariates, including cardiovascular risk scores, which were not independent predictors. Of the non-invasive indicators of fibrosis, the NAFLD fibrosis score was the only independent predictor of cardiovascular disease. Other histologic features, including steatohepatitis, were not associated with incident cardiovascular disease. In conclusion, these data suggest that liver fibrosis is an independent CVD risk factor.
Article: Flaxseed oil in the context of a weight loss program ameliorates fatty liver grade in patients with non-alcoholic fatty liver disease: a randomized double-blind controlled trial.
Reviewed by: D. Beard
Authors: Rezaei S, Sasani MR, Akhlaghi M, et al.
Published in: Br J Nutr 2020
Comment: Long-chain omega-3 fatty acids have shown to regulate lipid metabolism and reduce fat accumulation in the liver. Masoumeh Akhlaghi et al. (Nutrition Research Center, School of Nutrition and Food Sciences, Shiraz University of Medical Sciences, Shiraz, Iran) investigated the effect of flaxseed oil, as a rich source of alpha-linolenic acid, on fatty liver and cardiometabolic risk factors in patients with non-alcoholic fatty liver disease.
Overall, the results showed that in the context of a low-calorie diet and moderate physical activity, flaxseed oil may benefit NAFLD patients to improve fatty liver grade, weight, and interleukin-6 compared to sunflower oil.
Decreasing aminotransferases, waist circumference, and systolic and diastolic blood pressure were benefits that came along with weight loss program as they changed similarly in both treatments. Benefits of flaxseed oil may be more substantial in patients with more severe cases of NAFLD and with higher levels of aminotransferases.
Article: Longitudinal Association of Non-Alcoholic Fatty Liver Disease With Changes in Myocardial Structure and Function: The CARDIA Study.
Reviewed by: C. D. Byrne
Authors: VanWagner LB et al.
Published in: J Am Heart Assoc. 2020;9(4):e014279.
Comment: Non-alcoholic fatty liver disease (NAFLD) is associated with high cardiovascular morbidity/mortality, including heart failure. Abnormalities in left ventricular (LV) structure/function are associated with heart failure risk. Participants from the population-based CARDIA (Coronary Artery Risk Development in Young Adults) study year 25 exam (2010-2011, aged 43-55 years, 61% women, 48% black) with computed tomography measured liver fat and comprehensive echocardiography were included. Echocardiography was repeated at year 30 follow-up (aged 47-62 years, N=1827). NAFLD was defined as liver attenuation ≤40 HU after exclusions. NAFLD prevalence was 8.7% (n=159). NAFLD participants had higher LV mass, relative wall thickness, incident LV hypertrophy and abnormal LV geometry versus non-NAFLD (P<0.02). NAFLD participants had impaired LV relaxation (E/A ratio 1.1 versus 1.2), higher LV filling pressures (E/e’ ratio 7.9 versus 7.2), worse longitudinal strain (-13.9% versus -15.3%), and lower LV ejection fraction (58.9% versus 60.2%, P<0.01).
In multivariable analyses adjusted for heart failure risk factors, NAFLD was independently associated with incident LV hypertrophy (odds ratio: 1.9, 95% CI: 1.1-3.4), abnormal LV geometry (odds ratio: 1.9, 1.1-3.3) and greater change in strain (odds ratio: 2.2, 1.1-4.7). Adjustment for body mass index attenuated associations to non-significance. Thus, these data provide evidence that NAFLD is a risk factor for LV dysfunction.
Article: Diet and Non-Alcoholic Fatty Liver Disease: The Mediterranean Way
Reviewed by: By D. Beard
Authors: Abenavoli L, Boccuto L, Federico A, et al.
Published in: Int J Environ Res Public Health. 2019;16(17):E3011.
Comment: Nowadays, the cornerstone in the clinical management of NAFLD includes two easy and pivotal concepts that are: dietary modification associated with improvement of physical activity.
In the era of evidence-based medicine, for L. Abenavoli et al. (Department of Health Sciences, University “Magna Graecia”, Catanzaro, Italy), Mediterranean diet can be considered the gold standard in preventive medicine targeting a vast spectrum of disorders involving the imbalance of the oxidative metabolism. On the basis of the data currently available in the literature, the authors suggest the prescription of Mediterranean diet in NAFLD patients, as an appropriate therapeutic approach, to prevent its onset and to contrast (or counteract?) the development of severe forms. Of course, longer-term trials testing the health benefits effects of Mediterranean diet remain warranted.
Article: Applying Non-Invasive Fibrosis Measurements in NAFLD/NASH: Progress to Date.
Authors: Albhaisi S, Sanyal AJ.
Published in: Pharmaceutical Medicine, 2019
Comment: To date, histological assessment of the liver using liver biopsy has served as the reference standard for evaluation of the presence and severity of NAFLD as well as for the assessment of disease progression or regression.
Non-invasive tests to evaluate fibrosis rely on either changes in the physical properties of the liver or on changes in levels of specific chemical moieties reflective of fibrogenesis.
Simple non-invasive laboratory aids can be used to rule out clinically significant fibrosis in those with chronic liver disease. Tests with higher specificity are being developed to increase the positive predictive value of testing and enhance the ability to rule in advanced fibrosis. Vibration-controlled transient elastography and magnetic resonance elastography are often used for this purpose.
Article: Diet, Gut Microbiota and NAFLD
Authors: Quesada-Vazquez S, Aragones G, Del Bas JM, et al.
Published in: Cells 2020
Comment: Diet is considered as one of the main drivers to modulate the composition of gut microbiota, which participate in different processes, affecting human metabolism. A disruption in the homeostasis of gut microbiota may lead to dysbiosis, i.e. a reduction of the beneficial species and an increment in pathogenic microbiota.
S. Quesada-Vázquez et al. (Unitat de Nutrició i Salut, Centre Tecnològic de Catalunya, Reus, Spain) highlight the association between diet, gut microbiota and liver, and how this axis may promote the development of NAFLD progression. Gut dysbiosis and bacterial translocation in combination with a Western diet and lifestyle with inflammasome dysfunction lead to NAFLD progression. This dysbiosis produces an increase in harmful bacteria and/or a decrease in beneficial bacteria, affecting the health of both the intestine and the liver.
Article: HbA1c at normal-range levels and NAFLD
Authors: Chen C, Zhu Z, Mao Y, et al.
Published in: Biosci Rep. 2020
Comment: Longitudinal observations were performed by C. Chen et al. in a cohort of 2,811 participants with no liver disease at inception. The rate of the conversion to NAFLD was 15.7%, with a steady increase in prevalence observed in sub-cohorts with increasing HbA1c levels.
The results suggest that increased levels of HbA1c may contribute to the progression of NAFLD either directly, by stimulating receptor for advanced glycation end products (RAGE), or indirectly, through the promotion of hypoxia and suppression of the release of NO.
Article: Anti-NASH Drug Development Hitches a Lift on PPAR Agonism.
Authors: Boeckmans J, Natale A, Rombaut M, et al.
Published in: Cells. 2019
Comment: Well-established drugs that are indicated for the treatment of type 2 diabetes and hyperlipidemia are thought to exert effects that alleviate the pathological features of NASH. One class of these drugs targets peroxisome proliferator-activated receptors (PPARs), which are nuclear receptors that play a regulatory role in lipid metabolism and inflammation.
PPARs are now also being investigated as potential anti-NASH druggable targets. J. Boeckmans et al. review the mechanisms of action and physiological functions of PPARs. They discuss the position of the different PPAR agonists in the therapeutic landscape of NASH.
Different approaches are currently investigated with PPAR-α/δ Agonists (Elafibranor is currently under clinical phase III evaluation), PPAR-α/γ Agonists and PPAR-pan Agonists (Lanifibranor is one of the most recently developed potential anti-NASH drugs, and is the first PPAR-pan agonist, targeting all three PPAR isotypes).
Article: DNA Hydroxymethylation at the Interface of the Environment and Nonalcoholic Fatty Liver Disease.
Authors: Tommasi S, Besaratinia A.
Published in: Int J Environ Res Public Health. 2019
Comment: NAFLD is a multi-faceted disease with metabolic, genetic, epigenetic, and environmental determinants. An increasing number of studies has also provided evidence for the role of xenobiotics in the genesis of steatosis and steatohepatitis, through increased ROS production and oxidative stress. Based on the current evidence, it is plausible that imbalances in the redox state of the cells, induced by exposure to a variety of pollutants, alter the hydroxymethylome, thus affecting the epigenetic reprogramming and transcriptional regulation of key genes involved in lipid metabolism or oxidative stress response. Aberrant expression of these genes may contribute to liver steatosis and exacerbate liver injury, thus promoting the progression to NASH.
Article: Evaluation of Dietary Approaches for the Treatment of Non-Alcoholic Fatty Liver Disease: A Systematic Review.
Authors: Saeed N, Nadeau B, Shannon C, et al.
Published in: Nutrients.
Comment: The optimal nutritional approach to treat NAFLD remains unclear. N. Saeed et al. (Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor) conducted a systematic review is to evaluate the effectiveness of different nutritional patterns on hepatic, metabolic, and weight-loss endpoints.
Reduction in hepatic steatosis (HS) was statistically significant in 3/5 Mediterranean Diet, one low-carbohydrate, one intermittent fasting and 1/2 low fat diet interventions.
There appears to be most data in support of Mediterranean Diet-based interventions, though further randomized trials are needed to assess comparative effectiveness for NAFLD.
Article: Intrahepatic bacterial metataxonomic signature in non-alcoholic fatty liver disease.
Authors: Sookoian S, Salatino A, Castano GO, et al.
Published in: Gut 2020
Comment: Silvia Sookoian et al. (Institute of Medical Research A Lanari, University of Buenos Aires Faculty of Medicine, Buenos Aires, Argentina) aimed to characterise the liver tissue bacterial metataxonomic signature in two independent cohorts of patients with biopsy-proven NAFLD diagnosis, as differences in the host phenotypic features-from moderate to severe obesity-may be associated with significant changes in the microbial DNA profile.
Their study shows that liver bacterial DNA profile significantly differs between morbidly obese and non-morbidly obese patients with NAFLD. Proteobacteria DNA was consistently associated with lobular and portal inflammation scores. Microbial DNA composition corresponded to predicted functional differences.
Article: Does SEN-V and other non-A-E hepatotropic viruses contribute to the development and progression of non-alcoholic fatty liver disease?
Authors: Grubert Van Iderstine M, Osiowy C, Rumbolt C, et al.
Published in: Med Hypotheses 2019;137:109528.
Comment: Approximately 10-20% of patients with non-alcoholic fatty liver disease (NAFLD) are at risk of progressing to cirrhosis. The cause of such progression is unclear. SEN-V is a hepatotropic virus that has been associated with more severe and advanced liver disease in patients with chronic hepatitis C virus infections.
M. Grubert Van Iderstine et al. (section of Hepatology, Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada) tested 32 NAFLD patients for evidence of SEN-V infection and correlated the results with histologic findings. Their study revealed similar disease severity and stage of progression in SEN-V positive and negative patients.
Other non-A-E hepatotropic viruses may contribute to the development and course of NAFLD, as discussed in this study.
Article: Small but mighty: Platelets in NASH and other chronic liver diseases.
Authors: Hilscher MB, Shah VH.
Published in: Hepatology 2020
Comment: Several pleiotropic effects of platelets on liver homeostasis and disease have been identified in recent studies. These effects are distinct from their long-recognized roles in hemostasis and coagulation. Recent evidence suggests that pro-thrombotic tendencies may exceed the bleeding diathesis traditionally associated with advanced liver disease. This implies that anti-platelet therapy (APT) may in fact be safely used in certain patients with chronic liver disease.
Article: Unmasking a Stealth Killer: The Need for Increased Awareness of NASH.
Authors: Sherif ZA.
Published in: Dig Dis Sci 2019.
Comment: The challenge with NAFLD and its variations is not merely lack of awareness of the disease, but also lack of a full understanding of its diagnosis, etiology, pathophysiology, and treatment throughout the community. This deficiency in knowledge or awareness can adversely impact patients, health professionals, health providers, and researchers alike. Most importantly, however, the biggest challenge is to increase awareness and improve education in a multi-pronged approach that could include national advocacy with national public health groups; patient advocacy with patient support groups; and continued basic science research and clinical trials for a full understanding of the disease and to design the and appropriate treatment course.
Article: Advancing the understanding of NAFLD to hepatocellular carcinoma development: From experimental models to humans.
Authors: Chen K, Ma J, Jia X, et al.
Published in: Biochim Biophys Acta Rev Cancer 2019;1871:117-125.
Comment: Nonalcoholic fatty liver disease (NAFLD) has recently been recognized as an important etiology contributing to the increased incidence of hepatocellular carcinoma (HCC). The more aggressive form, nonalcoholic steatohepatitis (NASH), is characterized by hepatocyte necrosis and inflammation. The development of effective approaches for disease prevention and/or treatment heavily relies on deep understanding of the mechanisms underlying NAFLD to HCC development. This review will comprehensively describe the current in vitro and mouse models for studying NAFLD/NASH/HCC.
Article: Non-alcoholic fatty liver disease after liver transplantation in patients with non-alcoholic steatohepatitis and cryptogenic cirrhosis: the impact of pre-transplant graft steatosis
Authors: Eshraghian A, Nikeghbalian S, Kazemi K, et al.
Published in: HPB (Oxford) 2019. pii: S1365-182X(19)30634-3
Comment: Nonalcoholic fatty liver disease (NAFLD) may occur in liver transplant recipients. This study aimed to investigate the prevalence and risk factors of NAFLD after liver transplantation in patients with NASH and cryptogenic cirrhosis, focusing on the impact of graft steatosis.
Patients with NASH and cryptogenic cirrhosis who had undergone liver transplantation in 73 patients with NASH and 389 with cryptogenic cirrhosis were included.
Obesity and post-transplant hyperlipidemia were independent predictors of NAFLD after liver transplantation. Liver graft steatosis before transplantation was not associated with the occurrence of NAFLD after liver transplantation: NAFLD was diagnosed in 32.9% of patients with graft macrosteatosis compared to 29.9% in patients without graft macrosteatosis.
Article: Epidemiology of NAFLD and advanced fibrosis in the French general population: A population-based cohort study in 118, 664 subjects (NASH-CO study).
Authors: Serfaty L, Nabi O, Boursier J, et al.
Published in: Journal of Hepatology 2019;70:e309-e310.
Comment: The aim of this study by L. Serfaty et al. was to assess the prevalence and risk factors of NAFLD and associated liver fibrosis in a French population-based cohort (118, 664 participants) by using using the Fatty Liver Index and Forns Index.
The global prevalence of NAFLD in the study population was 16.7%. NAFLD was significantly associated (all p < 0.001) with older age, male sex, obesity, diabetes, metabolic syndrome, high blood pressure, hypertriglyceridemia and ALT above normal threshold. Advanced fibrosis was observed in 2.6% of NAFLD subjects, and in 7.6% of NAFLD subjects with diabetes. Age, male sex and metabolic disorders appear as independent risk factors of both NAFLD and advanced fibrosis.
Article: Analysis of human leukocyte antigen allele polymorphism in patients with non alcoholic fatty liver disease
Authors: Karrar A, Hariharan S, Fazel Y, et al.
Published in: Medicine (Baltimore) 2019;98:e16704
Comment: The human leukocyte antigen (HLA) genes may play a role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and its progressive form, non-alcoholic steatohepatitis (NASH). A. Karrar et al. aimed to assess the association of HLA class I and II alleles with NASH and its histological features. The findings of this study indicate that HLA class I and II gene polymorphism may be associated with susceptibility to NASH, fibrosis and other pathologic features and may be involved in the pathogenesis of NAFLD.
Article: Cardio-Metabolic Disorders in Non-Alcoholic Fatty Liver Disease.
Authors: El Hadi H, Di Vincenzo A, Vettor R, et al
Published in: Int J Mol Sci 2019;20.
Comment: Recent clinical evidence suggests that NAFLD is directly associated with an increased risk of cardio-metabolic disorders. This mini review describes briefly the current understanding of the pathogenesis of NAFLD, summarizing the link between NAFLD and cardio-metabolic complications, focusing mainly upon ischemic stroke, type 2 diabetes mellitus, hypertension, chronic kidney disease and cardiac arrhythmias. In addition, it describes briefly the current understanding of the pathogenesis of NAFLD.
Article: Angiopoietin-2 promotes pathological angiogenesis and is a novel therapeutic target in murine non-alcoholic fatty liver disease.
Authors: Lefere S, Van de Velde F, Hoorens A, Raevens S, Van Campenhout S, Vandierendonck A, Neyt S, Vandeghinste B, Vanhove C, Debbaut C, Verhelst X, Van Dorpe J, Van Steenkiste C, Casteleyn C, Lapauw B, Van Vlierberghe H, Geerts A, Devisscher L.
Published in: Hepatology. 2019 Mar;69(3):1087-1104.
Comment: This original study demonstrates that serum angiopoietin-2 levels are increased in patients with NASH and correlate with liver steatosis, inflammation and hepatocyte ballooning, but not with liver fibrosis. Similar findings were observed with two murine models of NASH, namely mice fed a methionine and choline deficient diet and mice with neonatal injection of streptozotocin followed by 16 weeks of western diet. The main source of hepatic angiopoietin-2 was liver sinusoidal endothelial cells (LSECs). Inhibiting angiopoietin-2 levels using the angiopoietin-2/Tie2 receptor inhibiting peptibody L1-10 reduced hepatic angiogenesis and normalized vascular microarchitecture. These findings provide evidence for angiopoietin -2 inhibition as a therapeutic strategy to target pathological angiogenesis in NASH.
Article: Endothelial fatty liver binding protein 4: a new targetable mediator in hepatocellular carcinoma related to metabolic syndrome.
Authors: Laouirem S, Sannier A, Norkowski E, Cauchy F, Doblas S, Rautou PE, Albuquerque M, Garteiser P, Sognigbé L, Raffenne J, van Beers BE, Soubrane O, Bedossa P, Cros J, Paradis V.
Published in: Oncogene. 2019 Apr;38(16):3033-3046.
Comment: This original study demonstrates that liver sinusoidal endothelial cells (LSECs) exposed to conditions mimicking NAFLD -namely high concentrations of glucose, insulin, or VEGFA- release FABP4. They also observed that fatty acid-binding protein 4 (FABP4) released by LSECs, partly in microvesicles, exerts pro-oncogenic effects, since it induces hepatocyte proliferation. In mice fed a high-fat diet, specific inhibition of FABP4 reduces hepatocellular carcinoma growth. In conclusion, this study demonstrates the emerging oncogenic role of liver endothelial cells through FABP4 in hepatocellular carcinoma related to metabolic syndrome.
Article: Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPARα expression.
Authors: Loyer X, Paradis V, Hénique C, Vion AC, Colnot N, Guerin CL, Devue C, On S, Scetbun J, Romain M, Paul JL, Rothenberg ME, Marcellin P, Durand F, Bedossa P, Prip-Buus C, Baugé E, Staels B, Boulanger CM, Tedgui A, Rautou PE.
Published in: Gut. 2016 Nov;65(11):1882-1894.
Comment: This original study demonstrated that microRNA-21 is overexpressed in the liver of patients with NASH, but not in those with bland steatosis. Liver microRNA-21 in NASH is primarily expressed in inflammatory and biliary cells. Using different mouse models of NASH, authors demonstrated that microRNA-21 contributes to key features of NASH, i.e. cell injury, inflammation and fibrosis, through PPARα inhibition.
Article: A defect in endothelial autophagy occurs in patients with nonalcoholic steatohepatitis and promotes inflammation and fibrosis.
Authors: Hammoutene A, Biquard L, Lasselin J, Kheloufi M, Tanguy M, Vion AC, Mérian J, Colnot N, Loyer X, Tedgui A, Codogno P, Lotersztajn S, Paradis V, Boulanger CM, Rautou PE.
Published in: A defect in endothelial autophagy occurs in patients with nonalcoholic steatohepatitis and promotes inflammation and fibrosis.
Comment: Autophagy is a physiological process controlling endothelial homeostasis in vascular beds outside the liver. This original study demonstrates that autophagy is defective in liver endothelial cells of patients with NASH and that this defect promotes liver inflammation and fibrosis at early stages of NASH, but also at advanced stages of chronic liver disease. This study thus provides new insights into our understanding of the role of LSECs in the development of NASH and liver fibrosis. Targeting specifically liver endothelial autophagy may be an attractive strategy for NASH treatment.
Article: Molecular pathways between obesity, non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC).
Authors: Petrucciani N, Gugenheim J.
Published in: Hepatobiliary Surg Nutr 2019;8:395-397.
Comment: This article highlights the importance of the recent study by Grohmann et al. published in the November, 2018 issue of Cell. It contributes to the understanding of molecular mechanisms which relate obesity with NASH and HCC. This study highlights the respective roles of STAT-1 signaling in inducing NASH and fibrosis and of STAT-3 in promoting HCC formation. Probably the most relevant finding is that STAT-3 signaling can drive tumor onset in a context of obesity with NAFLD, independently of the presence of NASH and fibrosis.
Article: Pediatric Fatty Liver Disease
Authors: Jain A
Published in: Mo Med 2019;116:123-128.
Comment: Reports of NAFLD in patients as young as 2 years of age have been documented. It tends to be more common in children who are obese but has been known to occur in patients who have normal weight. Children with NAFLD are at increased risk of early onset type 2 diabetes and NAFLD is estimated to increase the risk of early cardiovascular disease by almost five-fold. The natural progression of NASH in children also remains ill defined. Many children with NASH can develop fibrosis
Article: Short sleep duration is a risk of incident nonalcoholic fatty liver disease: a population-based longitudinal study.
Authors: Okamura T, Hashimoto Y, Hamaguchi M, et al
Published in: J Gastrointestin Liver Dis 2019;28:73-81.
Comment: Previous cross-sectional studies revealed that short sleep duration has a close relationship with the presence of non-alcoholic fatty liver disease (NAFLD). This historical cohort study of 12,306 participants is the first study showing that short sleep duration was a risk factor for incident NAFLD.
During the 7-year follow-up, 2,280 participants developed NAFLD. In Cox proportional hazards models, sleep duration of ≤5 h in both men and women were revealed to be a significant risk for incident NAFLD, compared to men and women with a sleep duration of >7 h (men: hazard ratio 1.39, 95% confidence interval 1.13-1.72, p=0.002; women; 1.46, 1.05-2.04, p=0.023).
Article: Can Nonfibrotic Nonalcoholic Steatohepatitis Be Effectively Identified by Supersonic Shear Imaging?
Authors: Yang J, Lin L, Xue E, et al.
Published in: Anal Cell Pathol (Amst) 2019;2019:2013674.
Comment: Supersonic shear imaging (SSI) is a relatively new technique to measure the elasticity of target tissues based on the shear wave propagation. In this study, J. Yang et al. aimed to evaluate the value of SSI in discriminating NASH from NAFLD, NASH with fibrosis, and the normal liver, as well as the relationship between various NAFLD pathologic or biochemical findings and SSI liver elasticity.
Rabbits with NAFLD of different degrees were subjected to SSI for liver elasticity measurement. The results indicate that SSI can effectively identify nonfibrotic NASH in rabbits based on the difference in liver elasticity and the difference is related to the various pathologic changes, including fibrosis, inflammation, steatosis, and ballooning degeneration.
Article: Depression is associated with non-alcoholic fatty liver disease among adults in the United States.
Authors: Kim D, Yoo ER, Li AA, et al.
Published in: Aliment Pharmacol Ther 2019.
Comment: To determine whether depression is associated with NAFLD and NAFLD-related advanced fibrosis in a large population sample, D. Kim et al. performed a cross-sectional analysis using the 2007-2016 NHAHES database among adults in the United States.
Depression and associated functional impairment were assessed with the Patient Health Questionnaire. NAFLD was defined by utilising the US fatty liver index (USFLI), hepatic steatosis index (HSI) and the fatty liver index (FLI), and advanced fibrosis in NAFLD were defined by Fibrosis-4 score.
Of the 10 484 subjects, compared to subjects without depression, those with depression were 1.6-2.2-fold more likely to have NAFLD, but depression was not associated with NAFLD-related advanced fibrosis.
Article: A new method to induce nonalcoholic steatohepatitis (NASH) in mice.
Authors: Savari F, Mard SA, Badavi M, et al.
Published in: BMC Gastroenterol 2019;19:125.
Comment: F. Savari et al. studied the effect of fructose, fat-rich and Western diet feeding along with aggravative effect of cigarette smoking on liver status in 64 male mice. The mice were assigned into 4 groups that fed standard, fructose-rich, high fat-, and western-diet for 8 weeks. Then each group was divided in two smoker and nonsmoker subgroups according to smoke exposing in the last 4 weeks.
Serum liver enzymes and lipid profile levels in Western diet fed mice were significantly higher than in other diets. Exposing to cigarette smoke led to a significant increase in hepatic damage shown as more severe fat accumulation, hepatocyte ballooning and inflammation infiltrate. Elevated TNF-α level confirmed incidence of liver injury.
Article: A Review of Non-Alcoholic Fatty Liver Disease in HIV-Infected Patients: The Next Big Thing?
Authors: van Welzen BJ, Mudrikova T, El Idrissi A, et al.
Published in: Infect Dis Ther 2019;8:33-50.
Comment: The burden of liver-related morbidity remains high among HIV-infected patients, with a prevalence of up to 50%. The pathogenesis of NAFLD and the reasons for progression to non-alcoholic steatohepatitis (NASH) are still not fully elucidated.
Both HIV-infection itself and combination antiretroviral therapy can contribute to the development of NAFLD/NASH in various ways. In addition, the use of early-generation nucleoside reverse transcriptase inhibitors and protease inhibitors is also associated with the development of NAFLD/NASH.
The epidemiology and etiology of NAFLD/NASH in HIV-positive patients is likely to change in the near future. Current guidelines recommend early initiation of cART that is less likely to induce insulin resistance, mitochondrial dysfunction and dyslipidemia. In contrast, this population will adopt the more traditional risk factors for NAFLD/NASH.
HIV-treating physicians should be aware of the etiology, pathogenesis and treatment of NAFLD/NASH in order to identify and treat the patients at risk.
Article: Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts.
Authors: Alexander M, Loomis AK, van der Lei J, et al.
Published in: BMC Med 2019;17:95
Comment: M Alexander et al. used healthcare records of 18 million adults to estimate the risk of acquiring advanced liver disease diagnoses in patients with NAFLD or NASH compared to individually matched controls. Data were extracted from databases representing the UK, Netherlands, Italy and Spain.
Out of 18,782,281 adults, the authors identified 136,703 patients with NAFLD/NASH. These patients were more likely to have diabetes, hypertension and obesity than matched controls. The strongest independent predictor of a diagnosis of HCC or cirrhosis was baseline diagnosis of diabetes. This real-world population data show that diabetes is an independent predictor of advanced liver disease diagnosis, emphasising the need to identify specific groups of patients at highest risk.
Article: Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease
Authors: Hammoutene A, Rautou PE.
Published in: J Hepatol 2019;70:1278-1291.
Comment: Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells localized at the interface between the blood derived from the gut and the adipose tissue on the one side, and other liver cells on the other side. In physiological conditions, LSECs are gatekeepers of liver homeostasis. LSECs display anti-inflammatory and anti-fibrogenic properties by preventing Kupffer cell and hepatic stellate cell activation and regulating intrahepatic vascular resistance and portal pressure. Lipotoxicity and inflammation induce endothelial inflammation. Activated LSECs release cytokines and chemokines and over-express adhesion molecules, thus sustaining liver inflammation. Altered LSECs also fail to maintain hepatic stellate cell quiescence and release fibrogenic mediators, including Hedgehog signalling molecules, promoting liver fibrosis. Liver angiogenesis is increased in NAFLD and contributes to liver inflammation and fibrosis, but also to hepatocellular carcinoma development.
Article: Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer.
Authors: Malehmir M, Pfister D, Gallage S, Szydlowska M, et al.
Published in: Nat Med. 2019 Apr;25(4):641-655.
Comment: Here, the authors show that platelet number, platelet activation and platelet aggregation are increased in NASH but not in steatosis or insulin resistance. Platelet cargo, platelet adhesion and platelet activation but not platelet aggregation were identified as pivotal for NASH and subsequent hepatocarcinogenesis. In particular, platelet-derived GPIbα proved critical for development of NASH and subsequent HCC, independent of its reported cognate ligands vWF, P-selectin or Mac-1, offering a potential target against NASH.
Article: Biological mechanisms and related natural modulators of liver X receptor in nonalcoholic fatty liver disease.
Authors: Ni M, Zhang B, Zhao J, Feng Q, Peng J, Hu Y, Zhao Y
Published in: Biomed Pharmacother. 2019 May 113
Comment: In this review, the authors discuss the mechanisms of LXR in NASH and summarize the natural products reported to modulate NAFLD via LXR or the LXR pathway, offering an alternative approach for LXR-related drug development in NAFLD.
Article: Role of Vitamin E for Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes: A Randomized Controlled Trial.
Authors: Bril F et al.
Published in: Diabetes Care 2019
Comment: This proof of concept study was designed to assess if vitamin E, alone or combined with pioglitazone, improves histology in patients with T2DM and NASH. It showed no effect of vitamin E on ballooning or inflammation, although some effect on NASH resolution was seen. Albeit small sample size, it challenges the effect of vitamin E on NASH in patients with type-2 diabetes but larger studies are needed so settle the issue.
Article: A review of the studies on food-derived factors which regulate energy metabolism via the modulation of lipid-sensing nuclear receptors.
Authors: Goto T.
Published in: Biosci Biotechnol Biochem. 2019 Apr;83(4):579-588. Epub 2018 Dec 20.
Comment: In this review, the author describes current knowledge of the role of PPARs in the regulation of whole-body energy metabolism and several examples of food factors that act as ligands of PPARs, which may be useful in the management of obesity and the accompanying energy metabolism abnormalities.
Article: Nutritional Intake and the Risk for Non-Alcoholic Fatty Liver Disease (NAFLD) .
Authors: Schattenberg JM, Bergheim I .
Published in: Nutrients 2019.
Comment: The editorial accompanying a special issue of nutrition in NAFLD, highlights the relevance of the topic and open issues for future studies.
Article: Pharmacological treatments of the “Fibrotic-NASH”: Towards a delivery on time?
Authors: Gual P
Published in: Clin Res Hepatol Gastroenterol 2019.
Comment: The molecular mechanisms involved in the development and progression of NAFLD are complex and multi- factorial. Intrahepatic but also extrahepatic mechanisms play an important role. In the future, pharmacological innovations may be available for patients with fibrotic-NASH. An increasing number of pre-clinical and clinical studies are in progress targeting ‘‘metabolism-inflammation-fibrogenesis’’.
As stated by P. Gual in an editorial, to optimize the action of these future treatments, “adapted lifestyle modifications towards a healthy diet and habitual physical activity would also be a therapeutic approach to reduce the cardiovascular complications (or even cancers?) associated with NAFLD.”
These lifestyle modifications together with future pharmacological approaches could also help the correction of the altered biological clock associated with obesity and obesity complications.
Article: Crosstalk between adipose tissue insulin resistance and liver macrophages in Non Alcoholic Fatty Liver Disease
Authors: Rosso C, Kazankov K, Younes R, et al.
Published in: Journal of hepatology 2019.
Comment: Elisabetta Bugianesi et al. undertook this study to elucidate the interplay between macrophage activation, insulin resistance in target organs and tissues and hepatic damage.In 40 non-diabetic patients with biopsy-proven NAFLD the authors assessed endogenous glucose production, glucose clearance and indexes of insulin resistance in the adipose tissue, and macrophage activity, and hepatic expression of CD163.
This study may suggest a different perspective in considering macrophage activation in the liver of patients with NAFLD, along with (and possibly in addition to) macrophage activation in the adipose tissue.
It is likely that the overflow of free fatty acids to the liver is one of the main metabolic sources of activation of resident hepatic macrophages in patients with NAFLD and can provide one of the mechanisms linking adipose tissue insulin resistance and liver fibrosis in these patients. This is the first study to confirm in humans and in vivo a major mechanism of progression to NASH, that has been previously postulated in animal models.
Article: Non-alcoholic fatty liver disease in non-obese individuals: Prevalence, pathogenesis and treatment
Authors: Molina-Molina E, Krawczyk M, Stachowska E, et al.
Published in: Clin Res Hepatol Gastroenterol 2019.
Comment: A remarkable number of lean individuals in the United States suffer from NAFLD, likely due to distinct components of MetS, such as diabetes and/or hypertension.
Indeed, as noticed in the Kangbuk Samsung Health Study, 16,279 non-obese patients with different grades of liver steatosis and fibrosis were at increased risk of sub-clinical atherosclerosis. They are also at higher risk of mortality.
For the European population, the NAFLD Clinical Study Group, a multicentre biopsy-based cohort formed by 515 German patients, reported 12% of these NAFLD patients to be non-diabetic and non-obese.
The occurrence of NAFLD in non-obese subjects remains a challenge and raises several questions regarding the pathophysiological mechanisms governing fat deposition/accumulation in the liver of apparently healthy subjects. A combination of both genetic and non-genetic factors may play a role in this context.
Article: Macrophages in obesity and non-alcoholic fatty liver disease; Crosstalk with metabolism.
Authors: Lefere, S and Tacke, F
Published in: Lefere, S and Tacke, F
Comment:This article summarises the (mainly preclinical) evidence of the role of adipose tissue inflammation and NAFLD via macrophages that play an important role in connecting adipose tissue inflammation to liver inflammation (the adipose tissue-liver) axis. It concludes that macrophage targeting has potential as a therapeutic strategy in metabolic disease and that we may see advances in the future.
Article: Pioglitazone Discontinuation in Patients with Nonalcoholic Steatohepatitis (NASH) Is Associated withDisease Recurrence
Authors: Bril F, Cusi K et al
Published in: Diabetes 2019 Jun; 68 (Supplement 1)
Comment: Pioglitazone (PIO) is effective for long-term treatment of patients with nonalcoholic steatohepatitis(NASH) with prediabetes or type 2 diabetes. It reduces liver fibrosis and increases adipose tissue insulin sensitivity.
In this article, the authors found that PIO rapidly normalizes plasma aminotransferases (LFTs) in NASH and improves liver histology, but its discontinuation results in an abrupt increase in LFTs, likely reflecting NASH recurrence. Therefore, PIO therapy for NASH should be considered as a long-term management approach.
Article: Natural Killer Cells and Type 1 Innate Lymphoid Cells Are New Actors in Non-alcoholic Fatty Liver Disease
Authors:Luci C, Vieira E, Perchet T, et al.
Published in: Front Immunol 2019;10:1192.
Comment:Lipid accumulation in the liver contributes to hepatocyte cell death and promotes liver injury. Local immune cells are activated either by Danger Associated Molecular Patterns (DAMPS) released by dead hepatocytes or by bacterial products (PAMPS) reaching the liver due to increased intestinal permeability. The resulting low-grade inflammatory state promotes the progression of liver complications toward more severe grades.
Innate lymphoid cells (ILC) are an heterogeneous family of five subsets including circulating Natural Killer (NK) cells, ILC1, ILC2, ILC3, and lymphocytes tissue-inducer cells (LTi). NK cells and tissue- resident ILCs are prompt to rapidly react to environmental changes to mount appropriate immune responses.
Recent works have demonstrated the interplay between ILCs subsets and the environment within metabolic active organs such as liver, adipose tissue and gut during diet-induced obesity leading or not to hepatic abnormalities. C. Luci et al. provide an overview of the newly roles of NK cells and ILC1 in metabolism focusing on their contribution to the development of NAFLD.
Article: Modulation of Insulin Resistance in NAFLD.
Authors: Khan, R. , Bril, F. , Cusi, K. and Newsome, P
Published in: Hepatology. 2018 Dec 16 doi: 10.1002/hep.30429. [Epub ahead of print].
Comment: Since there is a close relationship between insulin resistance and NAFLD, modulation of insulin resistance has a considerable interest in the quest for effective treatments of NAFLD. This review article focuses on possible mechanisms linking insulin resistance and NAFLD and discusses the main pharmacological approaches and their potential benefits, among which Peroxisome Proliferator-Activated Receptor (PPAR- γ/ α/δ).
Article: Non-alcoholic fatty liver disease and the interface between primary and secondary care.
Authors: Emmanuel A Tsochatzis and Philip N Newsome .
Published in: in Lancet Gastroenterol Hepatol 2018; 3: 509–17.
Comment: The prevalence of Non-alcoholic fatty liver disease (NAFLD) is estimated to be 25–30% in unselected populations. Its prevalence is high but severity is low. However, many patients are now referred to hepatology departments and they need to screen further those at risk of advanced
fibrosis (5%). The interface between primary and secondary care has become a topic for research because it is very important for patients care in terms of diagnosis and management. The authors conclude that there is urgent need for an integrated management plan between primary and secondary care, with robust pathways.