From the Literature

9th September 2020

Article: Comparison of four non-alcoholic fatty liver disease detection scores in a Caucasian population

Reviewed by: D. Beard

Authors: Lind L, Johansson L, Ahlstrom H, et al.

Published in: World J Hepatol 2020

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336289/

Comment: Several scores based on easily measurable biochemical and clinical parameters, including the fatty liver index (FLI), hepatic steatosis index (HSI), lipid accumulation product (LAP), and NAFLD liver fat score (LFS), have been developed for the detection of NAFLD. However, comparative information regarding the efficacy of these scores for predicting NAFLD in normal and high-risk individuals is lacking.

In order to evaluate these four NAFLD detection scores, L. Lind et al. (Uppsala University, Sweden) performed NAFLD screening in a population-based sample of 50-year-old individuals in Uppsala, Sweden (Prospective investigation of obesity, energy and metabolism – POEM study) and a high-risk population (EFFECT studies). NAFLD was defined as liver fat > 5.5% using magnetic resonance imaging-proton density fat fraction.

In the population-based setting (POEM), FLI showed the highest ROC AUC and was significantly better than the LAP score for detection of NAFLD. The other three indices performed equally.

In the high-risk setting (EFFECT), LFS performed best. The ROC AUC for LFS was significantly higher than that for fatty liver index and LAP, but not HSI.

In conclusion, FLI seems preferable in the population-based setting, while LFS performed best in the high-risk setting in this study.

9th September 2020

Article: Physical Activity, Measured Objectively, is Associated With Lower Mortality in Patients With Nonalcoholic Fatty Liver Disease

Reviewed by: D. Beard

Authors: Kim D, Murag S, Cholankeril G, et al

Published in: Clin Gastroenterol Hepatol 2020

Link: https://www.cghjournal.org/article/S1542-3565(20)30985-X/fulltext?rss=yes

Comment: D. Kim et al. (Stanford University School of Medicine, Stanford, California, United States) studied whether physical activity, measured by accelerometer, is associated with all-cause and cardiovascular mortality among individuals with NAFLD.

The authors performed a longitudinal analysis using the 2003-2006 US National Health and Nutrition Examination Survey data of adults and collecting mortality data through December 2015. NAFLD was defined based on hepatic steatosis index or US fatty liver index scores, in the absence of other causes of chronic liver disease. Physical activity was measured from participants who wore accelerometers 10 hrs/day for a minimum of 4 days over a 7-day period and classified as total physical activity, moderate to vigorous physical activity, and sedentary behaviour.

Total physical activity was associated with reduced risk of death, from any cause, in an age- and sex-adjusted model among individuals with NAFLD. Increasing duration of moderate to vigorous physical activity was associated with a lower risk of death from any cause in individuals with NAFLD. Furthermore, longer total physical activity was associated with a lower risk for cardiovascular disease-related death in individuals with NAFLD.

2nd September 2020

Article: MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease

Reviewed by: D. Beard

Authors: Eslam M, Sanyal AJ, George J, et al.

Published in: Gastroenterology 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32044314/

Comment: The exclusion of other chronic liver diseases including “excess” alcohol intake are usually necessary to establish a diagnosis of metabolic dysfunction-associated fatty liver disease (MAFLD). However, “positive criteria” to diagnose the disease are required.

A panel of international experts from 22 countries propose a new definition for the diagnosis of MAFLD.

Metabolic associated fatty liver disease (MAFLD) is present if hepatic steatosis is accompanied by either obesity or overweight, type 2 diabetes mellitus or evidence of metabolic dysregulation. At least two metabolic risk factors should be present for definition of metabolic dysregulation: excessive waist circumference; prediabetes; inflammation with elevated high-sensitive serum CRP level; elevated blood pressure or specific drug treatment; decreased HDL-cholesterol levels; increased plasma triglycerides levels; and homeostasis model assessment (HOMA)-insulin resistance score ≥2.5. Heterogenous factors lead to MAFLD, including ethnicity, sex, dietary habits, genetic predisposition, age, gut microbiota and metabolic status.

The expert consensus statement propose that disease assessment and stratification of severity should extend beyond a dichotomous classification to steatohepatitis vs. non-steatohepatitis.

2nd September 2020

Article: From NAFLD to MAFLD: when pathophysiology succeeds

Reviewed by: D. Beard

Authors: Tilg H, Effenberger M.

Published in: Nat Rev Gastroenterol Hepatol 2020

Link: https://www.nature.com/articles/s41575-020-0316-6?draft=marketing

Comment: Two new position papers convincingly propose that non-alcoholic fatty liver disease needs a new name — metabolic associated fatty liver disease (MAFLD). A new name for this disease affecting nearly one billion people globally is overdue, as knowledge gained from the past decades has definitely demonstrated that MAFLD is a purely metabolic disorder.

Such a concept is also supported by the fact that patients with MAFLD can fluctuate between steatosis and steatohepatitis over rather short timeframes, and steatohepatitis might slowly or rapidly progress towards fibrosis and fibrosis can even spontaneously regress, all reflecting a highly dynamic disease process.

Renaming NAFLD as MAFLD brings this disease closer to type 2 diabetes. Diabetologists and hepatologists should have to intensify their collaborative actions with support from epidemiologists and basic scientists and was accompanied by a significant decrease in the overall number of leukocytes. Hepatic monocytes were decreased as well.

28th August 2020

Article: Non-alcoholic fatty liver disease: correlation with hyperuricemia in a European Mediterranean population.

Reviewed by: D. Beard

Authors: Catanzaro R, Sciuto M, He F, et al.

Published in: Acta Clin Belg 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32559142/

Comment: Several studies have investigated the association between serum uric acid and metabolic syndrome / NAFLD. Four meta-analysis on retrospective and prospective studies confirmed this association, especially in women. However, most of the studies included in the analysis were performed on Asian populations. Despite high quality and large population of European studies, they were targeted mainly on the diagnostic aspects of metabolic syndrome.

The aim of this retrospective study by Roberto Catanzaro et al. (Department of clinical and experimental Medicine, University of Catania, Italy) was to investigate the overlap between NAFLD, metabolic syndrome, and hyperuricemia also in a population of Southern Europe. They have found a significant correlation between NAFLD and hyperuricemia. The higher serum uric acid levels accompanied the risk of NAFLD.

28th August 2020

Article: Experimental steatohepatitis: lanifibranor early reduces NASH activity and macrophage infiltration.

Reviewed by: D. Beard

Authors: Lefere S, Puengel T, Hundertmark J, et al.

Published in: J Hepatol 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32360434/

Comment: In a CDAA-HFD (choline-deficient, amino acid-defined high-fat diet-induced) model, which induces severe inflammation and liver fibrosis, S. Lefere et al. studied the efficacy of single and pan-PPAR agonists in the treatment of progressive steatohepatitis.

To examine the pathophysiological sequence of steatohepatitis amelioration upon treatment with PPAR agonists, the authors analysed the effects of short-term treatment. PPAR agonists were administered for 2 weeks in mice. Similar to the long-term treatment, lanifibranor reduced grading of steatosis, lobular inflammation and ballooning, and thus the overall NAFLD activity score.

This was accompanied by a significant reduction in hepatic lipid content and expression of inflammatory cytokines in lanifibranor-treated mice. Liver fibrosis was significantly improved by lanifibranor.

Lanifibranor decreased the number of hepatic macrophages already after 2 weeks of treatment. The proportion and absolute number of hepatic pro-inflammatory monocyte-derived macrophages were reduced specifically by lanifibranor compared to the single PPAR agonists and was accompanied by a significant decrease in the overall number of leukocytes. Hepatic monocytes were decreased as well.

5th August 2020

Article: Metabolic liver disease in diabetes – from mechanisms to clinical trials.

Reviewed by: D. Beard

Authors: Dewidar B, Kahl S, Pafili K, et al.

Published in: Metabolism 2020

Link: https://www.sciencedirect.com/science/article/pii/S0026049520301633

Comment: Non-alcoholic fatty liver disease (NAFLD) is tightly associated with the most frequent metabolic disorders, such as obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM).

Excessive lipid and later cytokine release by dysfunctional adipose tissue, intestinal dysbiosis and ectopic fat deposition in skeletal muscle lead to insulin resistance due to abnormal lipid handling and mitochondrial function. Over time, cellular oxidative stress and activation of inflammatory pathways, supported by multiorgan crosstalk, determine NAFLD progression.

Recent studies show that particularly the severe insulin resistant diabetes subgroup associates with NAFLD and its accelerated progression and increases the risk of diabetes-related cardiovascular and kidney diseases.

This review by Bedair Dewidar et al. (Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany) addresses the bidirectional relationship between mechanisms underlying T2DM and NAFLD, the relevance of novel biomarkers for improving the diagnostic modalities and the identification of subgroups at specific risk of disease progression.

5th August 2020

Article: Clinical characteristics and management of a liver transplanted patient admitted with SARS-CoV-2 infection.

Reviewed by: D. Beard

Authors: De Gottardi A, Fratila C, Bertoli R, et al.

Published in: Clin Res Hepatol Gastroenterol 2020

Link: https://www.sciencedirect.com/science/article/pii/S2210740120301595

Comment: A. de Gottardi et al. (Gastroenterology and Hepatology, Ente Ospedaliero Cantonale, Lugano, Switzerland) present a case of SARS-CoV-2 infection reported in the literature in a liver transplanted patient. In this immunosuppressed patient, the evolution of the infection was characterized by a moderate to severe interstitial pneumonia over a period of 10 days with a minimal initial increase of ALT.

The findings presented in this article confirm that the liver may be only mildly affected during SARS-CoV-2 infection and suggest that this is also true in liver transplanted patients.

30rd July 2020

Article: Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages.

Reviewed by: D. Beard

Authors: Lefere S, Puengel T, Hundertmark J, et al.

Published in: J Hepatol 2020

Link: https://www.journal-of-hepatology.eu/article/S0168-8278(20)30269-5/fulltext

Comment: In an experimental study, S. Lefere et al. investigated the efficacy of single and pan-PPAR agonists in the treatment of progressive steatohepatitis. The authors employed the CDAA-HFD (choline-deficient, amino acid-defined high-fat diet-induced) model, which induces severe inflammation and liver fibrosis. Mice were fed the CDAA-HFD for 12 weeks, and PPAR agonist treatment was administered during the last 6 weeks of diet feeding.

In this study, lanifibranor decreased serum triglyceride levels. The PPAR agonists were well tolerated, and no significant effects on body weight or adipose tissue weight were observed, while the liver-to-body weight ratio was lower in mice treated with lanifibranor.

Importantly, treatment with lanifibranor reversed steatohepatitis, as evidenced by highly significant reductions in the NAFLD activity score (NAS) as well as the subcomponent scoring of steatosis (validated by reduced hepatic triglyceride content), lobular inflammation and hepatocellular ballooning.

Lanifibranor ameliorated liver fibrosis, with significant reductions in collagen area, liver hydroxyproline, and a reduced expression of fibrogenic mediators.

30rd July 2020

Article: Physical activity intervention for non-diabetic patients with non-alcoholic fatty liver disease: a meta-analysis of randomized controlled trials.

Reviewed by: D. Beard

Authors: Wang ST, Zheng J, Peng HW, et al.

Published in: BMC Gastroenterol 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32164541/

Comment: Nowadays, dramatic changes in the lifestyle and diet of the global population are causing the prevalence of NAFLD increasing rapidly, in parallel with that of obesity and diabetes. Previous studies found an inverse relationship between physical activity and the risk of NAFLD. However, clinical trials examining the therapeutic benefit of physical activity in NAFLD have reported inconsistent results.

ST Wang et al. (Department of Epidemiology and Health Statistics, Fujian Medical University, Fuzhou, China) performed a comprehensive search for English and Chinese language publications on PubMed and China National Knowledge Infrastructure (CNKI) databases for their meta-analysis of 9 randomized controlled trials with a cumulative total of 951 participants.

Physical activity was found associated with small reductions in hepatic enzyme parameters, and significant small improvements in serum lipid parameters. Significant improvement was also found in intra-hepatic lipid content. Subgroup analysis suggested both aerobic exercise alone and resistance exercise alone can improve most liver function and longer period of exercise generally had better improvement effect.

These findings suggest that physical activity alone can only slightly improve hepatic enzyme levels, most serum lipid levels and intra-hepatic lipid content in non-diabetic patients with NAFLD.

22nd July 2020

Article: Human hepatic in vitro models reveal distinct anti-NASH potencies of PPAR agonists.

Reviewed by: D. Beard

Authors: Boeckmans J, Natale A, Rombaut M, et al.

Published in: Cell Biol Toxicol 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32613381/

Comment: In this study, J. Boeckmans et al. (Faculty of Medicine and Pharmacy, Vrije Universiteit, Brussels, Belgium) reproduced key NASH characteristics in vitro by exposing primary human hepatocytes, human skin stem cell-derived hepatic cells, HepaRG and HepG2 cell lines, as well as LX-2 hepatic stellate cells to multiple factors that play a role in the onset of NASH. These in vitro disease models showed intracellular lipid accumulation, secretion of inflammatory chemokines, induced ATP content, apoptosis, and increased pro-fibrotic gene expression.

These cell systems were then used by the authors to evaluate the anti-NASH properties of peroxisome proliferator-activated receptor agonists. They developed an in vitro scoring system in order to grade the anti-NASH potencies. Their results corroborate available clinical data and show the relevance of these in vitro models for the preclinical investigation of anti-NASH compounds.

22nd July 2020

Article: Awareness of Non-alcoholic Fatty Liver Disease Is Increasing but Remains Very Low in a Representative US Cohort.

Reviewed by: D. Beard

Authors: Singh A, Dhaliwal AS, Singh S, et al.

Published in: Dig Dis Sci 2020

Link: https://www.ncbi.nlm.nih.gov/pubmed/31187324

Comment: Low awareness can delay healthcare screening and prevention of NAFLD and its related complications. Therefore, low awareness of NAFLD among the general population is a matter of great concern. This is also important for resource allocation, and the creation and implementation of awareness programs.

A. Singh et al. (Cleveland Clinic Foundation, Cleveland, OH, USA) aimed to assess the awareness of suspected NAFLD and factors associated with being aware of having a liver disease in a large adult US sample population using the NHANES database.

This study highlights the critical findings that despite an increase in awareness of having a liver disease, especially among subjects with suspected NAFLD and hepatic steatosis index > 36, more than 95% of the adult US population with suspected NAFLD is still unaware of having any liver disease. Moreover, only 3–3.5% of the high-risk patients had awareness of having liver disease over the past decade. A significant increase in BMI, waist circumference, severe obesity, diabetes, MetS, and hypertriglyceridemia was noted among the participants, indicating the increase in risk factors for NAFLD.

This first and large study highlights the low awareness of having a liver disease among the representative US population, especially in subjects with suspected NAFLD and advanced fibrosis.

22nd July 2020

Article: Effects of sodium-glucose cotransporter 2 inhibitors on non-alcoholic fatty liver disease in patients with type 2 diabetes: A meta-analysis of randomized controlled trials.

Reviewed by: D. Beard

Authors: Xing B, Zhao Y, Dong B, et al.

Published in: J Diabetes Investig 2020

Link: https://www.ncbi.nlm.nih.gov/pubmed/32083798

Comment: Some studies showed that the effect of SGLT2 inhibitors on weight loss was useful for the alleviation of NAFLD and SGLT2 inhibitors can significantly reduce bodyweight in NAFLD patients. In addition, a recent cohort study suggested that the administration of SGLT2 inhibitors to patients with type 2 diabetes mellitus could improve serum alanine aminotransferase (ALT) levels in clinical practice. However, there are no specific statistics on the degree of reduction of ALT by SGLT2 inhibitors.

Therefore, B. Xing et al. (Department of Endocrine and Metabolic Diseases, Hospital of Qingdao, China) carried out a meta‐analysis on the effects of several common SGLT2 inhibitors on ALT, liver fat and bodyweight. Six studies including 309 participants were eligible for the meta‐analysis. The authors found that compared with other oral antidiabetic drugs, SGLT2 inhibitors can significantly decrease ALT (−11.05 IU/L). Bodyweight and visceral fat area were also reduced. As pointed out by B. Xing et al., the limitation of this meta-analysis is that the sample size of the included studies was small. Therefore, more large randomized controlled trials specified on NAFLD are required to evaluate these results.

24th June 2020

Article: The amount of liver fat predicts mortality and development of type 2 diabetes in non-alcoholic fatty liver disease.

Reviewed by: D. Beard

Authors: Nasr P, Fredrikson M, Ekstedt M, et al.

Published in: Liver Int 2020

Link: https://onlinelibrary.wiley.com/doi/full/10.1111/liv.14414

Comment: NAFLD is closely related to features of the metabolic syndrome including type 2 diabetes. P. Nasr et al. (Linköping University, Sweden) investigated the importance of the amount of liver fat on mortality and the risk of developing type 2 diabetes.

In 129 patients with biopsy proven NAFLD prospectively re-evaluated on two occasions, the severity of hepatic fat accumulation was able to predict both T2D development and the overall survival. Automated quantification of hepatic fat by stereological point counting (SPC) predicted these outcomes independently of adiposity, histological steatosis grade, and also of hepatic inflammation and fibrosis.

As stated in the accompanying editorial by Luca Valenti and Serena Pelusi (Milan, Italy), limitations of this study include the monocentric design, limited sample size, and lack of independent replication. For L. Valenti and S. Pelusi, these results “suggest that quantitative assessment of liver fat is superior to qualitative histological evaluation of steatosis and of the presence of NASH, which is currently the standard of diagnostic sub-classification of NAFLD, and may likely represent a useful prognostic marker for mortality and extra-hepatic complications of FLD.”

24th June 2020

Article: Correlation between serum 25-OH vitamin D expression and non-alcoholic fatty liver disease.

Reviewed by: D. Beard

Authors: Cai J, Zhang Z, Liu J, et al.

Published in: Exp Ther Med 2020

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027146/

Comment: J. Cai et al. (Department of Geriatric Medicine, Zhongshan Hospital, Xiamen, P.R. China) investigated changes in the level of serum 25-OH vitamin D [25-hydroxyvitamin D, 25(OH)D] in patients with NAFLD and the correlation between the severity of NAFLD and 25(OH)D. Their retrospective analysis was performed on 385 NAFLD patients and 347 healthy people.

The level of 25(OH)D in the NAFLD group was lower than that in control group. There was a significant negative correlation between 25(OH)D and the severity of patients in the NAFLD group. Lowly expressed in the serum of NAFLD patients, 25(OH)D has a significant negative correlation with the severity of NAFLD. This confirms previous results, and is of guiding significance for the prevention and treatment.

17th June 2020

Article: Cilofexor, a Nonsteroidal FXR Agonist, in Non-Cirrhotic Patients with Nonalcoholic Steatohepatitis: A Phase 2 Randomized Controlled Trial.

Reviewed by: D. Beard

Authors: Patel K, Harrison SA, Elkashab M, et al.

Published in: Hepatology 2020

Link: https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.31205

Comment: Cilofexor is a small molecule nonsteroidal agonist of farnesoid X receptor (FXR). K. Patel et al. (University of Toronto, Canada) evaluated the safety and efficacy of cilofexor in patients with NASH in a double-blind, placebo-controlled, phase 2 trial. 140 non-cirrhotic patients with NASH were randomized to receive cilofexor 100 mg, 30 mg, or placebo orally once daily for 24 weeks.

At week 24, patients receiving cilofexor 100 mg had a median relative decrease in MRI-PDFF of -22.7%, compared with an increase of 1.9% in those receiving placebo.

Serum gamma-glutamyltransferase, C4, and primary bile acids decreased significantly at week 24 in both cilofexor treatment groups, whereas significant changes in ELF and liver stiffness were not observed. Cilofexor was generally well tolerated. Moderate to severe pruritus was more common in patients receiving cilofexor 100 mg than in those receiving cilofexor 30 mg and placebo.

17th June 2020

Article: Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: Results from randomized phase III STELLAR trials.

Reviewed by: D. Beard

Authors: Harrison SA, Wong VW, Okanoue T, et al.

Published in: J Hepatol 2020

Link: https://www.journal-of-hepatology.eu/article/S0168-8278(20)30126-4/pdf

Comment: Apoptosis signal-regulating kinase 1 (ASK1) plays a key role in hepatocyte injury, inflammation, and fibrosis in nonalcoholic steatohepatitis (NASH). Selonsertib is an investigational selective inhibitor of ASK1.

In order to evaluate the safety and anti-fibrotic effect of selonsertib, Stephen A. Harrison et al. conducted two randomized, double-blind, placebo-controlled, phase 3 trials in patients with NASH and bridging fibrosis (F3, STELLAR-3 trial) or compensated cirrhosis (F4, STELLAR-4 trial). Patients were randomized to receive selonsertib 18 mg, selonsertib 6 mg, or placebo once daily for 48 weeks.

The primary efficacy endpoint was the proportion of patients with ≥1-stage improvement in fibrosis without worsening of NASH at week 48. Additional endpoints included changes in NITs, progression to cirrhosis (in STELLAR-3), and liver-related clinical events.

Neither trial met the primary efficacy endpoint. In STELLAR-3, fibrosis improvement without worsening of NASH was observed in 10%, 12% and 13% of patients in the selonsertib 18 mg, selonsertib 6 mg, and placebo groups, respectively. In STELLAR-4, the primary endpoint was achieved in 14%, 13%, and 13% of patients, respectively.

Selonsertib had no significant effect on liver biochemistry, NITs, progression to cirrhosis, or adjudicated clinical events. Forty-eight weeks of selonsertib monotherapy had no anti-fibrotic effect in NASH patients with stage F3 and F4 fibrosis – those most in need of treatment. Nonetheless, important lessons were learned from this and similar trials about the extent of confidence needed to progress to a phase 3 program, as we learn more about the natural history of this enigmatic disease.

10th June 2020

Article: Non-Alcoholic Fatty Liver Disease and Vascular Disease.

Reviewed by: D. Beard

Authors: Forlano R, Mullish BH, Nathwani R, et al.

Published in: Curr Vasc Pharmacol 2020

Link: https://www.ncbi.nlm.nih.gov/pubmed/32188385

Comment: Non-Alcoholic Fatty Liver Disease (NAFLD) represents an increasing cause of liver disease worldwide. However, notably, the primary cause of morbidity and mortality in patients with NAFLD is cardiovascular disease (CVD), with fibrosis stage being the strongest disease-specific predictor. Within the next few years, NAFLD will contribute considerably to the overall CVD burden.

In their review, R. Forlano et al. (Imperial College London, Liver Unit/Division of Integrative Systems Medicine and Digestive Disease, Department of Surgery and Cancer. United Kingdom) discuss the role of NAFLD as an emerging cardiovascular risk factor. Pathological drivers of vascular damage in patients with NAFLD are reviewed, as well as the impact of NAFLD on the development, severity and the progression cardiovascular disease.

10th June 2020

Article: The risk of atrial fibrillation in patients with non-alcoholic fatty liver disease and a high hepatic fibrosis index.

Reviewed by: D. Beard

Authors: Park HE, Lee H, Choi SY, et al.

Published in: Sci Rep 2020

Link: https://www.nature.com/articles/s41598-020-61750-4

Comment: Epidemiological studies focusing on the association between liver disease and atrial fibrillation show inconsistent findings. Patients with liver disease have a higher atrial fibrillation risk. A recent meta-analysis by Karn Wijarnpreecha et al. (Department of Internal Medicine, Bassett Medical Centre, Cooperstown, NY, USA), published in 2017, showed that the risk of atrial fibrillation in patients with NAFLD was significantly higher than subjects without NAFLD with the pooled risks ratio of 2.06 (95% confidence interval, 1.10–3.85). However, it is unknown whether the liver fibrosis index can predict atrial fibrillation risk.

The medical records of a healthy population undergoing routine health examinations at Healthcare System Gangnam Centre, Seoul National University Hospital, were reviewed retrospectively. After excluding subjects with a history of liver disease and known cardiovascular disease, 74,946 subjects with non-alcoholic fatty liver disease (NAFLD) were evaluated.

The fibrosis 4 index (FIB 4) showed significant correlations with atrial fibrillation (adjusted with cardiometabolic risk factors OR 2.255 and 95% CI 1.744-2.915, p = 0.000). The non-invasive determination of liver fibrosis indices can have clinical implications on the early identification of NAFLD in patients at risk for AF.

27th May 2020

Article: Association of serum vitamin D level and nonalcoholic fatty liver disease: a meta-analysis.

Reviewed by: D. Beard

Authors: Liu T, Xu L, Chen FH, et al.

Published in: Eur J Gastroenterol Hepatol 2020

Link: https://pubmed.ncbi.nlm.nih.gov/31895886/?from_term=Association+of+serum+vitamin+D+level+and+nonalcoholic+fatty+liver+disease%3A+a+meta-analysis&from_pos=2

Comment: T. Liu et al. aimed to explore the potential link of serum vitamin D level with NAFLD. Of the 309 initially retrieved studies, 15 studies of high quality involving a total of 20 096 participants (including 7803 NAFLD patients) were included in this meta-analysis.

Meta-analysis of continuous data indicated that NAFLD patients had lower levels of 25-hydroxyvitamin D compared with the non-NAFLD subjects. Serum vitamin D level is negatively associated with NAFLD. Patients with hypovitaminosis D might benefit from extra supplement of vitamin D against the risk of NAFLD

27th May 2020

Article: Evaluation of Dietary Approaches for the Treatment of Non-Alcoholic Fatty Liver Disease: A Systematic Review.

Reviewed by: D. Beard

Authors: Saeed N, Nadeau B, Shannon C, et al.

Published in: Nutrients 2019

Link: https://www.mdpi.com/2072-6643/11/12/3064

Comment: There is a paucity of high-quality data that has evaluated the isolated impact of different diets on NAFLD and NASH specifically. This is in large part due to the logistical challenges of conducting randomized controlled trials focused on diets. The available data clearly highlight the correlation with intake of high-fructose corn syrup and red and processed meats, as well as diets high in saturated fat.

As an alternative to content modification, other studies have focused on total caloric restriction, with an estimated reduction in caloric intake by ≥30%, or by 750–1000 Kcal/day, linked with improved insulin resistance and hepatic steatosis. Overall, there remains a lack of consensus regarding the most effective diet for the treatment or prevention of NAFLD.

In their systematic review, Saeed et al. evaluate the effectiveness of different nutritional patterns on hepatic endpoints of interest, including reduction of hepatic steatosis and fibrosis, weight loss, and metabolic endpoints.

20th May 2020

Article: Vitamin E is an effective treatment for nonalcoholic steatohepatitis in HIV mono-infected patients.

Reviewed by: D. Beard

Authors: Sebastiani G, Saeed S, Lebouche B, et al.

Published in: AIDS. 2020

Link: https://journals.lww.com/aidsonline/Abstract/2020/02010/Vitamin_E_is_an_effective_treatment_for.9.aspx

Comment: Liver disease is common among patients infected with HIV. The proportion of deaths caused by liver-related aetiologies has increased between 8 to 10-fold in the post-antiretroviral therapy (ART) era while AIDS-related mortality has fallen more than 90-fold.

NAFLD is an important contributor to this trend. Higher rates of the disease are reported in HIV-infected patients, ranging from 7.3% to 57.1%. This is likely due to both high frequency of metabolic conditions underlying the pathogenesis of NASH and ART-related hepatotoxicity.

Despite the disease burden, there are no proven treatments to reduce HIV-associated NASH. Vitamin E treatment seems safe and leads to rapid and sustained normalization of Alanine aminotransferase and reduction of hepatic steatosis in a significant number of HIV mono-infected patients with a non-invasive diagnosis of NASH.

20th May 2020

Article: Thyromimetics as emerging therapeutic agents for nonalcoholic steatohepatitis: rationale for the development of resmetirom (MGL-3196).

Reviewed by: D. Beard

Authors: Alkhouri N.

Published in: Expert Opin Investig Drugs. 2020

Link: https://www.tandfonline.com/doi/full/10.1080/13543784.2020.1708899

Comment: Hypothyroidism has been linked to certain elements of the metabolic syndrome such as obesity and dyslipidemia which may explain its association with NAFLD. The pathogenesis of NAFLD might be partly attributed to a state of relative intra-hepatic hypothyroidism, a condition of decreased liver thyroid hormone levels. Although the systemic levels of thyroid hormones may stay within the normal range, the intracellular signaling machinery consisting of transporters, deiodinases and receptors are affected in patients with NAFLD.

Therefore, selectivity for a thyromimetic at the predominant liver thyroid hormone receptor, has the potential of providing the metabolic benefits of thyroid hormone and at the same time avoiding unwanted systemic actions. Other pharmacologic strategies to target the thyroid-liver axis include the use of less iodinated versions of the thyroid hormone which has profound effects on lipid metabolism and insulin sensitivity in hepatocytes, and the modulation of deiodinases that can inactivate thyroid hormones.

6th May 2020

Article: Treatment of nonalcoholic fatty liver disease: from adult trials to perspectives in the management of children and adolescents.

Reviewed by: D. Beard

Authors: Doulberis M, Polyzos SA, Papaefthymiou A, et al.

Published in: Expert Opin Pharmacother 2020

Link: https://www.tandfonline.com/doi/full/10.1080/14656566.2019.1702967

Comment: NAFLD is considered the most predominant form of chronic liver disease in childhood/adolescence and its prevalence ranges from 7.6% to 34.2%. Since longitudinal studies of NAFLD/NASH in pediatric populations are mostly lacking, its management is extrapolated from adult studies. Beyond lifestyle modifications, the cornerstone of pediatric NAFLD treatment, numerous medications and supplements have been introduced for the management of pediatric NAFLD.

In clinical practice, diabetologists should consider NAFLD in patients with T2DM, a disease with high NAFLD prevalence and higher rates of NASH than the general population [7]. Patients with biopsy-proven NASH and/or significant fibrosis currently qualify for pharmacotherapy. Given the variety of pharmacological agents under investigation, the therapeutic future of NAFLD seems to be promising.

6th May 2020

Article: Diet quality and its association with nonalcoholic fatty liver disease and all-cause and cause-specific mortality.

Reviewed by: D. Beard

Authors: Yoo ER, Kim D, Vazquez-Montesino LM, et al.

Published in: Liver Int 2020

Link: https://onlinelibrary.wiley.com/doi/abs/10.1111/liv.14374

Comment: Healthy diet has been recommended for NAFLD, although it is not clear whether improving diet quality can prevent mortality. ER Yoo et al. aim to assess the impact of quality of diet on NAFLD and mortality in subjects with and without NAFLD.

High diet quality was inversely associated with NAFLD and was positively associated with a lower risk for cancer-related and all-cause mortality in subjects without NAFLD. Primary prevention against NAFLD with high diet quality in those without the condition may be the ideal way to reduce all-cause mortality in subjects without NAFLD and curb the rising incidence of NAFLD.

29th April 2020

Article: The molecular basis for current targets of NASH therapies.

Reviewed by: D. Beard

Authors: Qureshi K, Neuschwander-Tetri BA.

Published in: Expert Opin Investig Drugs. 2020

Link: https://www.tandfonline.com/doi/abs/10.1080/13543784.2020.1703949?journalCode=ieid20

Comment: Metabolic substrate overload, insulin resistance, lipotoxicity, endoplasmic reticulum stress, inflammasome activation, inflammation, hepatocyte death, and fibrogenesis represent a potential target area of therapy and many are now being evaluated in preclinical studies as well as phase 1, 2, and 3 clinical trials.

Like patients with other complex diseases, patients with NASH likely arrive at this histologic phenotype for a variety of genetic, epigenetic, behavioral and environmental reasons that probably differ among patients. The implication of this complexity and heterogeneity is that no single therapy will likely work for all patients.

29th April 2020

Article: Association between non-alcoholic fatty liver disease and risk of new-onset atrial fibrillation in healthy adults.

Reviewed by: C. D. Byrne

Authors: Roh JH, Lee JH, Lee H, et al.

Published in: Liver Int. 2020

Link: https://onlinelibrary.wiley.com/doi/abs/10.1111/liv.14236

Comment: Previous studies demonstrated conflicting results regarding the association between non-alcoholic fatty liver disease (NAFLD) and atrial fibrillation (AF). The statistical power was not sufficient because of modest sample sizes of these studies. We analysed a large population-based cohort to evaluate the association between NAFLD and AF. The authors evaluated 334 280 healthy individuals without comorbidities who underwent National Health check-ups in South Korea from 2009 to 2014. NAFLD was defined by a surrogate marker, the fatty liver index (FLI).

The association between FLI and AF incidence was analysed using multivariate Cox proportional hazards regression models. Adjusted hazard ratios (HRs) indicated that a higher FLI was independently associated with an increased risk for AF (HR between Q4 and Q1, 1.35; 95% confidence interval [CI], 1.11-1.63; P = .002). After further adjustment for the interim events (diabetes, hypertension, heart failure and myocardial infarction), this association remained statistically significant (HR between Q4 and Q1, 1.55; 95% CI, 1.19-2.03; P = .001). In conclusion NAFLD, assessed by FLI, was independently associated with increased risk for AF in healthy Korean population. Moreover, NAFLD itself predisposes to AF independently of the interim events.

24th April 2020

Article: A cross-sectional study of the public health response to non-alcoholic fatty liver disease in Europe

Reviewed by: D. Beard

Authors: Lazarus JV, Ekstedt M, Marchesini G, et al.

Published in: J Hepatol 2020

Link: https://www.journal-of-hepatology.eu/article/S0168-8278(19)30521-5/fulltext

Comment: In 2018 and 2019, NAFLD experts in 29 European countries completed an English-language survey on policies, guidelines, awareness, monitoring, diagnosis and clinical assessment in their country. The data were compiled, quality checked against existing official documents and reported descriptively.

The authors found that a comprehensive public health response to NAFLD is lacking in the surveyed European countries. This includes policy in the form of a strategy, clinical guidelines, awareness campaigns, civil society involvement, and health systems organisation, including registries.

24th April 2020

Article: Increased risk of low bone mineral density in patients with non-alcoholic fatty liver disease: a cohort study.

Reviewed by: C. D. Byrne

Authors: Shen Z, et al.

Published in: Eur J Endocrinol. 2020

Link: https://eje.bioscientifica.com/view/journals/eje/182/2/EJE-19-0699.xml

Comment: Non-alcoholic fatty liver disease (NAFLD) has been suggested to be a risk factor associated with low BMD (bone mineral density) in several cross-sectional studies. The present longitudinal cohort study aims to explore the effect of NAFLD and its severity on low BMD. Between January 2013 and August 2018, individuals who participated in annual comprehensive health examinations were included.

BMD was presented using dual-energy X-ray absorptiometry (DXA). These subjects were diagnosed with fatty liver by ultrasound detection. A total of 1720 subjects were included (1064 subjects with normal BMD and 656 subjects with low BMD) at baseline. NAFLD and its severity were independently associated with an increased incidence of low BMD. Obesity and female sex are risk factors associated with low BMD. These findings indicate NAFLD can be a significant contributor to low BMD, requiring further studies to elucidate the potential mechanisms.

15th April 2020

Article: Diagnostic Accuracy of Shear Wave Elastography as a Non-invasive Biomarker of High-Risk Non-alcoholic Steatohepatitis in Patients with Non-alcoholic Fatty Liver Disease.

Reviewed by: D. Beard

Authors: Ozturk A, et al.

Published in: Ultrasound Med Biol. 2020

Link: https://www.umbjournal.org/article/S0301-5629(19)31640-0/fulltext

Comment: In this study, A. Ozturk et al. (Center for Ultrasound Research & Translation, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA) evaluated the diagnostic accuracy of shear wave elastography for differentiating high-risk NASH from non-alcoholic fatty liver and low-risk NASH.

One hundred sixteen adult patients underwent liver biopsy for the evaluation of NAFLD. The area under the receiver operating characteristic curve of shear wave elastography for high-risk NASH diagnosis was 0.73 (95% confidence interval: 0.61-0.84, p <0.001). The optimal stiffness cut-off value for high-risk NASH diagnosis was calculated as 8.4 kPa (1.67 m/s), with a sensitivity of 77% and specificity of 66%.

15th April 2020

Article: Association between non-alcoholic fatty liver disease and coronary calcification depending on sex and obesity.

Reviewed by: C. D. Byrne

Authors: Kim SH, et al.

Published in: Sci Rep. 2020

Link: https://www.nature.com/articles/s41598-020-57894-y

Comment: Non-alcoholic fatty liver disease (NAFLD) is considered a hepatic manifestation of metabolic syndrome and is associated with cardiovascular outcomes. The authors investigated whether NAFLD was associated with coronary artery calcification (CAC) in participants without a previous history of cardiovascular disease and whether this association differed according to sex and obesity status after adjustment for other atherosclerosis risk factors, alcohol intake, and liver enzyme levels.

Among 67,441 participants, data from 8,705 participants who underwent a fatty liver status and CAC assessment during routine health screening were analysed. CAC scores were calculated using computed tomography. NAFLD was diagnosed in patients with evidence of liver steatosis on ultrasonography. Multivariate analysis showed a significant association between NAFLD and CAC in non-obese participants (odds ratio, 1.24 [95% confidence interval, 1.01-1.53]), whereas NAFLD and CAC were not associated in obese participants.

8th April 2020

Article: Microbiome as a therapeutic target in alcohol-related liver disease.

Reviewed by: D. Beard

Authors: Sarin SK, Pande A, Schnabl B.

Published in: J Hepatol. 2019

Link: https://www.journal-of-hepatology.eu/article/S0168-8278(18)32503-0/fulltext

Comment: Alcohol-related liver disease is associated with significant changes in gut microbial composition. Treatment approaches on the gut microbiota, such as diet, probiotics, antibiotics and faecal microbial transplantation can restore intestinal homeostasis and improve alcohol-related liver disease (1).

Dysbiosis of the intestinal microbiota has been associated with NAFLD. In this randomized trial of patients with NAFLD by E. Scorletti et al., administration of a symbiotic combination (probiotic and prebiotic) altered faecal microbiomes but did not reduce liver fat content or markers of liver fibrosis (2).

1. Sarin SK, Pande A, Schnabl B. Microbiome as a therapeutic target in alcohol-related liver disease. J Hepatol 2019;70:260-272.
2. Scorletti E, Afolabi PR, Miles EA, et al. Synbiotic Alters Fecal Microbiomes, but not Liver Fat or Fibrosis, in a Randomized Trial of Patients With Non-alcoholic Fatty Liver Disease. Gastroenterology 2020.

8th April 2020

Article: The association between nonalcoholic fatty liver disease and esophageal, stomach, or colorectal cancer: National population-based cohort study.

Reviewed by: C. D. Byrne

Authors: Lee JM, Park YM, Yun JS, et al.

Published in: PLoS One. 2020

Link: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226351

Comment: The authors investigated the association between nonalcoholic fatty liver disease (NAFLD) and gastrointestinal tract cancer in the general population. Retrospective data on individuals aged ≥20 years who received healthcare checkups from January 1, 2009 to December 31, 2009 were analyzed using the National Health Insurance Database in Korea. NAFLD was defined based on the fatty liver index (FLI ≥60).

The primary outcome was newly diagnosed esophageal, stomach, or colorectal cancer using ICD-10 codes during follow-up until 31 December 2017. The results show that NAFLD defined using FLI was a good predictive indicator for GI tract malignancy and all-cause mortality in the general population. The authors suggest that subjects with NAFLD are needed for active surveillance of esophageal, stomach, and colorectal cancers.

1st April 2020

Article: Causes of mortality in Non-Alcoholic Fatty Liver Disease (NAFLD) and Alcohol related Fatty Liver Disease (AFLD).

Reviewed by: C. D. Byrne

Authors: Johnston MP, Patel J, Byrne CD.

Published in: Current Pharmaceutical Design. 2020

Link: http://www.eurekaselect.com/178691/article

Comment: Non-alcoholic fatty liver disease (NAFLD) and alcohol related fatty liver disease (AFLD) both represent a spectrum of liver disease severity from hepatic steatosis to fibrosis and cirrhosis. It is often not possible to distinguish between NAFLD and AFLD on examination of liver histology, consequently, differentiation between NAFLD and AFLD is heavily reliant on a history of alcohol consumption. In NAFLD and AFLD, the key causes of increased liver-related mortality are advanced liver fibrosis and cirrhosis leading to complications such as hepatocellular carcinoma and decompensated cirrhosis.

NAFLD and AFLD are also associated with an increased risk of all-cause mortality including an increased risk of extra-hepatic malignancy. Both NAFLD and AFLD are associated with extra-hepatic risk factors and complications such as metabolic syndrome encompassing obesity, hypertension, type 2 diabetes mellitus, and chronic kidney disease. AFLD is associated with hypertension and cardiovascular disease as well as other organ damage. This narrative review discusses the associations, risk factors and diagnostic biomarkers linking NAFLD and AFLD with increased mortality.

1st April 2020

Article: Fibroblast growth factor signalling in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis: Paving the way to hepatocellular carcinoma

Reviewed by: By D. Beard

Authors: Ocker M.

Published in: World J Gastroenterol. 2020

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969880/

Comment: Fibroblast growth factors and their receptors play an important role in maintaining metabolic homeostasis also in the liver and disorders in signalling what have been identified to contribute to those pathophysiologic conditions leading to hepatic lipid accumulation and chronic inflammation.

While specific and well tolerated inhibitors of fibroblast growth factor receptor activity are currently developed for (non-liver) cancer therapy, treatment of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis is still limited. Fibroblast growth factor-mimicking or restoring approaches have recently evolved as a novel therapeutic option, reviewed by Matthias Ocker (Department of Gastroenterology, Charité University Medicine Berlin).

Specific Fibroblast growth factor receptor 4 inhibitors are currently tested in clinical trials in HCC. The positive preclinical results are reflected in encouraging early clinical data. Yet, the overall efficacy of these compounds needs to be carefully investigated compared to current multi-kinase inhibitors and the emerging immune checkpoint inhibitors.

24th March 2020

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

Link: https://link.springer.com/article/10.1007%2Fs40520-020-01487-2

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.

24th March 2020

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

Link: https://www.metabolismjournal.com/article/S0026-0495(20)30034-2/fulltext

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.

10th March 2020

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

Link: https://onlinelibrary.wiley.com/doi/full/10.1111/apt.15660

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.

10th March 2020

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

Link: https://www.cambridge.org/core/journals/british-journal-of-nutrition/article/flaxseed-oil-in-the-context-of-a-weight-loss-program-ameliorates-fatty-liver-grade-in-patients-with-nonalcoholic-fatty-liver-disease-a-randomized-doubleblind-controlled-trial/2929E806A0013110ECC12CBD551BF048

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.

3rd March 2020

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.

Link: https://www.ahajournals.org/doi/full/10.1161/JAHA.119.014279?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed

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.

3rd March 2020

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.

Link: https://www.mdpi.com/1660-4601/16/17/3011

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.

25th Feb 2020

Article: Applying Non-Invasive Fibrosis Measurements in NAFLD/NASH: Progress to Date.

Authors: Albhaisi S, Sanyal AJ.

Published in: Pharmaceutical Medicine, 2019

Link: https://link.springer.com/article/10.1007%2Fs40290-019-00305-z

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.

18th Feb 2020

Article: Diet, Gut Microbiota and NAFLD

Authors: Quesada-Vazquez S, Aragones G, Del Bas JM, et al.

Published in: Cells 2020

Link: https://www.mdpi.com/2073-4409/9/1/176

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.

11th Feb 2020

Article: HbA1c at normal-range levels and NAFLD

Authors: Chen C, Zhu Z, Mao Y, et al.

Published in: Biosci Rep. 2020

Link: https://portlandpress.com/bioscirep/article-lookup/doi/10.1042/BSR20193996

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.

4th Feb 2020

Article: Anti-NASH Drug Development Hitches a Lift on PPAR Agonism.

Authors: Boeckmans J, Natale A, Rombaut M, et al.

Published in: Cells. 2019

Link: https://www.mdpi.com/2073-4409/9/1/37

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).

29th Jan 2020

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

Link: https://www.mdpi.com/1660-4601/16/15/2791

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.

29th Jan 2020

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.

Link: https://www.mdpi.com/2072-6643/11/12/3064

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.

22nd Jan 2020

Article: Intrahepatic bacterial metataxonomic signature in non-alcoholic fatty liver disease.

Authors: Sookoian S, Salatino A, Castano GO, et al.

Published in: Gut 2020

Link: https://gut.bmj.com/content/early/2020/01/02/gutjnl-2019-318811.long

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.

15th Jan 2020

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.

Link: https://www.sciencedirect.com/science/article/abs/pii/S0306987719312083

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.

10th Jan 2020

Article: Small but mighty: Platelets in NASH and other chronic liver diseases.

Authors: Hilscher MB, Shah VH.

Published in: Hepatology 2020

Link: https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.31101

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.

7th Jan 2020

Article: Unmasking a Stealth Killer: The Need for Increased Awareness of NASH.

Authors: Sherif ZA.

Published in: Dig Dis Sci 2019.

Link: https://link.springer.com/article/10.1007%2Fs10620-019-05832-y

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.

5th Dec 2019

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.

Link: https://www.ncbi.nlm.nih.gov/pubmed/30528647

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.

30th Nov 2019

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

Link: https://www.ncbi.nlm.nih.gov/pubmed/31431413

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.

25th Nov 2019

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.

Link: https://www.journal-of-hepatology.eu/article/S0618-8278(19)30603-6/pdf

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.

23th Nov 2019

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

Link: https://www.ncbi.nlm.nih.gov/pubmed/31393374

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.

18th Nov 2019

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.

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539803/

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.

15th Nov 2019

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.

Link: http://www.ncbi.nlm.nih.gov/pubmed/30259536

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.

12th Nov 2019

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.

Link: http://www.ncbi.nlm.nih.gov/pubmed/30575815

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.

8th Nov 2019

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.

Link: http://www.ncbi.nlm.nih.gov/pubmed/26338827

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.

5th Nov 2019

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.

Link: https://www.ncbi.nlm.nih.gov/pubmed/31489312

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.

1st Nov 2019

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.

Link: https://www.ncbi.nlm.nih.gov/pubmed/31489312

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.

25th October 2019

Article: Pediatric Fatty Liver Disease

Authors: Jain A

Published in: Mo Med 2019;116:123-128.

Link: https://www.ncbi.nlm.nih.gov/pubmed/31040498

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

20th October 2019

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.

Link: https://www.ncbi.nlm.nih.gov/pubmed/30851175

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).

15th October 2019

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.

Link: https://www.ncbi.nlm.nih.gov/pubmed/31011515

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.

9th October 2019

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.

Link: https://www.ncbi.nlm.nih.gov/pubmed/31328300

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.

5th October 2019

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.

Link: https://www.ncbi.nlm.nih.gov/pubmed/31271665

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.

4th October 2019

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.

Link: https://www.ncbi.nlm.nih.gov/pubmed/30607807

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.

2nd October 2019

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

Link: https://www.ncbi.nlm.nih.gov/pubmed/31104631

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.

30 September 2019

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.

Link: https://www.sciencedirect.com/science/article/pii/S0168827819301278

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.

25 September 2019

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.

Link: https://www.ncbi.nlm.nih.gov/pubmed/30936549

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.

20 September 2019

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

Link: https://www.ncbi.nlm.nih.gov/pubmed/30897538

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.

10 September 2019

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

Link: https://care.diabetesjournals.org/content/42/8/1481

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.

10 September 2019

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.

Link: https://www.ncbi.nlm.nih.gov/pubmed/30572788

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.

10 September 2019

Article: Nutritional Intake and the Risk for Non-Alcoholic Fatty Liver Disease (NAFLD) .

Authors: Schattenberg JM, Bergheim I .

Published in: Nutrients 2019.

Link: https://www.mdpi.com/2072-6643/11/3/588/htm

Comment: The editorial accompanying a special issue of nutrition in NAFLD, highlights the relevance of the topic and open issues for future studies.

15 August 2019

Article: Pharmacological treatments of the “Fibrotic-NASH”: Towards a delivery on time?

Authors: Gual P

Published in: Clin Res Hepatol Gastroenterol 2019.

Link:  https://www.ncbi.nlm.nih.gov/pubmed/31300372

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.

8 August 2019

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.

Link:  https://www.journal-of-hepatology.eu/article/S0168-8278(19)30404-0/fulltext

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.

20 July 2019

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.

Link: https://doi.org/10.1016/j.clinre.2019.04.005

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.

10 July 2019

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

Link: https://www.jhep-reports.eu/article/S2589-5559(19)30003-5/fulltext

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.

01 July 2019

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)

Link: https://diabetes.diabetesjournals.org/content/68/Supplement_1/223-OR 

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.

22 June 2019

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.

Link: https://www.frontiersin.org/articles/10.3389/fimmu.2019.01192/full

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.

20 May 2019

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].

Link: https://aasldpubs.onlinelibrary.wiley.com
/doi/abs/10.1002/hep.30429

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).

16 April 2019

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.

Link: https://www.thelancet.com/journals/langas
/article/PIIS2468-1253(18)30077-3/fulltext

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.