From the Literature

5th May 2021

Article: Comparative analysis of different guidelines

Reviewed by: G. Bozet, MD

Authors: LAndo Y, Jou JH

Published in:  Clin Liver Dis (Hoboken) 2021

Link: https://pubmed.ncbi.nlm.nih.gov/33552482/

Comment: In their review, Y. Ando and J. H. Jou (Oregon Health & Science University Hospital, Portland, Oregon, USA) summarise updated guideline and guidance recommendations for the management of adult NAFLD. They highlight key difference between US, Asian, and European recommendations; and provide key updates.

– American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association (Hepatology 2012;55:2005‐2023).
– AASLD: Hepatology 2018;67:328‐357.
– EASL‐EASD‐EASO: J Hepatol 2016;64:1388‐1402.
– Asia‐Pacific: J Gastroenterol Hepatol 2018;33:70‐85 & J Gastroenterol Hepatol 2018;33:86‐98.

5th May 2021

Article: Is Europe ready to meet the challenge of fatty liver disease?

Reviewed by: D. Beard

Authors: Lazarus JV, Palayew A, Carrieri P, et al.

Published in:  JHEP Rep 2021

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937562/

Comment: NAFLD is closely associated with obesity, metabolic syndrome, and diabetes. NAFLD can be optimally managed through a multidisciplinary patient-centred approach. National preparedness to address NAFLD is essential to allow for effective public health measures.

NAFLD preparedness means having adequate policies and civil society engagement, guidelines, epidemiology, and care management.

According to this study by JV Lazarus et al., NAFLD preparedness was found to be deficient in all 29 countries studied, with great variation among the countries. The index highlights key gaps in policies, civil society engagement, guidelines, epidemiology, and care management. These findings can initiate critical discussions as countries seek to improve their state of preparedness to address the NAFLD pandemic.

3rd May 2021

Article: Changing trends of liver transplantation and mortality from NAFLD

Reviewed by: G. Bozet, MD

Authors: Majumdar A, Tsochatzis EA

Published in:  Metabolism 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32531295/

Comment: This review by A. Majumdar (Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, Sydney, and University of Sydney, Australia) and E. Tsochatzis (UCL Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, and Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK) outlines the current epidemiology, natural history and outcomes of NAFLD with a focus on pre- and post-liver transplant settings.

NAFLD poses several challenges in the peri-transplant setting including the management of multiple metabolic co-morbidities, post-transplant obesity and cardiovascular risk. However, post-liver transplantation outcomes in well-selected NAFLD patients appear similar to non-NAFLD indications, including in the setting of hepatocellular carcinoma.

3rd May 2021

Article: Premenopausal NAFLD women: testosterone is associated with NASH and fibrosis

Reviewed by: D. Beard

Authors: Sarkar MA, Suzuki A, Abdelmalek MF, et al

Published in:  Clin Gastroenterol Hepatol 2020

Link: https://pubmed.ncbi.nlm.nih.gov/33010412/

Comment: The association of free testosterone with NASH was determined in pre-menopausal women with biopsy-confirmed NAFLD.

Interaction testing was performed for age and free testosterone given decline in testosterone with age, and association of aging with NASH.

In this study, higher free testosterone levels were associated with NAFLD severity in younger women. In young women with NAFLD, higher testosterone levels conferred a 2-fold higher risk of NASH and NASH fibrosis, and increased risk of abdominal adiposity.

Free testosterone was additionally associated with abdominal adiposity among all pre-menopausal women.

Testosterone may represent an early risk factor for NASH progression in young women, prior to their onset of more dominant, age-related metabolic risk factors.

28th April 2021

Article: Prevalence of steatosis and fibrosis in young adults in the UK

Reviewed by: G. Bozet, MD

Authors: Abeysekera KWM, Fernandes GS, Hammerton G, et al.

Published in:  Lancet Gastroenterol Hepatol 2020

Link: https://pubmed.ncbi.nlm.nih.gov/31954687/

Comment: The study by KWM Abeysekera et al. (Population Health Sciences, Bristol Medical School, University of Bristol, and University Hospitals Bristol NHS Foundation Trust, Bristol, UK) is the first to determine the prevalence of NAFLD in young adults with use of transient electrography, in an age group in which NAFLD burden is poorly characterized.

The group of young adults from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort has already been assessed for NAFLD between the ages of 17 and 18 years, which acts as a comparator.

The authors identified that around 20% of young adults had steatosis of grade S1 or higher around the age of 24 years. One in 40 also had evidence of liver fibrosis.

28th April 2021

Article: NAFLD patients: cost effectiveness of different strategies for detecting cirrhosis

Reviewed by: D. Beard

Authors: Stahmeyer JT, Hemmerling M, Burger B, et al.

Published in:  Z Gastroenterol 2021

Link: https://pubmed.ncbi.nlm.nih.gov/33757144/

Comment: JT Stahmeyer et al. aimed to assess administrative incidence and prevalence, or the number of patients diagnosed with NAFLD in the period from 2008 to 2018 in the German population. Analyses were based on administrative data of a large statutory health insurance fund.

In 2018, 4.66 % of insured persons had a NAFLD diagnosis, 0.87 % were diagnosed first-time. Diagnoses of NASH were comparatively rare. Data show an uptake of NAFLD diagnoses over time.

The number of incident cases per year has hardly changed. Patients with diseases of the metabolic syndrome had an increased chance of being diagnosed with NAFLD.

NAFLD is frequently diagnosed in everyday medical practice, although data from population-based studies suggest an even higher prevalence.

25th April 2021

Article: NAFLD patients: cost effectiveness of different strategies for detecting cirrhosis

Reviewed by: G. Bozet, MD

Authors: Vilar-Gomez E, Lou Z, Kong N, et al.

Published in:  Clin Gastroenterol Hepatol 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32289535/

Comment: Several strategies are available for detecting cirrhosis in patients with NAFLD, but their cost effectiveness is not clear. E. Vilar-Gomez et al. (Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA) developed a decision model to quantify the accuracy and costs of 9 single or combination strategies, including FIB-4, vibration-controlled transient elastography, and magnetic resonance elastography, and liver biopsy, for the detection of cirrhosis in patients with NAFLD. This cost-effectiveness analysis is based on the US health care system.

These authors found that results from FIB-4, followed by either VCTE, MRE, or liver biopsy, detect cirrhosis in patients with NAFLD with a high level of accuracy and low cost.

25th April 2021

Article: Randomized Control Trial: Fecal microbiota transplantation in NAFLD patients

Reviewed by: D. Beard

Authors: Craven L, Rahman A, Nair Parvathy S, et al.

Published in:  Am J Gastroenterol 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32618656/

Comment: The gut microbiome plays a role in metabolism and maintaining gut barrier integrity, and fecal microbiota transplantation can be used to alter the gut microbiome.

The authors hypothesized that a fecal microbiota transplantation from a thin and healthy donor given to patients with NAFLD would improve insulin resistance, hepatic proton density fat fraction, which is a fundamental property of tissue that measures hepatic triglyceride concentration, and intestinal permeability.

This study demonstrated that fecal microbiota transplantation from lean healthy donors failed to improve insulin sensitivity, the primary outcome. This intervention also did not improve the percentage of fat in the liver on MRI at 6 months, but did have the potential to reduce small intestinal permeability in patients with NAFLD.

19th April 2021

Article: From NASH to hepatocellular carcinoma

Reviewed by: G. Bozet, MD

Authors: Peiseler M, Tacke F.

Published in:  Cancers (Basel) 2021

Link: https://pubmed.ncbi.nlm.nih.gov/33578800/

Comment: End-stage NAFLD with liver cancer has an abysmal prognosis and effective medical therapies are lacking, therefore a better understanding of the disease mechanisms will ultimately help to improve patients’ care. The pathogenesis of NAFLD and transition to HCC is multifactorial, yet inflammation is considered a key element. It is now established that inflammatory processes drive fibrosis and disease progression in NASH. They prepare the ground for hepatocellular carcinoma development, while immunity also exerts antitumour activities. Interestingly, novel techniques are available to better understand inflammation.

In their review, M. Peiseler and F. Tacke, one of the PanNASH editors (University Medicine Berlin, Germany), highlight some of the emerging paradigms, and summarise recent advances in preclinical and clinical studies aimed at modulating the inflammatory cascade.

As stated by the authors in their conclusion, “clinically, more personalised diagnostics based on microbiome, tumour immune landscape and liver immune cell heterogeneity, will help to identify and tailor therapies for different patient cohorts.”

19th April 2021

Article: Perils of the western diet

Reviewed by: D. Beard

Authors: Kim JY, He F, Karin M.

Published in:  Cancers (Basel) 2021

Link: https://pubmed.ncbi.nlm.nih.gov/33806428/

Comment: NAFLD and hepatocellular carcinoma are strongly associated with obesity, insulin resistance and the metabolic syndrome and directly attributed to changes in lifestyle, especially dietary patterns and sedentary behaviour. Western diet and cholesterol contained in the diet exacerbate hepatic accumulation of free cholesterol, resulting in the toxic effects on the liver.

In their review, JY Kim et al. (University of California San Diego, USA) discuss the metabolic processes that control the progression from NAFLD to NASH and from NASH to HCC. They note the importance of focusing on lifestyle modifications for HCC prevention, of developing better mouse models to reflect the human NASH and HCC signatures, and of understanding the molecular mechanisms of disease pathogenesis.

14th April 2021

Article: Type 2 Diabetes, NAFLD, and cardiovascular risk

Reviewed by: D. Beard

Authors: Caussy C, Aubin A, Loomba R.

Published in:  Curr Diab Rep 2021

Link: https://pubmed.ncbi.nlm.nih.gov/33742318/

Comment: Patients with T2DM and NAFLD exhibit higher risk of CVD compared with T2DM without NAFLD. In their review, C. Caussy et al. (Hopital Lyon Sud, France) underline that several studies have provided evidence that NAFLD could be an independent cardiovascular risk factor.

A potential synergistic increase of cardiovascular risk between T2DM and NAFLD is supported by several shared pathophysiological pathways. Thus, patients with T2DM and NAFLD should be considered at high risk of CVD and could benefit from more intensive CV prevention.

14th April 2021

Article: Hepatic fibrosis, cardiometabolic risk factors: The Framingham Heart Study

Reviewed by: G. Bozet, MD

Authors: Long MT, Zhang X, Xu H, et al.

Published in:  Hepatology 2021

Link: https://pubmed.ncbi.nlm.nih.gov/33125745/

Comment: Liver stiffness, as assessed by vibration-controlled transient elastography (VCTE), correlates with hepatic fibrosis, an important predictor of liver-related and all-cause mortality. Although liver fat is associated with cardiovascular risk factors, the association between hepatic fibrosis and cardiovascular risk factors is less clear.

The authors performed vibration-controlled transient elastography, assessing controlled attenuation parameter and liver stiffness measurement in 3,276 Framingham Heart Study adult participants presenting for a routine study visit.

In this large, community-based sample of middle-aged and older adults unselected for liver disease, 8.8% of participants, a substantial minority, exceeded the threshold of potentially clinically significant hepatic fibrosis. Hepatic fibrosis was associated with multiple obesity-, glucose-, vascular- and cholesterol-related traits. Hepatic fibrosis remained significantly associated with obesity-related traits, hypertension, low HDL-cholesterol and, most strongly, with diabetes, even after accounting for controlled attenuation parameter which suggests an association between hepatic fibrosis and cardiometabolic disease over and above the association with hepatic steatosis.

6th April 2021

Article: HSI screening for metabolic steatopathy in patients with T2D

Reviewed by: G. Bozet, MD

Authors: Fennoun H, Mansouri SE, Tahiri M, et al.

Published in:  Pan Afr Med J 2020

Link: https://pubmed.ncbi.nlm.nih.gov/33598084/

Comment: The purpose of this study by H. Fennoun et al. (University Hospital, Casablanca, Morocco) was to determine the interest of hepatic steatosis index in the detection of hepatic steatosis in patients with type 2 diabetes in order to establish an appropriate screening program of this disease in the population of diabetics hospitalized in Morocco.

This was a cross-sectional study involving 281 type 2 diabetics. The hepatic steatosis index score of> 36 predicted the presence of fatty liver.

Prevalence of NAFLD was 45.2% based on the HSI score > 36 (sensitivity 93%), consistent with the liver ultrasound findings (47.7% of cases). The sensitivity of HSI was 89.55%.

The hepatic steatosis index is a simple non-invasive tool and a validated screening for NAFLD, with performance characterized by an AUROC of 0.81. HSI score < 30 excludes hepatic steatosis. A score > 36 has a. In our study, the sensitivity of hepatic steatosis index was 89.55% in this study.

6th April 2021

Article: NASH histology and artificial intelligence

Reviewed by: G. Bozet, MD

Authors: Noureddin M.

Published in:  Hepatology 2021

Link: https://pubmed.ncbi.nlm.nih.gov/33638172/

Comment: Artificial intelligence uses computational methods that enable machines to learn from patterns and relationships in data in order to make predictions. Natural language processing can be used to extract knowledge from text, data can be modelled for the prediction of outcomes, and machine vision can analyse and recognise images.

Various demographic, laboratory, and histopathologic factors can be combined to determine which patients have the greatest risk of NASH.

Although non-invasive tests have shown promise and potential to replace liver biopsy, liver histology likely will remain the primary end point for phase 2b/3 trials and a key regulatory approval criterion for NASH drugs in the next few years. Unfortunately, histological evaluation of liver tissue has well-known limitations — sample variability, lack of patient acceptance, low reproducibility among readers, and variable placebo effects — that have been troublesome in NASH trials. Artificial intelligence can be used in order to reduce the shortcomings of this imperfect gold standard.

1st April 2021

Article: Liver regeneration and nanotubes: an intercellular communication

Reviewed by: G. Bozet, MD

Authors: Hsu MJ, Christ M, Christ B.

Published in:  Methods Mol Biol 2021

Link: https://pubmed.ncbi.nlm.nih.gov/33687678/

Comment: Human mesenchymal stromal cells are adult stem cells, which feature hepatotropism. They support liver regeneration through amelioration of hepatic inflammation and lipid accumulation in a mouse model of NASH.

To study mesenchymal stromal cells actions on fatty liver mechanistically, MJ Hsu et al. (Applied Molecular Hepatology Lab, University of Leipzig Medical Center, Leipzig, Germany) established an in vitro model of co-culture comprising mesenchymal stromal cells and isolated mouse hepatocytes. Lipid storage in hepatocytes was induced by the treatment with medium deficiency of methionine and choline.

The protocol allowed the authors to detect the formation of extensions named filopodia from mesenchymal stromal cells to contact the fatty hepatocytes or other mesenchymal stromal cells within 24 hours of co-culture. Filopodia are thin finger-like, actin-rich structures often found protruding from the lamellipodial actin network. These structures may represent tunneling nanotubes, actin-based cytoplasmic extensions that function as intercellular channels, allowing for long-range intercellular communication.

1st April 2021

Article: Sedentary behaviour, an independent predictor of NAFLD

Reviewed by: G. Bozet, MD

Authors: Kim D, Vazquez-Montesino LM, Li AA, et al.

Published in:  Hepatology 2020

Link: https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.31158

Comment: Physical activity and NAFLD have an inverse association. However, studies assessing the impact of the widely accepted Physical Activity Guidelines for Americans on NAFLD are lacking.

D. Kim et al. (Stanford University School of Medicine, Stanford, USA) performed a serial, cross-sectional analysis among adults by using the 2007-2016 United States National Health and Nutrition Examination Survey. Of the 24,588 individuals, leisure-time physical activity (≥150 minutes/week) demonstrated 40% lower odds of NAFLD, whereas transportation-related physical activity was associated with 33% risk reduction in NAFLD.

Analysis of total physical activity and sitting times simultaneously showed a dose-response association between sitting time and NAFLD. Sedentary behaviour appears as an independent predictor of NAFLD.

29th March 2021

Article: NALFD in the Asia-Pacific region

Reviewed by: G. Bozet, MD

Authors: Sarin SK, Kumar M, Eslam M, et al.

Published in:  Lancet Gastroenterol Hepatol 2020

Link: https://pubmed.ncbi.nlm.nih.gov/31852635/

Comment: Data on NALFD epidemiology in the Asia-Pacific region indicate a rapid increase in the disease’s burden over the past three decades, which is supported by a systematic review and meta-analysis that assessed the prevalence, incidence, and outcomes of NAFLD in Asia. The analysis estimated that the overall prevalence of NAFLD was 29-62%, with prevalence increasing significantly over time.

Obesity and NAFLD are being increasingly recognized and are an emerging epidemic in the region, irrespective of country or regional income. The whole Asia-Pacific region is shifting towards increased consumption of energy-dense food and reduced physical activity, leading to increasing prevalence of NAFLD risk factors, such as diabetes and obesity.

The authors of the Lancet Gastroenterology & Hepatology Commission document here the burden of liver diseases in the Asia-Pacific region and formulate recommendations to tackle it. Commissioners were invited from each of the selected countries and territories and were provided with an outline for data collation and literature review. After this information was synthesised.

29th March 2021

Article: NAFLD burden in Saudi Arabia and United Arab Emirates

Reviewed by: G. Bozet, MD

Authors: Alswat K, Aljumah AA, Sanai FM, et al.

Published in:  Saudi J Gastroenterol 2018

Link: https://pubmed.ncbi.nlm.nih.gov/29956688/

Comment: Morbidity related to NAFLD and resulting NASH is likely to increase dramatically in the coming decades, especially in the Gulf countries, where there is already an epidemic of obesity and diabetes melittus.

In their article, K. Alswat et al. (Liver Disease Research Center, College of Medicine, King Saud University, Riyad) estimated NAFLD and NASH disease progression, primarily based on changes in adult prevalence rates of adult obesity and diabetes mellitus, in Saudi Arabia and United Arab Emirates.

In both countries, the prevalence of NAFLD will increased through 2030 parallel to projected increases in the prevalence of obesity and diabetes mellitus. Increases in NASH cases are relatively greater than the NAFLD cases due to aging of the population and disease progression.

This analysis confirms a large and growing burden of disease associated with NAFLD and NASH, in tandem with a global pandemic of obesity.

24th March 2021

Article: Machine learning-based approach to liver histology assessment

Reviewed by: G. Bozet, MD

Authors: Taylor-Weiner A, Pokkalla H, Han L, et al.

Published in:  Hepatology 2021

Link: https://pubmed.ncbi.nlm.nih.gov/33570776/

Comment: Manual histologic assessment is currently the accepted standard for diagnosing and monitoring disease progression in nonalcoholic steatohepatitis (NASH), but is limited by variability in interpretation and insensitivity to change.

A. Taylor-Weiner et al. (PathAI, Boston, Massachusetts, USA) describe here a machine learning-based approach to liver histology assessment, which accurately characterises disease severity and heterogeneity, and sensitively quantifies treatment response in NASH.

The machine learning-based predictions show strong correlations with expert pathologists and are prognostic of progression to cirrhosis and liver-related clinical events.

The authors also developed a new heterogeneity-sensitive metric of fibrosis response, the Deep Learning Treatment Assessment (DELTA) Liver Fibrosis score.

24th March 2021

Article: Mechanisms, screening, prevention, and management of CVD in patients with NAFLD

Reviewed by: G. Bozet, MD

Authors: Shroff H, VanWagner LB.

Published in:  Curr Hepatol Rep 2020

Link: https://pubmed.ncbi.nlm.nih.gov/33585157/

Comment: Cardiovascular disease, rather than liver decompensation, remains the leading cause of morbidity and mortality in patients with NAFLD and NASH. A significant proportion of the cardiovascular risk in NASH is likely attributable to shared metabolic risk factors. Nevertheless, there is much interest in understanding the independent contribution of hepatic steatosis and associated inflammation and fibrosis to the cardiovascular risk in patients with NASH. It is imperative that clinicians understand the metabolic risk factors and subsequent manifestations of CVD in this population.

The purpose of this review by H. Shroff and LB VanWagner (Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA) is to provide an up-to-date summary focused on highlighting recent advances in the understanding of mechanisms, screening, prevention, and management of CVD in patients with NAFLD.

22nd March 2021

Article: Management of NAFLD in the Middle East

Reviewed by: G. Bozet, MD

Authors: Sanai FM, Abaalkhail F, Hasan F, et al.

Published in:  World J Gastroenterol 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32742124/

Comment: The global prevalence of NAFLD is estimated at approximately 25%. In a recent meta-analysis on the global epidemiology of NAFLD, Younossi et al. reported the prevalence to be highest (32%) in the Middle East, and is estimated to grow further with an increase in its risk factors such as obesity, metabolic syndrome, and type 2 diabetes mellitus. NAFLD thus causes a substantial burden on healthcare systems and it is imperative that appropriate strategies are discussed at a regional level to facilitate effective management tailored to the needs of the region.

To fulfil this unmet need, experts from the region came together in three advisory board meetings conducted in Saudi Arabia, United Arab Emirates, and Kuwait, to discuss current local challenges in NAFLD screening and diagnosis, and the different available management options. This opinion review by FM Sanai et al. (King Abdulaziz Medical City, Jeddah, Makkah, Saudi Arabia) summarises the discussions and opinion of the expert panel on the management of NAFLD/NASH and also presents an extensive literature review on the topic.

22nd March 2021

Article: Significant fatigue and pruritus are common in patients with advanced NASH

Reviewed by: G. Bozet, MD

Authors: Younossi ZM, Wong VW, Anstee QM, et al.

Published in:  Hepatol Commun 2020

Link: https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep4.1581

Comment: Although early stages of NASH may not be associated with severe symptoms, it is increasingly appreciated that NASH is not an asymptomatic disease. In fact, systematic assessments of patients with NASH using validated health-related quality- of-life instruments suggest significant impairment of patient-reported outcomes. Fatigue and pruritus are common in patients with chronic liver diseases of all aetiologies, but clinical awareness is mostly restricted to those with cholestatic liver diseases.

ZM Younossi et al. (Betty and Guy Beatty Center for Integrated Research, Inova Health System, and Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, Virginia, USA) assessed the impact of fatigue and pruritus on patient-reported outcomes of patients with advanced NASH. Among the included 1,669 patients with advanced NASH, 33% and 27% had fatigue and pruritus, respectively. All patient-reported outcomes were impaired by up to −19% in patients with NASH with pruritus.

It appears that clinically significant fatigue and pruritus are common in patients with advanced NASH, and these symptoms negatively affect patient-reported outcomes.

18th March 2021

Article: Impact of Ramadan fasting on NASH severity

Reviewed by: G. Bozet, MD

Authors: Mari A, Khoury T, Baker M, et al.

Published in:  Isr Med Assoc J 2021

Link: https://pubmed.ncbi.nlm.nih.gov/33595214/

Comment: The aim of the current study by A. Mari et al. (Nazareth Hospital EMMS, Nazareth, and Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel) was to assess the impact of caloric restrictions during Ramadan fasting on severity index of NASH severity scores.

The authors conducted a retrospective, case control study in Nazareth Hospital between 2017 and 2019. Intermittent fasting showed significant improvement on inflammatory markers, insulin sensitivity, and non-invasive measures for NASH severity assessment. Future prospective and laboratory studies are needed to confirm the positive effect of intermittent fasting among NASH subjects.

18th March 2021

Article: Review: Non-invasive tests of hepatic steatosis and fibrosis: confounding factors

Reviewed by: G. Bozet, MD

Authors: Wai JW, Fu C, Wong VW.

Published in: J Gastroenterol 2020

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376510/

Comment: Non-invasive tests of NAFLD can be classified by the target disease state or the type of test. Disease states of interest include the detection of hepatic steatosis (for the diagnosis of NAFLD or using steatosis improvement as treatment outcomes in early phase studies), NASH, and fibrosis. Types of tests include simple scores based on routine clinical and laboratory parameters, specific blood biomarkers, and imaging techniques.
This review by JW Wai et al. (The Chinese University of Hong Kong, Hong Kong, China) summaries the known and potential confounding factors that affect the performance of non-invasive tests of hepatic steatosis and fibrosis in patients with NAFLD.

15th March 2021

Article: Performance of non-invasive tests for the detection of advanced fibrosis in morbidly obese patients with NAFLD

Reviewed by: G. Bozet, MD

Authors: Alqahtani SA, Golabi P, Paik JM, et al.

Published in: Obes Surg 2021

Link: https://pubmed.ncbi.nlm.nih.gov/33616848/

Comment: It is critically important to determine the stage of liver fibrosis in patients with Nonalcoholic Fatty Liver Disease (NAFLD) for treatment planning and accurate prognosis. In addition, NAFLD is highly prevalent in morbidly obese patients. Liver biopsy remains the gold standard, but its limitations are known (costs, interpretation). SA Alqahtani et al. (Center for Outcomes Research in Liver Diseases, Washington DC, Johns Hopkins University, Baltimore, Maryland and King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia) aimed to assess the performance of three non-invasive tests for the detection of advanced fibrosis (NAFLD fibrosis score, NFS, fibrosis-4 index, FIB-4, and aspartate aminotransferase-to-platelet ratio, APRI), in the identification of advanced fibrosis among morbidly obese patients.

In this study, NFS, FIB-4, and APRI fall short to detect advanced fibrosis but are valuable for excluding advanced fibrosis. Combinations of the tests did not improve their performance.

More research is needed to develop new non-invasive tests with high positive predictive value.

15th March 2021

Article: Review: Tumour incidence in patients with NAFLD

Reviewed by: G. Bozet, MD

Authors: Huber Y, Labenz C, Michel M, et al.

Published in: Dtsch Arztebl Int 2020

Link: https://pubmed.ncbi.nlm.nih.gov/33559592/

Comment: The spectrum that ranges from non-alcoholic fatty liver disease (NAFLD) to the more aggressive form of non-alcoholic steatohepatitis (NASH) all the way to liver cirrhosis is associated with complications and hepatocellular carcinoma. Extrahepatic malignancies are among the leading causes of death in patients with NAFLD, but little is known about the specific types of cancer affecting this group of patients. In this study, Y. Huber et al. (University Medical Center Mainz, Germany) aimed to investigate the significance of NAFLD for the incidence of various kinds of cancer. They developed a retrospective, observational analysis in Germany.

The incidence of cancer was 1.5 times higher in patients with NAFLD than in the matched control cohort. Especially breast cancer, tumours of the male genital organs, and skin cancer occurred more often in patients with NAFLD during the 10-year observation period.

According to the authors’ conclusion, the data from their analysis show that the NAFLD population exhibits a slightly increased risk of cancer. The identification of patients with NAFLD can help to identify patients who have an increased risk of cancer.

10th March 2021

Article: NAFLD and heart failure with preserved LV ejection fraction

Reviewed by: G. Bozet, MD

Authors: Itier R, Guillaume M, Ricci JE, et al.

Published in: ESC Heart Fail 2021

Link: https://pubmed.ncbi.nlm.nih.gov/33534958/

Comment: The prevalence of NAFLD in heart failure preserved left ventricular ejection fraction (HFpEF) patients could reach 50%. Therefore, NAFLD is considered an emerging risk factor.

The purpose of this review by R. Itier et al. (Department of Cardiology, CHU, Toulouse, France) is to provide an overview of the relationships between NAFLD and HFpEF and to discuss its impact in clinical setting.

NAFLD and HFpEF share common risk factors, co-morbidities, and cardiac outcomes, in favour of a pathophysiological continuum. Identifying HF patients at risk of NAFLD is a critically important issue. As soon as NAFLD is confirmed and its severity determined, patients should be proposed a management focused on symptoms and co-morbidities.

10th March 2021

Article: Review: outcome of hepatocellular carcinoma in patients with NAFLD

Reviewed by: G. Bozet, MD

Authors: Chin KM, Prieto M, Cheong CK, et al.

Published in: HPB (Oxford) 2021

Link: https://pubmed.ncbi.nlm.nih.gov/33608215/

Comment: Background: This systematic review and meta-analysis by KM Chin et al. (Singapore General Hospital, Singapore) aimed to compare the outcomes of curative therapy for hepatocellular carcinoma from NAFLD and non-NAFLD aetiologies. They pooled and examined findings for 5579 patients from 9 studies.

In NAFLD-HCC patients undergoing liver resection, they observed improved disease-free survival and improved disease-free survival as compared to non-NAFLD HCC patients.

As stated by the authors, peri- and post-operative morbidity should be mitigated with pre-operative optimisation of comorbidities, and deliberately close post-operative monitoring.

8th March 2021

Article: Extrahepatic manifestations of NAFLD: a review

Reviewed by: G. Bozet, MD

Authors: Wijarnpreecha K, Aby ES, Ahmed A, et al.

Published in: Clin Mol Hepatol 2020

Link: https://pubmed.ncbi.nlm.nih.gov/33317243/

Comment: Diagnosis and management of extrahepatic manifestations of NAFLD are crucial for the treatment of these patients. These manifestations include cardiovascular disease, type 2 diabetes mellitus, metabolic syndrome, chronic kidney disease, obstructive sleep apnea, polycystic ovarian syndrome, hypothyroidism, psoriasis, and extrahepatic malignancy.

The leading cause of death in NAFLD is primarily from CVD, followed by liver-related mortality, extrahepatic cancer, liver cancer, and diabetes-related mortality.

In their review, K. Wijarnpreecha et al. (Mayo Clinic College of Medicine, Florida, USA) focus on the monitoring and management of the extrahepatic manifestations of NAFLD in order to help clinicians to identify high-risk patients earlier in the disease course and to improve liver disease outcomes.

8th March 2021

Article: Kupffer cells and development of liver fibrosis in NASH

Reviewed by: G. Bozet, MD

Authors: Kanamori Y, Tanaka M, Itoh M, et al.

Published in: iScience 2021

Link: https://pubmed.ncbi.nlm.nih.gov/33521599/

Comment: Although recent evidence suggests the involvement of iron accumulation in the pathogenesis of NASH, the underlying mechanisms remain poorly understood. Previously, Y. Kanamori et al. (Nagoya, Japan) reported a unique histological structure termed ‘‘crown-like structure (CLS),’’ where liver-resident macrophages (Kupffer cells) surround dead hepatocytes, scavenge their debris, and induce inflammation and fibrosis in NASH.

In this study, using magnetic column separation, the authors show that iron-rich Kupffer cells exhibit proinflammatory and profibrotic phenotypic changes during the development of NASH, at least partly, through activation of MiT/TFE transcription factors, that mediate iron-induced Kupffer cells’ phenotypic changes. Activation of MiT/TFE transcription factors is observed in Kupffer cells forming CLSs in murine and human NASH. Iron chelation effectively attenuates liver fibrosis in a murine NASH model.

This study provides insight into the pathophysiologic role of iron in NASH. A unique macrophage subset rich in iron contributes to crown-like structure formation and serves as a driver of liver fibrosis.

3rd March 2021

Article: NAFLD: a year in review

Reviewed by: G. Bozet, MD

Authors: Abdelmalek MF.

Published in: Nat Rev Gastroenterol Hepatol 2021

Link: https://pubmed.ncbi.nlm.nih.gov/33420415/

Comment: The field of NAFLD and its progressive form, NASH, has, despite the challenges of the COVID-19 pandemic, continued to rapidly evolve in 2020. There have been substantial advances in NAFLD mechanisms, diagnostics, and treatment.

Key developments include the identification of a multiparametric cellular and tissue signature to define disease progression and new insights into the definition of disease progression and advancements in non-invasive diagnostics. The FibroScan-AST (FAST) score non- invasively identifies patients at risk of progressive NASH for clinical trials and potentially in clinical practice.

3rd March 2021

Article: Early NASH development: myosteatosis rather than sarcopenia

Reviewed by: G. Bozet, MD

Authors: Nachit M, De Rudder M, Thissen JP, et al.

Published in: J Cachexia Sarcopenia Muscle 2021

Link: https://pubmed.ncbi.nlm.nih.gov/33244884/

Comment: A substantial body of literature supports that a low muscle mass, low strength, and/or muscle fatty infiltration (myosteatosis) are associated with NAFLD severity. In order to decipher the kinetics of muscle alterations in relation with liver disease progression, M. Nachit et al. (Institute of Experimental and Clinical Research, UCLouvain, Brussels, Belgium) evaluated the muscle compartment in NASH preclinical models. They developed and validated a micro‐computed tomography‐based methodology to prospectively study skeletal muscle mass and density in muscle and liver in three preclinical NAFLD/NASH rodent models.

Their data support that sarcopenia, as evidenced by a low muscle strength, but a not low muscle mass, is present in mice with fibrosing NASH, but not in those with early NASH or NAFL. In contrast, the severity of myosteatosis reflects on hepatocellular damage and inflammation during early NASH development.

This observation suggests that myosteatosis could represent a surrogate diagnostic marker for NASH.

1st March 2021

Article: Review: outcome of hepatocellular carcinoma in patients with NAFLD

Reviewed by: G. Bozet, MD

Authors: Chin KM, Prieto M, Cheong CK, et al.

Published in: HPB (Oxford) 2021

Link: https://pubmed.ncbi.nlm.nih.gov/33608215/

Comment: This systematic review and meta-analysis by KM Chin et al. (Singapore General Hospital, Singapore) aimed to compare the outcomes of curative therapy for hepatocellular carcinoma from NAFLD and non-NAFLD aetiologies. They pooled and examined findings for 5579 patients from 9 studies.

In NAFLD-HCC patients undergoing liver resection, they observed improved disease-free survival and improved disease-free survival as compared to non-NAFLD HCC patients.

As stated by the authors, peri- and post-operative morbidity should be mitigated with pre-operative optimisation of comorbidities, and deliberately close post-operative monitoring.

1st March 2021

Article: Performance of non-invasive tests for the detection of advanced fibrosis in morbidly obese patients

Reviewed by: G. Bozet, MD

Authors: Alqahtani SA, Golabi P, Paik JM, et al.

Published in: Obes Surg 2021

Link: https://pubmed.ncbi.nlm.nih.gov/33616848/

Comment: SA Alqahtani et al. remind us of the burden of non-alcoholic fatty liver disease (NAFLD). In the USA, it is the most common cause of chronic liver disease and the prevalence is estimated to be about 25% and will increase in future years. For the management of patients with NAFLD, the determination of the fibrosis is essential. Liver biopsy is the gold standard but is invasive. The authors aimed to assess the performance of three non-invasive tests for the detection of advanced fibrosis (NAFLD fibrosis score, NFS, fibrosis-4 index, FIB-4, and aspartate aminotransferase-to-platelet ratio, APRI), in the identification of advanced fibrosis among morbidly obese patients.

In this study, these 3 tests (NFS, FIB-4, and APRI) showed important limitations: they fell short to detect advanced fibrosis but proved valuable for excluding advanced fibrosis. Combinations of the tests did not improve their performance.

Therefore, more research is needed to develop new non-invasive tests with high positive predictive value.

24th February 2021

Article: :Metabolic drivers of NAFLD

Reviewed by: G. Bozet, MD

Authors: Bence KK, Birnbaum MJ.

Published in: Mol Metab 2020

Link: https://pubmed.ncbi.nlm.nih.gov/33346069/

Comment: Significant progress has been made over the past decade in our understanding of NASH pathogenesis, but gaps remain in our mechanistic knowledge of the precise metabolic triggers for disease worsening.

Many factors associated with dysregulated systemic metabolism have been implicated in some way with the progression from hepatic steatosis to NASH, including altered lipid metabolism, mitochondrial dysfunction, alterations in gut microbiome, oxidative stress, inflammatory cytokines, immune response, and others; however, it remains unclear which combination of these mechanisms are the key drivers of the disease.

This review by KK. Bence et al. focuses on early metabolic events in the establishment of NAFL and initial stages of NASH.

Similar to other metabolic diseases, the progression to more serious pathologic states is likely driven by several risk factors and manifests slightly differently in each individual depending on genetic risk, presence of other metabolic comorbidities (obesity and/or diabetes), lifestyle, diet, and environment.

As we learn more about the importance of interorgan communication in driving NASH pathogenesis, it is clear that this is a disease of altered systemic metabolism rather than a liver disease in isolation.

24th February 2021

Article: :MAFLD, severe COVID-19 and the gut-liver axis

Reviewed by: G. Bozet, MD

Authors: Assante G, Williams R, Youngson NA

Published in: J Hepatol 2021

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305888/

Comment: As pointed out by Gabriella Assante et al. (The Institute of Hepatology, Foundation for Liver Research, London, UK), two recent studies in the Journal of Hepatology suggest that MAFLD is a risk factor for progression to severe COVID-19. More studies are required to confirm this. However, it potentially adds MAFLD to a list of risk factors that also includes obesity, type 2 diabetes, chronic lung disease, inflammatory bowel disease, asthma, cardiovascular disease, immunodeficiency, and renal failure.

MAFLD, obesity and T2D are major contributors to the overall number of patients with COVID-19 that require hospitalisation. Therapeutics that have been developed for IBD could reduce the number of patients with MAFLD/obesity/T2D that progress to severe COVID-19, and caution may have to be taken with drugs that disturb intestinal microbiota composition or abundance.

22nd February 2021

Article: : Pan-PPAR agonist lanifibranor improves portal hypertension and hepatic fibrosis in experimental advanced chronic liver disease
Reviewed by: G. Bozet, MD

Authors: Boyer-Diaz Z, Aristu-Zabalza P, Andrés-Rozas M, et al.

Published in: J Hepatol 2020

Link: https://www.journal-of-hepatology.eu/article/S0168-8278(20)33832-0/fulltext

Comment: Advanced chronic liver disease (ACLD) is a serious public health issue for which a safe and effective treatment is still lacking. It is often associated with portal hypertension and liver fibrosis.

Over the recent years, peroxisome proliferator-activated receptors family (PPARs) have been considered as a relevant therapeutic option. Z Boyer-Diaz et al. tried to evaluate the therapeutic potential of pan-PPAR activation for the treatment of advanced cirrhosis.

This study demonstrated for the first time that lanifibranor exerts beneficial effects in a pre-clinical model of decompensated cirrhosis, leading to a marked improvement of fibrosis and portal hypertension.

Evaluation of lanifibranor in liver cells from patients suffering from ACLD further supports its beneficial effects. This should encourage further clinical evaluation of lanifibranor for the treatment of ACLD and portal hypertension.

22nd February 2021

Article: : Sarcopenia: pathophysiological processes in NAFLD
Reviewed by: G. Bozet, MD

Authors: Chakravarthy MV, Siddiqui MS, Forsgren MF, et al.

Published in: Front Endocrinol (Lausanne) 2020

Link: https://pubmed.ncbi.nlm.nih.gov/33424768/

Comment: A growing body of evidence places skeletal muscle and the muscle-liver axis at the centre of the NAFLD pathogenic cascade. Skeletal muscle is implicated via its impact on insulin resistance and systemic inflammation.

Population-based studies suggest that sarcopenia is an effect-modifier across the NAFLD spectrum and is tightly linked to an increased risk of non-alcoholic fatty liver, NASH, and advanced liver fibrosis, independently of obesity and insulin resistance. Conversely, longitudinal studies suggest that increases in skeletal muscle mass over time may both reduce the incidence of NAFLD and improve preexisting NAFLD. Similarly, adverse muscle composition, comprising both low muscle volume and myosteatosis, is highly prevalent in patients with NAFLD. In their review, MV Chakravarthy et al. discuss key pathophysiological processes driving sarcopenia in NAFLD.

19th February 2021

Article: : NAFLD and T2D: A bidirectional relationship

Reviewed by: G. Bozet, MD

Authors: Muzica CM, Sfarti C, Trifan A, et al.

Published in: Can J Gastroenterol Hepatol 2020

Link: https://pubmed.ncbi.nlm.nih.gov/33425804/

Comment: NAFLD has been reported to be associated with extrahepatic manifestations such as cardiovascular disease, T2DM, chronic kidney disease, extrahepatic malignancies, endocrine diseases, obstructive sleep apnea, and iron overload.

Current data define a more complex relationship between NAFLD and T2DM than was previously believed, underlining a bidirectional and mutual association between the two entities. This review by CM Muzica et al. (Grigore T. Popa University of Medicine and Pharmacy and St. Spiridon Emergency Hospital, Iasi, Romania) aims to summarise the current literature regarding the incidence of T2DM among patients with NAFLD and the prevalence of NAFLD in T2DM patients, highlighting the recent key studies.

The components of NAFLD lead to insulin resistance and T2DM through various physiopathological pathways, and T2DM may promote the progression to NASH as an independent risk factor. Thus, clinicians should be aware of these NAFLD-related extrahepatic manifestations considering that an early acknowledgement of T2DM is the key point in the management of these patients.

19th February 2021

Article: : Extra-hepatic manifestations of NAFLD

Reviewed by: G. Bozet, MD

Authors: Tariq R, Axley P, Singal AK.

Published in: J Clin Exp Hepatol 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32025167/

Comment: There is growing evidence to support that NAFLD is a multisystem disease, and it involves extra-hepatic organ systems. Most of the studies have evaluated the association of NAFLD with cardiovascular disease, T2DM, and chronic kidney disease. Studies have also suggested association of NAFLD with colorectal cancer, obstructive sleep apnea, polycystic ovarian syndrome, and hypothyroidism. In this review, R. Tariq et al. (University of Rochester, Rochester, New York, USA) discuss the current literature regarding the pathogenesis and clinical implications of these associations among patients with NAFLD.

15th February 2021

Article: : Cost-effectiveness of screening for NAFLD in patients with T2D

Reviewed by: G. Bozet, MD

Authors: Noureddin M, Jones C, Alkhouri N, et al.

Published in: Gastroenterology 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32763241/

Comment: The authors hypothesised that screening for NAFLD in type 2 diabetes (T2D) patients, starting with ultrasound (US) and alanine aminotransferase (ALT) or aspartate aminotransferase (AST), followed with non-invasive testing for fibrosis to detect those most likely to have fibrosis stage ≥F2, is more cost effective than not screening this population.

The authors developed a Markov model to test various screening strategies and treatment for NASH in T2DM.

Patients identified as NASH ≥F2 following screening approaches and underwent a 1-year duration intensive lifestyle intervention (ILI). In an exploratory analysis, those with NASH ≥F2.

Patients were alternatively treated with pioglitazone until death or treatment non-adherence. Screening strategies 3 and 6 were also cost effective with pioglitazone as the treatment intervention. Screening strategy 3: If US+ALT suspected likely fatty liver, US+ALT was followed by transient elastography, with 1-year ILI prescribed to suspected patients (NASH stage ≥2). Screening strategy 6: If US+AST suspected likely fatty liver, US+AST was followed by transient elastography, with 1-year ILI prescribed to suspected patients (NASH stage ≥2).

The authors conclude the results indicate the potential value and cost effectiveness of NAFLD screening in T2D persons. Given the increasing burden of NAFLD/NASH and the expected rapid increase in approved medications, they recommend screening patients with T2D for NAFLD.

15th February 2021

Article: : NAFLD fibrosis and bone mineral density in diabetic postmenopausal women

Reviewed by: G. Bozet, MD

Authors: Zhu X, Yan H, Chang X, et al.

Published in: BMJ Open Diabetes Res Care 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32759166/

Comment: X. Zhu et al. (Division of Digestive and Liver Diseases, Comprehensive Transplant Center, Cedars Sinai Medical Center, Los Angeles, California) aimed to evaluate the association of NAFLD-associated hepatic fibrosis with bone mineral density in postmenopausal women with type 2 diabetes mellitus or impaired glucose regulation.

For this purpose, two cohorts including 46 subjects with biopsy-proven NAFLD and 445 subjects with proton magnetic resonance spectrum-proven NAFLD were enrolled in their study. Bone mineral density at the lumbar spine L1–L4 and hip was measured using dual-energy X-ray absorptiometry. NAFLD fibrosis stage and NAFLD fibrosis score were used to evaluate the severity of liver fibrosis.

In subjects with NAFLD, bone mineral density in the advanced fibrosis group were significantly lower than that in the non-advanced fibrosis group after adjusting for age, body mass index and fasting plasma glucose. These results were validated in a large cohort of 445 subjects. Additionally, bone metabolism-associated factors, including calcium and phosphate, were associated with liver fibrosis, indicating that bone metabolism may play a critical role in the association between liver fibrosis and bone mineral density.

Liver fibrosis decreased bone mineral density probably via increasing bone turnover.

11th February 2021

Article: : NASH clinical trials during the SARS-CoV-2 pandemic

Reviewed by: G. Bozet, MD

Authors: Alkhouri N, Kohli A, Loomba R, et al.

Published in: Hepatology 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32794597/

Comment: As the COVID-19 continues to pose extreme challenges to healthcare systems, it is becoming impossible to avoid the overlap between COVID-19 and NASH pandemics. Numerous trials are being conducted despite the crisis and the COVID-19 pandemic has disrupted many aspects of NASH clinical trials, such as patient recruitment, administration of the therapeutic agents safety monitoring to data integrity.

In their commentary, the authors stress that there are solid scientific and ethical reasons to continue ongoing NAFLD/ NASH trials, particularly in view of the fact that there are no Food and Drug Administration (FDA)–approved therapies for NASH. However, they point out that patients with NAFLD have higher risk of progressive COVID-19, requiring mitigation strategies. One of them is to consider testing for SARS‐CoV‐2 within 72 hours prior to bringing patients in for a liver biopsy.

Take home message: The rationale for the continuation of NASH clinical trials during the COVID-19 pandemic is strong. It is necessary to implement strategies to mitigate the effects of the pandemic on the continuity and veracity of the data being collected and continue trial programs. The therapeutic options that are being investigated have the potential to benefit millions of people with NASH and fibrosis long after the coronavirus pandemic has ended.

11th February 2021

Article: : The diabetologist, NAFLD and T2D

Reviewed by: G. Bozet, MD

Authors: Tomah S, Alkhouri N, Hamdy O.

Published in: Clin Diabetes Endocrinol 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32518675/

Comment: The prevalence of NASH among patients with type 2 diabetes (T2D) is high, putting them at a significantly higher risk for developing end-stage liver disease, HCC, and CVD. There is a vicious circle, each condition worsening the other. Patients with NAFLD have an increased risk of developing type 2 diabetes, while the latter promotes the progression of simple fatty liver to a more advanced form called nonalcoholic steatohepatitis (NASH). Increased awareness about NASH and NASH-related complications is warranted among diabetologists, especially with the prospective induction of NASH-specific therapies.

Shaheen Tomah et al. review the two-way pathophysiologic relationship between NAFLD and T2D as well as the various management options currently available.

Take home message: An interdisciplinary approach is needed for the care of patients with type 2 diabetes and NAFLD, starting with early identification through non-invasive biomarkers and imaging modalities in the diabetes clinic to lifestyle modification and NASH-specific therapy in the hepatology clinic.

8th February 2021

Article: : COVID-19: incidence in patients with metabolic syndrome and NASH

Reviewed by: G. Bozet, MD

Authors: Ghoneim S, Butt MU, Hamid O, et al.

Published in: Metabol Open 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32924000/

Comment: Although a relationship between metabolic syndrome and COVID-19 severity might exist, it is currently unclear whether NASH is associated with a higher risk of SARS-CoV-2 infection. The primary objective of this study by S. Ghoneim et al. (Department of Internal Medicine, MetroHealth Medical Center, Cleveland, Ohio, USA) was to identify whether metabolic syndrome or its components are independently associated with the diagnosis of COVID-19. The secondary objective was to investigate whether a relationship exists between NASH and COVID-19.

The authors reviewed data (61.4 million active adult patients) from a large commercial database from 26 large nationwide healthcare systems. They included patients with the diagnosis of COVID-19 from December 2019 to May 2020.

The cumulative incidence of COVID-19 was higher if metabolic syndrome was the primary diagnosis. The adjusted odds of having COVID-19 were higher in patients if they were hypertensive, obese, diabetic, hyperlipidaemic or diagnosed with NASH (OR 4.93, 95% confidence interval 4.06-6.00).

Take home message: The incidence of COVID-19 in patients with metabolic syndrome is high. Among all comorbid metabolic conditions, NASH had the strongest association with COVID-19.

7th February 2021

Article: : COVID-19 in NAFLD

Reviewed by: G. Bozet, MD

Authors: Prins GH, Olinga P.

Published in: Liver Int 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32306495/

Comment: Recent papers confirm that the relation between metabolic syndrome and mortality rate of COVID-19 is more and more evident. These diseases are often treated with ACE inhibitors, which might upregulate ACE2 expression.

ACE2 is normally expressed in low amounts in cholangiocytes and hepatocytes, but was shown to increase in chronic liver damage and in experimental set-ups of diet-induced NAFLD. While under normal conditions, ACE2 may exert anti-obesity and anti-inflammatory effects, it is also the way of entry for SARS- CoV-2.

Patients suffering from NAFLD might be especially vulnerable to SARS-CoV-2 infection and COVID-19 complications, where the latter may also increase NAFLD progression to NASH in the long-term.

Take home message: It is important to identify and monitor patients with pre-existing liver disease, especially those with metabolic disorder, during and after the COVID-19 crisis.

1st February 2021

Article: : Weight gain and risk of NAFLD: the Nurses’ Health Study II cohort

Reviewed by: G. Bozet, MD

Authors: Kim MN, Lo CH, Corey KE, et al.

Published in: Metabolism 2020

Link: https://pubmed.ncbi.nlm.nih.gov/33058854/

Comment: Obesity has been identified as a major risk factor for the development of Non-alcoholic fatty liver disease (NAFLD). However, the influence of dynamic changes in adiposity over the life course on NAFLD risk remains poorly understood. MN Kim et al. collected data from 110,054 women enrolled in the Nurses’ Health Study II cohort. They documented 3,798 NAFLD cases over a total of 20 years of follow-up. Within this large cohort, early adulthood weight gain was significantly and independently associated with an increased risk of developing NAFLD in mid-life. Furthermore, the trajectory of body shape between early- and mid-life was also significantly associated with incident NAFLD, regardless of underlying BMI.

Given the increasing prevalence of NAFLD, this article encourages a prevention strategy with the development of public health approaches to maintain a healthy weight and body shape throughout life.

1st February 2021

Article: : Economic and Clinical Burden of NASH in T2D patients in the U.S.

Reviewed by: G. Bozet, MD

Authors: Younossi ZM, Tampi RP, Racila A, et al.

Published in: Diabetes Care 2020

Link: https://pubmed.ncbi.nlm.nih.gov/31658974/

Comment: Nonalcoholic steatohepatitis (NASH), the aggressive form of nonalcoholic fatty liver disease (NAFLD) is strongly associated with type 2 diabetes mellitus. Patients with both T2DM and NASH have increased risk for adverse clinical outcomes, leading to higher risk for mortality and morbidity. Using a Markov model with 1-year cycles and 20-year horizon ZM Younossi et al. tried to estimate the economic burden of NASH with T2DM in the U.S. This is the first study to assess the economic and clinical burden of NASH and NAFLD in patients with T2DM and their findings are staggering.

They estimated that there were 18.2 million people in the U.S. living with T2DM and NAFLD, of which 6.4 million had NASH. Twenty-year costs for NAFLD in these patients were $55.8 billion. Over the next 20 years, NASH with T2DM will account for 65,000 transplants, 1.37 million cardiovascular-related deaths, and 812,000 liver-related deaths. For the authors, this analysis suggests that the clinical and economic burden of NASH in patients with T2DM is currently substantial. As the prevalence of T2DM increases globally, this burden will continue to rise. However, it can be projected that interventions reducing morbidity and mortality in NASH patients with T2DM could potentially reduce this projected clinical and economic burden.

19th January 2021

Article: : The epidemic of the 21st century in search of the most appropriate name

Reviewed by: G. Bozet, MD

Authors: Polyzos SA, Kang ES, Tsochatzis EA, et al.

Published in: Metabolism 2020

Link: Commentary: Nonalcoholic or metabolic dysfunction-associated fatty liver disease? The epidemic of the 21st century in search of the most appropriate name – PubMed (nih.gov)

Comment: Despite their high prevalence, nonalcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) remain largely underdiagnosed and undertreated. Some question the name of the disease. To address this issue, some academic societies contribute to the debate. The American Gastroenterological Association and the Endocrine Society recently issued a “Call to Action” and the American Gastroenterological Association is drafting a non-alcoholic steatohepatitis (NASH) Clinical Care Pathway, a practical tool for clinicians. As we know from literature reviews from 2020, several position articles recommended that NAFLD should be renamed to metabolic (dysfunction)-associated fatty liver disease (MAFLD).

SA Polyzos et al. believe a different process is necessary, while still involving several stakeholders. The authors recommend an individualised but holistic management of relevant metabolic comorbidities (e.g. obesity, T2DM, dyslipidaemia, hypertension, cardiovascular disease) by multidisciplinary teams of experts (i.e., hepatologists, endocrinologists, cardiologists, internists, pathologists). This could be a very important initiative towards decreasing the consequences of the NAFLD / NASH as we know NAFLD-related mortality and morbidity in terms of advanced liver disease will more than double from 2016 to 2030.

19th January 2021

Article: : MAFLD and risk of CKD

Reviewed by: G. Bozet, MD

Authors: Sun DQ, Jin Y, Wang TY, et al.

Published in: Metabolism 2020

Link: MAFLD and risk of CKD – PubMed (nih.gov)

Comment: Nonalcoholic fatty liver disease (NAFLD) is part of a systemic disease that affects many other parts of the body. The association between MAFLD (metabolic (dysfunction)-associated fatty liver disease) and extra-hepatic diseases is not known. The aim of the cross-sectional study by DQ Sun et al. was to compare the prevalence of chronic kidney disease (CKD) in patients with either MAFLD or NAFLD, and to examine the association between the presence and severity of MAFLD and CKD and abnormal albuminuria.

12,571 individuals from the Third National Health and Nutrition Examination Survey (1988-1994) were included in the analysis. The prevalence of MAFLD and NAFLD was 30.2 and 36.2%, respectively.

The key findings were that MAFLD individuals had a lower eGFR and a greater prevalence of CKD than NAFLD individuals. In addition, there was a higher prevalence of CKD in MAFLD than in non-metabolic dysfunction-associated NAFLD. The severity of MAFLD was associated with 1.34-fold higher risk of prevalent CKD.

14th January 2021

Article: : NAFLD cirrhosis: a predictive model of liver decompensation

Reviewed by: G. Bozet, MD

Authors: Calzadilla-Bertot L, Vilar-Gomez E, Wong VW, et al.

Published in: Hepatology 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32978796/

Comment: Non-alcoholic fatty liver disease (NAFLD) has become the most frequently encountered chronic liver disease and is an increasingly important cause of liver cirrhosis as well as other adverse events. The authors of this article retrospectively developed and validated a model to predict hepatic decompensation in NAFLD patients with cirrhosis and compared this with currently available models. Baseline variables from an international cohort of 299 biopsy-proven NAFLD patients with compensated cirrhosis were examined to construct a model using competing risk multivariate regression and Akaike/Bayesian information criteria. Validation was performed in 244 biopsy-proven NAFLD cirrhosis patients from the United States. Prognostic accuracy was compared with the NAFLD Fibrosis score (NFS), FIB-4, MELD, Child-Turcotte-Pugh (CTP) and ALBI-FIB-4 score using time-dependent area under the curve (tAUC) analysis. During a median follow-up of 5.6 years (range 2.4-14.1) and 5.4 years (range 1.5-13.8), hepatic decompensation occurred in 81 and 132 patients in the derivation and validation cohorts respectively. In the derivation cohort, independent predictors of hepatic decompensation (AST/ALT ratio, Bilirubin, INR, type 2 Diabetes and Oesophageal varices) were combined into the “ABIDE” model.

In clinical practice, ABIDE may be a useful tool to assess the initial risk of hepatic decompensation following a diagnosis of cirrhosis in patients with NAFLD. Very low scores in the bottom quintile were associated with a less than five percent risk of hepatic decompensation at five years, whereas a score in the top quintile was associated with a greater than 50% chance of decompensation at five years and almost 100% at ten years.

14th January 2021

Article: : Current management of NASH

Reviewed by: G. Bozet, MD

Authors: Muthiah MD, Sanyal AJ.

Published in: Liver Int 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32077609/

Comment: NASH is the most common cause of liver disease in Western populations, and its prevalence is increasing rapidly. It is a multifactorial and multisystem disease that can affect multiple organs such as the kidneys, heart and blood vessels, and is closely associated with the components of the metabolic syndrome.

Clinicians treating patients with NASH should not only focus on the management of NASH. The approach of associated comorbidities in individual patients is critical. The current management strategies of NASH include either limiting energy surplus alone, or in combination with targeting of downstream pathways of inflammation and fibrosis. ` In their mini-review, MD Muthiah et al. (Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, and Division of Gastroenterology and Hepatology, National University Hospital, National University Health System, Singapore) discuss the currently available treatment options for NASH, as well as those in late-stage clinical trials.

The authors discuss the challenges of managing these patients with a limited number of approved therapies. They also discuss the specific management of comorbidities in NASH patients, in particular diabetes, hypertension, dyslipidaemia and cardiovascular diseases. Finally, they present the screening protocols for both hepatocellular carcinoma and extrahepatic malignancies in these patients.

14th January 2021

Article: : PPARs and immune responses

Reviewed by: G. Bozet, MD

Authors: Christofides A, Konstantinidou E, Jani C, et al.

Published in: Metabolism 2020

Link: https://www.sciencedirect.com/science/article/abs/pii/S002604952030202X

Comment: Peroxisome proliferator-activated receptors (PPARs) are fatty acid-activated transcription factors of nuclear hormone receptor superfamily that regulate energy metabolism. Currently, three PPAR subtypes have been identified: PPARα, PPARγ, and PPARβ/δ. PPARα and PPARδ are highly expressed in oxidative tissues and regulate genes involved in substrate delivery and oxidative phosphorylation and regulation of energy homeostasis. In contrast, PPARγ is more important in lipogenesis and lipid synthesis, with highest expression levels in white adipose tissue. In addition to tissues regulating whole body energy homeostasis, PPARs are expressed in immune cells and have an emerging critical role in immune cell differentiation and fate commitment.

In their review, A. Christofides and colleagues (Division of Hematology-Oncology, Department of Medicine, and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts) discuss the actions of PPARs in the function of the innate and the adaptive immune system and their implications in immune-mediated inflammatory. Members of the PPAR family of nuclear hormone receptors are well- established regulators of lipid metabolism, mitochondrial biogenesis and energy homeostasis. Their activation has central implications in the function of oxidative tissues and organs such as cardiomyocytes, liver and muscle.

For many years, PPARs have been attractive therapeutic targets for the treatment of metabolic disorders. The role of various members of this nuclear receptor family is currently emerging in the differentiation and function of immune cells as they guide metabolism- mediated immune cell fate commitment.

12th January 2021

Article: : NAFLD/NASH and pleiotropic effects of statins

Reviewed by: G. Bozet, MD

Authors: Ahsan F, Oliveri F, Goud HK, et al.

Published in: Cureus 2020

Link: https://www.cureus.com/articles/39400-pleiotropic-effects-of-statins-in-the-light-of-non-alcoholic-fatty-liver-disease-and-non-alcoholic-steatohepatitis

Comment: Statins and NAFLD/NASH, a lipid-related pathology present a complex relationship. As a matter of fact, some statins are known to be hepatotoxic, even though it seems clinically significant hepatic injury caused by lipid-lowering medications remains rare.

A question can be asked: is it possible that statins prove to be a promising solution due to their pleiotropic properties in addition to the cholesterol-lowering effect?

A review of the literature through PubMed by F. Ahsan et al. (Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA) aims to assess the effectiveness of statins in NAFLD/NASH treatment and prevention of associated adverse outcomes.

In various animal studies, statins were found to improve hepatic lipotoxicity, oxidative stress, inflammatory responses, and fibrosis associated with NASH through multiple pathways. Statins exert these protective effects by recovering the gene expression level of peroxisomal proliferator-activated receptor alpha (PPARα) and therefore restore the mitochondrial and peroxisomal fatty acid oxidation.

NASH and NAFLD could be treated and prevented with statins owing to their pleiotropic properties. Of course, large clinical trials on humans are needed. However, this is a field of investigation regarding the treatment of NASH.

12th January 2021

Article: : AHA Life’s Simple 7 score and NAFLD

Reviewed by: G. Bozet, MD

Authors: Oni E, Ogunmoroti O, Allen N, et al.

Published in: Am J Med 2020

Link: https://pubmed.ncbi.nlm.nih.gov/33285128/

Comment: The American Heart Association has defined ideal cardiovascular health based on seven risk factors (Life’s Simple 7 – LS7) that people can improve through lifestyle changes: smoking status, physical activity, weight, diet, blood glucose, cholesterol, and blood pressure.

NAFLD is considered as a risk factor for cardiovascular disease. Oni Ebenezer et al. (Division of Cardiology, Heart and Vascular Institute, Albert Einstein Medical Center, Philadelphia, Pennsylvania) evaluated the association between LS7 and NAFLD in participants from The Multi-Ethnic Study of Atherosclerosis (MESA) cohort.

Cardiovascular health score was calculated from the Life’s simple 7 metrics. NAFLD was defined using non-contrast cardiac CT and a liver/spleen attenuation ratio (L/S) <1.

The overall prevalence of NAFLD was 18% with a distribution of 7%, 14%, and 25% in the optimal, average, and inadequate score categories, respectively (p <0.001).

Life’s simple 7 appears as independently associated with NAFLD in this population. This study reaffirms the relevance of the AHA’s 2020 strategic impact goals in promoting overall well-being. Focusing on the LS7 targets may be an appropriate prevention strategy for promoting hepatic health.

7th January 2021

Article: Cholecystectomy as a risk factor for non-alcoholic fatty liver disease development

Reviewed by: G. Bozet, MD

Authors: Rodriguez-Antonio I, Lopez-Sanchez GN, Garrido-Camacho VY, et al

Published in: HPB (Oxford) 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32773176/

Comment: Hepatic steatosis and gallstone disease are highly prevalent in the general population; the shared risk factors are age, ethnicity, obesity, insulin resistance, metabolic syndrome, atherosclerosis, risk of cardiovascular disease, and mortality. The presence of insulin resistance is the critical element in this association because it represents a crucial link between metabolic syndrome and NAFLD, as well as a higher susceptibility to gallstone formation. Clinical studies and systematic reviews suggest an association between gallstone disease, cholecystectomy, and hepatic steatosis.

As pointed out by I. Rodriguez-Antonio et al. (Translational Research Unit, Medica Sur Clinic & Foundation, Mexico), the bidirectional relationship between liver steatosis and gallstone disease and cholecystectomy is summarised in the role of insulin resistance, lipid metabolism, bile acids signalling pathways regulated by transcription factors expression, and to the gallbladder physiological role.

7th January 2021

Article: Volatomic analysis identifies compounds that can stratify non-alcoholic fatty liver disease

Reviewed by: G. Bozet, MD

Authors: Sinha R, Lockman KA, Homer NZM, et al.

Published in: JHEP Rep 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32775974/

Comment: Metabolic dysfunction in liver disease is reflected in the biocomposition of exhaled breath. Analysis of volatile organic compounds (VOCs) in exhaled breath, ‘volatomics’, provides opportunities for non-invasive biomarker discovery and novel mechanistic insights into a variety of diseases. The purpose of this pilot study by R. Sinha et al. (Liver Unit, The Royal Infirmary and The University of Edinburgh, United Kingdom) was to compare breath VOCs in an initial cohort of patients with NAFLD and healthy controls.

Terpinene, dimethyl sulfide, and D-limonene provided the highest predictive accuracy to discriminate between study groups. Combining dimethyl sulfide with D-limonene led to even better discrimination of patients with NAFLD cirrhosis from healthy volunteers and patients with NAFLD cirrhosis from those with non-cirrhotic NAFLD. Breath terpinene concentrations discriminated between patients with non-cirrhotic NAFLD and healthy volunteers.

23rd December 2020

Article: Resection of NAFLD-Associated HCC: Patient selection and reported outcomes

Reviewed by: G. Bozet, MD

Authors: Campani C, Bensi C, Milani S, et al.

Published in: J Hepatocell Carcinoma 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32802809/

Comment: Patients with hepatocellular carcinoma (HCC)-NAFLD are usually older, with more morbidities (especially cardiovascular diseases and metabolic disorders) and have advanced disease at the diagnosis due to the absence of surveillance.

Patients with HCC-NAFLD unlikely underwent curative treatments, and have been reported to have lower overall survival (OS) compared to individuals with HCC related to other aetiologies. However, this difference is not confirmed by data of patient subgroups who received curative treatment.

In their review, C. Campani et al. (Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy) selected studies published over the past 8 years that analyse characteristics and outcomes of HCC-NAFLD patients who underwent surgery with the aim of identifying features that could predict outcomes and potential selection criteria.

Surgery is a good curative option for patients with HCC-NAFLD, perhaps even better than transplantation in terms of overall survival. In this group of patients, it seems to be essential to evaluate cardio-pulmonary and general operative risk, in addition to the normal risk assessment related to liver function to avoid an underestimation, especially for patients without severe underlying fibrosis.

23rd December 2020

Article: Cost of non-alcoholic steatohepatitis in Europe and the USA: The GAIN study

Reviewed by: G. Bozet, MD

Authors: O’Hara J, Finnegan A, Dhillon H, et al.

Published in: JHEP Rep 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32775976/

Comment: Non-alcoholic steatohepatitis (NASH) leads to cirrhosis and is associated with a substantial socioeconomic burden, which, coupled with rising prevalence, is a growing public health challenge. Nevertheless, there has been little research into the socioeconomic burden associated with NASH.

Direct medical, direct non-medical and indirect costs resulting from NASH were captured in a real-world setting in the Global Assessment of the Impact of NASH (GAIN) study, a prevalence-based burden of illness study across Europe (France, Germany, Italy, Spain, and the UK) and the USA. Physicians provided demographic, clinical, and economic patient information via an online survey.

In total, 3,754 patients found to have NASH on liver biopsy were stratified by fibrosis score and by biomarkers as either early or advanced fibrosis. Per-patient costs were estimated using national unit price data and extrapolated to the population level to calculate the economic burden.

For 2018, the mean total annual per patient cost of NASH was € 2,763, € 4,917, and € 5,509 for direct medical, direct non-medical, and indirect costs, respectively. National per-patient cost was highest in the USA and lowest in France. As expected, costs increased with fibrosis and decompensation, driven by hospitalisation and comorbidities. Indirect costs were driven by work loss. Extrapolating the per-patient cost to a population level demonstrates the rising prevalence of NASH and related comorbidities.

16th December 2020

Article: Targeting Mitochondria-Located circRNA SCAR Alleviates NASH via Reducing mROS Output

Reviewed by: G. Bozet, MD

Authors: Zhao Q, Liu J, Deng H, et al.

Published in: Cell 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32931733/

Comment: Mitochondrial dysfunction plays a central role in nonalcoholic fatty liver disease (NASH). Zhao et al. report that the mitochondrial circular RNA steatohepatitis-associated circRNA ATP5B regulator (SCAR) account for a considerable fraction of downregulated circRNAs in NASH fibroblasts liver fibroblasts from patients with NASH.

Overexpression of SCAR in NASH fibroblasts blocks mitochondrial permeability transition pore opening, inhibiting mitochondrial reactive oxygen species output and subsequent fibroblast activation.

In high-fat diet-fed mice, delivery of SCAR to liver fibroblasts using mitochondria-targeting nanoparticles mitigated insulin resistance and cirrhosis. in patients with NASH, downregulation of SCAR correlated with steatosis-to-NASH progression.

The authors identify a mitochondrial circRNA that drives metaflammation and could serve as a therapeutic target for NASH.

16th December 2020

Article: NASH in HIV

Reviewed by: G. Bozet, MD

Authors: Cervo A, Shengir M, Patel K, et al.

Published in: Curr HIV/AIDS Rep 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32984925/

Comment: Ageing-related comorbidities, including liver disease, represent the main drivers of morbidity and mortality in people with HIV. NAFLD seems a frequent comorbidity in ageing people with HIV nowadays. Giada Sebastiani et al. (Division of Gastroenterology and Hepatology, Chronic Viral Illness Service Royal Victoria Hospital, McGill University Health Centre, Montreal, Canada) review the current status of knowledge regarding this emerging comorbidity in people with HIV, including epidemiology of NAFLD and NASH in HIV, Pathogenesis of NASH in the context of HIV infection, natural history, diagnosis and treatment.

Recent findings suggest that people with HIV are at higher risk for both NASH and NASH-related liver fibrosis. Several hypothesised pathogenic mechanisms may account for this finding. In clinical practice, non-invasive diagnostic tests may help identify patients with NASH-related fibrosis, thus improving risk stratification, and enhancing clinical management decisions.

Clinicians should remain informed of the frequency, significance, and diagnostic and management approach to NASH in people with HIV.

1st December 2020

Article: Patterns and predictors of mortality and disease progression among patients with non-alcoholic fatty liver disease

Reviewed by: G. Bozet, MD

Authors: Canbay A, Kachru N, Haas JS, et al.

Published in: Aliment Pharmacol Ther 2020

Link: https://onlinelibrary.wiley.com/doi/full/10.1111/apt.16016

Comment: Our current understanding of the natural history of NAFLD is incomplete due to a limited knowledge of patient and clinical factors in addition to fibrosis stages that are associated with progression to advanced liver diseases and death.

Thus, the aims of the analysis by Ali Canbay et al. (Department of Internal Medicine, Ruhr-University, Bochum, Germany) were firstly, to evaluate the probability of all-cause mortality and determine the impact of liver disease severity, demographics and comorbidities on the risk of all-cause mortality and secondly, to evaluate the probability of liver disease progression in a large real-world cohort of NAFLD patients in Germany. Data from the German Institut für angewandte Gesundheitsforschung database between 2011 and 2016 were analyzed retrospectively.

The longitudinal probability of mortality for non-progressors, compensated cirrhosis, decompensated cirrhosis and HCC was 3.6%, 18.7%, 28.8% and 68%, respectively. Independent predictors of mortality included cardiovascular disease, type 2 diabetes mellitus, hypertension, obesity and renal impairment.

Early identification and effective management to halt or reverse fibrosis are essential to prevent progression.

1st December 2020

Article: Prevalence of nonalcoholic fatty liver disease in patients with inflammatory bowel disease: A systematic review and meta-analysis

Reviewed by: G. Bozet, MD

Authors:Lin A, Roth H, Anyane-Yeboa A, et al.

Published in: Inflamm Bowel Dis 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32780094/

Comment: In this meta-analysis by A. Lin et al. based on data pooled from all 27 studies, the prevalence of NAFLD among Inflammatory Bowel Disease was 32% (95% CI, 24%-40%) with substantial heterogeneity (I2 = 98%). This prevalence of NAFLD among IBD patients is statistically significantly higher than the prevalence of NAFLD in the general population (25.2%; P < 0.001).

Factors associated with the development of NAFLD among patients with Inflammatory Bowel Disease included age, BMI, diabetes, Inflammatory Bowel Disease duration, and prior history of bowel resection.

There is a higher prevalence of NAFLD among patients with Inflammatory Bowel Disease compared with the general population. Previous treatment regimens may be a risk factor for the development of NAFLD. Future studies are needed to further clarify these risk factors and determine screening recommendations.

24th November 2020

Article: Role of agents for the treatment of diabetes in the management of non-alcoholic fatty liver disease

Reviewed by: G. Bozet, MD

Authors:Budd J, Cusi K.

Published in: Curr Diab Rep 2020

Link: https://pubmed.ncbi.nlm.nih.gov/33015726/

Comment: The goal of K. Cusi et al. (Division of Endocrinology, Diabetes and Metabolism, University of Florida, USA) was to review evidence about the complex association between NAFLD and T2DM, and highlight the potential for disease co-management with the available medications used for the treatment of diabetes.

Metabolic factors contribute to the pathogenesis and co-existence of NAFLD with T2DM. The presence of T2DM in patients with NAFLD increases the risk of disease progression to steatohepatitis (NASH) and advanced fibrosis, cirrhosis, and even hepatocellular carcinoma. In addition to lifestyle modification, pioglitazone and glucagon-like peptide 1 receptor agonists (GLP-1RAs) both reduce the high cardiovascular risk and improve liver histology in patients with NAFLD. The impact of SGLT-2 inhibitors on liver histology has not been fully established. Metformin, DPP-4 inhibitors, and insulin appear to have modest to no effect on modifying the natural history of NAFLD.

The presence of NASH in a patient with T2DM should call for taking advantage of antidiabetic medications with proven efficacy to improve cardiometabolic health and prevent liver disease progression.

24th November 2020

Article: : Association of non-alcoholic fatty liver disease and polycystic ovarian syndrome

Reviewed by: G. Bozet, MD

Authors: Asfari MM, Sarmini MT, Baidoun F, et al.

Published in: BMJ Open Gastroenterol 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32784205/

Comment: MM Asfari et al. aimed to evaluate the association between polycystic ovarian syndrome and NAFLD using a large national database.

Adult female patients (≥18 years) with polycystic ovarian syndrome using the National Inpatient Sample database between 2002 and 2014. The control group included patients who did not have a diagnosis of polycystic ovarian syndrome. Out of a total of 50 785 354 women, 77 415 (0.15%) had polycystic ovarian syndrome. Patients with polycystic ovarian syndrome have four times higher risk of developing NAFLD compared with women without polycystic ovarian syndrome.

Further studies are needed to assess if specific polycystic ovarian syndrome treatments can affect NAFLD progression.

17th November 2020

Article: : The changing global epidemiology of hepatocellular carcinoma

Reviewed by: G. Bozet, MD

Authors: Caines A, Selim R, Salgia R.

Published in: Clin Liver Dis 2020

Link: https://pubmed.ncbi.nlm.nih.gov/33012444/

Comment: Hepatocellular carcinoma is the fifth and ninth most commonly diagnosed cancer in men and women, respectively, and the fourth leading cause of cancer mortality worldwide. Risk factors for HCC include chronic hepatitis B and hepatitis C, alcohol addiction, metabolic liver disease (particularly non-alcoholic fatty liver disease) and exposure to dietary toxins such as aflatoxins and aristolochic acid.

In developing countries hepatocellular carcinoma is largely attributed to underlying hepatitis B virus infection, with more than 70% of hepatocellular carcinoma cases attributable to hepatitis B virus. Until recently, cirrhosis secondary to hepatitis C virus was the most common underlying aetiology of hepatocellular carcinoma, accounting for 60% of hepatocellular carcinoma cases.

More recently, the landscape of HCV and in turn hepatocellular carcinoma is changing owing to direct acting antiviral therapy and the opioid epidemic. Owing to the current epidemic of metabolic syndrome, more recent data show that the population affected by NAFLD and NASH continues to increase and now comprises a significant portion with hepatocellular carcinoma.

17th November 2020

Article: : Trimethylamine N-oxide levels are associated with NASH in obese subjects with type 2 diabetes

Reviewed by: G. Bozet, MD

Authors: Leon-Mimila P, Villamil-Ramirez H, Li XS, et al.

Published in: Diabetes Metab 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32791310/

Comment: Trimethylamine N-oxide (TMAO), choline and betaine serum levels have been associated with metabolic diseases including type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). These associations could be mediated by insulin resistance.

However, the relationships among these metabolites, insulin resistance and NAFLD have not been thoroughly investigated. Moreover, it has recently been suggested that TMAO could play a role in NAFLD by altering bile acid metabolism. The authors conclude, that in obese subjects, circulating TMAO levels were associated with NASH mainly in the presence of T2D.

Functional studies are required to evaluate the role of insulin resistance and T2D in this association, both highly prevalent in NASH patients.

10th November 2020

Article: : Non-alcoholic fatty liver disease and alcohol-related liver disease: Two intertwined entities

Reviewed by: G. Bozet, MD

Authors: Idalsoaga F, Kulkarni AV, Mousa OY, et al.

Published in: Front Med (Lausanne) 2020

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468507/

Comment: In their review, F. Idalsoaga et al. (Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile) aim to summarise current data on the overlapping pathophysiology of NAFLD and alcohol-related fatty liver disease, the available information on alcohol consumption in patients with NAFLD and the effects of MetS and overweight in alcohol-related fatty liver disease.

NAFLD and alcohol-related fatty liver disease share a number of features and often coexist. Alcohol consumption is often a confounding factor in patients with NAFLD. Although initially some studies suggested protective effects in moderate doses, current evidence shows that there is no safe threshold for alcohol consumption in the setting of NAFLD. On the other hand, the presence of MetS and obesity increases the progression of alcohol-related fatty liver disease as well the incidence of HCC and mortality.

For the authors, it is necessary to better define both diseases, acknowledge the presence of a dual aetiology of liver disease in a group of patients, and develop a multidisciplinary approach focused on preventive measures.

10th November 2020

Article: Peroxisome proliferator-activated receptors and their novel ligands as candidates for the treatment of non-alcoholic fatty liver disease

Reviewed by: G. Bozet, MD

Authors: Fougerat A, Montagner A, Loiseau N, et al.

Published in: Cells 2020

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408116/

Comment: Lanifibranor is a moderately potent and well-balanced modulator of the three PPAR isotypes and has a good safety profile. Beneficial effects of lanifibranor on NASH histology, including reduced fibrosis, were confirmed recently in a preclinical model of NASH and fibrosis (choline-deficient amino acid-defined HFD mouse model).

Interestingly, decreased macrophage infiltration in the liver has been observed upon lanifibranor treatment, suggesting that Kupffer cells may be important targets of lanifibranor to improve NAFLD.

Similar results of NASH histology were obtained in the Western diet model, together with a reduction in plasma TG levels.

Lanifibranor is also effective in reducing collagen deposition and increasing plasma adiponectin in mice with CCl4-induced liver fibrosis.

In vitro results have demonstrated that lanifibranor inhibits the proliferation and activation of HSCs, as well as the activation of hepatic macrophages. The anti-inflammatory and anti-fibrotic effects of lanifibranor were also demonstrated in preclinical mouse models of skin and pulmonary fibrosis.

In a relatively near future, the results of clinical trials will determine the therapeutic potential of these novel compounds in NAFLD. Given the role of PPARs in multiple pathways involved in NAFLD and the beneficial effects of each single isotype agonist, PPARs as a promising approach for NAFLD treatment because of potential optimization of the benefits and reduction of the side effects.

3rd November 2020

Article: Automated thermal imaging for the detection of fatty liver disease

Reviewed by: D. Beard

Authors: Brzezinski RY, Levin-Kotler L, Rabin N, et al.

Published in: Sci Rep 2020

Link: https://www.nature.com/articles/s41598-020-72433-5

Comment: NAFLD comprises a spectrum of progressive liver pathologies, ranging from simple steatosis to NASH, fibrosis, and cirrhosis. A liver biopsy is currently required to stratify high‐risk patients. Predicting the degree of liver inflammation and fibrosis using non‐invasive tests remains challenging.

Recent developments of commercially available thermal imaging products have attracted considerable attention for use of infrared thermography in biomedical imaging. Non-invasive thermal imaging combined with advanced image processing algorithms and machine learning-based analysis can correlate surface thermography with structural changes in internal organs of mice such as the heart. RY Brzezinski et al. (Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel) sought to develop a novel screening tool for NAFLD based on thermal imaging. They used a commercially available and non‐invasive thermal camera and developed a new image processing algorithm to automatically predict disease status in a small animal model of fatty liver disease.

They developed an image processing algorithm that measures relative spatial thermal variation across the skin covering the liver. It demonstrated a 100% detection rate and classified all mice correctly according to their disease status.

The authors conclude that non‐invasive thermal imaging combined with advanced image processing and machine learning‐based analysis successfully correlates surface thermography with liver steatosis and inflammation in mice.

3rd November 2020

Article: The role of the gut microbiome and exercise in non-alcoholic fatty liver disease

Reviewed by: D. Beard

Authors: Houttu V, Boulund U, Grefhorst A, et al.

Published in: Therap Adv Gastroenterol 2020

Link: https://journals.sagepub.com/doi/full/10.1177/1756284820941745

Comment: V. Houttu et al. (Department of Experimental Vascular Medicine, University of Amsterdam, Amsterdam, The Netherlands) review the current literature on exercise and the gut microbiome in NAFLD.

The human gut microbiome has been found to influence a multitude of non-communicable diseases such as cardiovascular disease, metabolic syndrome, type 2 diabetes mellitus and obesity. In regard to NAFLD, the causal role of the gut microbiome has not been fully established. The mechanisms by which the gut microbiome influences lipid accumulation, inflammatory responses, and occurrence of fibrosis in the liver are a topic of active research. The influence of exercise on gut microbiome composition is also being investigated. In clinical trials, exercise reduced hepatic steatosis independently of weight reduction and may modulate the gut microbiome.

This puts forward the question whether exercise could mediate its beneficial effects on NAFLD via changes in gut microbiome.

28th October 2020

Article: Contribution of sarcopenia and physical inactivity to mortality in people with non-alcoholic fatty liver disease

Reviewed by: D. Beard

Authors: Golabi P, Gerber L, Paik JM, et al.

Published in: JHEP Rep 2020

Link: https://www.sciencedirect.com/science/article/pii/S2589555920301051

Comment: Physical inactivity and sedentary lifestyle have contributed to the epidemic of obesity and NAFLD. Moreover, NAFLD and sarcopenia have similar pathophysiological profiles. ZM Younossi et al. assessed the association between physical activity, NAFLD, and sarcopenia, and their contributions to mortality, using data from the National Health and Nutrition Examination Survey (NHANES) 1999–2004 with Linked Mortality file (through 2015).

Of 4,611 NHANES participants, NAFLD was present in 29.3%, of whom 17.7% had sarcopenia. Of the NAFLD group, 46.3% was inactive. Sarcopenia was significantly and inversely related to higher physical activity level, both amongst NAFLD and non-NAFLD.

During a median follow-up of 13.5 years, amongst those who died with NAFLD, 33.0% had sarcopenia and 54.3% were inactive. Compared with NAFLD without sarcopenia, NAFLD with sarcopenia was associated with a higher risk of all-cause (HR = 1.78), cardiac-specific (HR = 3.19), and cancer-specific mortality (HR = 2.12).

Sarcopenia should be a part of clinical assessment of patients with NAFLD. Treatment of NAFLD should include optimal management of sarcopenia.

28th October 2020

Article: Vitamin D and non-alcoholic fatty liver disease: a meta-analysis of randomized controlled trials

Reviewed by: D. Beard

Authors: Guo XF, Wang C, Yang T, et al.

Published in: Food Funct 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32966467/

Comment: The results of randomised controlled trials (RCTs) investigating supplemental vitamin D on aminotransferases and cardio-metabolic risk factors in subjects with NAFLD have been inconsistent.

A meta-analysis of randomised controlled trials by XF Guo et al. (Institute of Nutrition & Health, Qingdao University, Qingdao, China) aimed to quantitatively evaluate whether supplementation with vitamin D has beneficial effects in treatment of NAFLD.

Ten trials with a total of 544 NAFLD subjects were included for data synthesis. The summary estimates indicated that supplemental vitamin D significantly reduced the levels of serum/plasma fasting glucose, insulin, and HOMA-IR, and marginally reduced the alanine aminotransferase and triglyceride levels.

However, the pooled effect did not support that supplemental vitamin D was beneficial for concentrations of aspartate aminotransferase, total cholesterol, HDL-cholesterol, and LDL-cholesterol.

This study provides substantial evidence that supplemental vitamin D has favourable effects on glycaemic control and insulin sensitivity in NAFLD patients. Vitamin D could be as an adjuvant pharmacotherapy of NAFLD.

21st October 2020

Article: Prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with type 1 diabetes mellitus: a systematic review and meta-analysis

Reviewed by: D. Beard

Authors: de Vries M, Westerink J, Kaasjager K, et al

Published in: J Clin Endocrinol Metab 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32827432/

Comment: NAFLD and type 2 diabetes are closely associated phenomena. In contrast to the knowledge about NAFLD and type 2 diabetes, there are limited and inconsistent data on NAFLD prevalence in patients with type 1 diabetes mellitus. Type 1 diabetes and type 2 diabetes show major pathophysiological differences but share certain similarities as well. The aim of the study by M. de Vries et al. (Department of Internal Medicine, Diabetology and Vascular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands) was to estimate the prevalence of NAFLD in patients with type 1 diabetes.

The authors performed a systematic review and meta-analysis on the prevalence of NAFLD and distribution of its different stages in patients with type 1 diabetes. Twenty studies between 2009 and 2019 were included (n=3901).

Pooled NAFLD prevalence was 19.3%, increasing to 22.0% in adults only. Pooled prevalence of ultrasound studies was high (27.1%), compared to studies using magnetic resonance imaging (8.6%), liver biopsy (19.3%), or transient elastography (2.3%).

In conclusion, NAFLD prevalence in patients with type 1 diabetes is considerable and is highly dependent on the specific diagnostic modality and NAFLD definition used.

21st October 2020

Article: Non-alcoholic fatty liver disease modifies serum gamma-glutamyl transferase in cigarette smokers

Reviewed by: D. Beard

Authors: Oni ET, Figueredo V, Aneni E, et al.

Published in: J Clin Med Res 2020

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430878/

Comment: Serum gamma-glutamyl transferase (GGT) is a marker of oxidative stress, associated with increased cardiovascular risk. The impact of smoking on oxidative stress may be aggravated in individuals with NAFLD.

ET Oni et al. (Cardiology Division, Heart and Vascular Institute, Einstein Medical Center, Philadelphia, PA, USA) aimed to ascertain the association of smoking on gamma-glutamyl transferase levels in the presence or absence of NAFLD. They evaluated 6,354 healthy subjects without clinical cardiovascular disease between December 2008 and December 2010. NAFLD was diagnosed by ultrasound and participants were categorised as current or non-smokers by self-report. A multivariate linear regression of the cross-sectional association between smoking and gamma-glutamyl transferase was conducted based on NAFLD status.

The prevalence of NAFLD was 36% and 9% were current smokers. Smokers had significantly higher GGT levels in the presence of NAFLD. After multivariable adjustment, current smoking was associated with higher GGT level, compared to non-smokers. The magnitude of this association was higher in subjects with NAFLD, however, no such relationship was observed in those without NAFLD.

In conclusion, smoking is independently associated with significantly increased oxidative stress as measured by GGT level. This association demonstrates effect modification by NAFLD status, suggesting that smoking may intensify CV risk in individuals with NAFLD.

13th October 2020

Article: A Close Relationship between Non-Alcoholic Fatty Liver Disease Marker and New-Onset Hypertension in Healthy Korean Adults

Reviewed by: D. Beard

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

Published in: Korean Circ J 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32281324/

Comment: Although there can be common pathogenic mechanisms for NAFLD and hypertension associated with the development of cardiovascular diseases, little data are showing the association between NAFLD and hypertension in a large-scale cohort study.

JH Roh et al. (department of cardiology in internal medicine, Chungnam National University Hospital, Daejeon, Korea) evaluated the ability of the fatty liver index (FLI) to predict the development of hypertension in healthy individuals.

They included 334,280 healthy individuals without known comorbidities who underwent the National Health check-ups in South Korea from 2009 to 2014.

During a median of 5.2 years’ follow-up, 24,678 subjects (7.4%) had new-onset hypertension. There was a significant correlation between the highest FLI and an increased risk of new-onset hypertension.

The authors concluded that higher FLI was associated with the increased risk of newly developed hypertension after 2 years. In detail, as pointed out in an accompanying editorial, individuals with pre-existing hypertension, diabetes, cardiovascular diseases and on lipid-lowering medications at baseline were excluded. The endpoint of study was a diagnosis of hypertension at a later health check-up. In the higher FLI quartile, the percentage of male, systolic blood pressure, current smoker rate, and the amount of alcoholic consumption were significantly higher. Fasting blood glucose, total cholesterol, LDL-cholesterol, and gamma GT were also significantly higher.

In the context of cardio-metabolic syndrome, although apparent clinical presentation is specific organs other than cardiovascular, patients with NAFLD/NASH should be provided comprehensive cardio-vascular.

13th October 2020

Article: Establishment of a Risk Prediction Model for Non-alcoholic Fatty Liver Disease in Type 2 Diabetes

Reviewed by: D. Beard

Authors: Zhang Y, Shi R, Yu L, et al.

Published in: Diabetes Ther 2020

Link: https://link.springer.com/article/10.1007/s13300-020-00893-z

Comment: The aim of this retrospective cohort study was to develop a risk nomogram for NAFLD in a Chinese population with T2DM. A questionnaire survey, physical examination and biochemical indicator testing were performed on 874 patients with T2DM.

A total of nine predictors, namely sex, age, total cholesterol, body mass index, waistline, diastolic blood pressure, serum uric acid, course of disease and high-density lipoprotein-cholesterol, were identified regression analysis from a total of 24 variables studied. The prediction model was established using LASSO regression, logistic regression, and a newly developed risk nomogram. The LASSO regression analysis minimises prediction error for a quantitative response variable by imposing a constraint on the model parameters that cause the regression coefficients for some variables to shrink toward zero.

This nomogram of NAFLD was validated, and the results were also verified by external verification methods (including ROC, C-INDEX, DCA), with good results.

6th October 2020

Article: Characterization and Proteome of Circulating Extracellular Vesicles as Potential Biomarkers for NASH

Reviewed by: D. Beard

Authors: : Povero D, Yamashita H, Ren W, et al.

Published in: Hepatol Commun 2020

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471415/

Comment: For many years, double-layer phospholipid membrane vesicles, released by most cells, were not considered to be of biological significance. This stance has dramatically changed with the recognition of extracellular vesicles (EVs) as carriers of biologically active molecules that can traffic to local or distant targets and execute defined biological functions.

A central barrier to the development of therapies is the requirement for an invasive liver biopsy for diagnosis of NASH. Discovery of reliable, non-invasive biomarkers are urgently needed. In their study, D. Povero et al. (Department of Pediatrics, Division of Pediatric Gastroenterology Hepatology and Nutrition, University of California San Diego) tested whether circulating EVs may serve as reliable non-invasive “liquid biopsies” for NASH diagnosis and assessment of disease severity.

Total circulating EVs and hepatocyte-derived EVs were isolated by differential centrifugation and size-exclusion chromatography from serum samples of healthy individuals, patients with pre-cirrhotic NASH, and patients with cirrhotic NASH.

Their findings suggest that levels of total and hepatocyte-derived EVs correlate with NASH clinical characteristics and disease severity.

6th October 2020

Article: Left ventricular diastolic dysfunction in liver transplantation: a stronger association with non-alcoholic steatohepatitis

Reviewed by: D. Beard

Authors: : Marella HK, Kamal F, Peravali R, et al.

Published in: Clin Exp Hepatol 2020

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380470/

Comment: Cardiovascular death is an important cause of mortality in end stage liver disease patients undergoing orthotopic liver transplant. Left ventricular diastolic dysfunction is often the early manifestation of cirrhotic cardiomyopathy.

In order to understand the risk factors for ventricular diastolic dysfunction in end stage liver disease patients undergoing orthotopic liver transplant, HK Marella et al. (University of Tennessee/Methodist University Hospital, Memphis, Tennessee, USA) reviewed the electronic medical records of 100 consecutive patients who underwent orthotopic liver transplant. Diastolic dysfunction had been evaluated by transthoracic echocardiogram.

In this cohort of patients, NASH and female gender were independent predictors of left ventricular diastolic dysfunction. However, presence of LVDD did not influence neither immediate post-transplant outcome nor 30-day all-cause mortality.

Limitations of this study include its sample size, short post-transplant outcomes follow-up, and retrospective design.

29th September 2020

Article: Determining the reliability of liver biopsies in NASH clinical studies

Reviewed by: D. Beard

Authors: : Longerich T, Schirmacher P.

Published in: Nat Rev Gastroenterol Hepatol 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32887953/

Comment: The topic of liver biopsy in clinical studies, such as for treatments for NASH, is highly important. Despite limitations, liver biopsy remains the gold standard for the study of liver disease. It is important for the exclusion of alternative diseases and co-morbidities such as autoimmune hepatitis or primary biliary cholangitis and provides unprecedented insights into the pathogenesis of the disease. T. Longerich and P. Schirmacher (Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany) make suggestions in the realisation of future clinical studies:

– The length and width of a biopsy sample are crucial quality criteria
– The accuracy of feature definition is key for the development of a reliable histopathological scoring system
– Histopathological scoring systems should report the grade of disease activity and the stage of fibrosis
– The four-eye principle to reach consensus for study inclusion is recommended for histopathological studies
– Quantitative measurements should be considered as an addendum during study design.

29th September 2020

Article: The effect of coffee consumption on the non-alcoholic fatty liver disease and liver fibrosis: a meta-analysis of eleven epidemiological studies

Reviewed by: D. Beard

Authors: : Hayat U, Siddiqui AA, Okut H, et al

Published in: Ann Hepatol 2020

Link: https://www.sciencedirect.com/science/article/pii/S1665268120301691

Comment: Coffee consumption may have a protective impact on NAFLD and liver fibrosis. However, the evidence from the previous studies is inconsistent. This study comprises two meta-analyses. The first meta-analysis summarises the effect of coffee consumption on NAFLD in patients who did or did not drink coffee. The second analysis compares the risk of liver fibrosis development between NAFLD patients who did or did not drink coffee.

Of the total collected 321 articles, 11 met the eligibility criteria to be included in the analysis. The risk of NAFLD among those who drank coffee compared to those who did not was significantly lower with a pooled Relative Risk value of 0.77.

In conclusion, regular coffee consumption is significantly associated with a reduced risk of NAFLD. It is also significantly associated with decreased risk of liver fibrosis development in already diagnosed NAFLD patients. Although coffee consumption may be considered an essential preventive measure for NAFLD, this subject needs further epidemiological studies.

22nd September 2020

Article: Fructose stimulated de novo lipogenesis is promoted by inflammation

Reviewed by: D. Beard

Authors: Todoric J, Di Caro G, Reibe S, et al.

Published in: Nature Metabolism 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32839596/

Comment: Excessive fructose intake causes dysbiosis and tight-junction proteins downregulation, resulting in intestinal-barrier deterioration and low-grade endotoxaemia. Fructose consumption stimulates hepatosteatosis and, when combined with other risk factors, can cause steatohepatitis and even hepatocellular carcinoma. It is well established that fructose is a more effective inducer of hepatic de novo lipogenesis than glucose is. However, the exact mechanism by which fructose preferentially drives de novo lipogenesis, other than its ketohexokinase-dependent conversion to acetyl-CoA via fructolysis, remained obscure.

J. Todoric et al. (Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, California and Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria) have shown that inflammation associated with fructose-induced barrier deterioration induces hepatic fructose-stimulated de novo lipogenesis, NASH development and hepatocellular carcinoma.

22nd September 2020

Article: Obstructive sleep apnea and severity of NAFLD

Reviewed by: D. Beard

Authors: Krolow GK, Garcia E, Schoor F, et al

Published in: Eur J Gastroenterol Hepatol 2020

Link: https://pubmed.ncbi.nlm.nih.gov/32925501/

Comment: Obstructive sleep apnea (OSA) is associated with the development and evolution of NAFLD, independent of obesity or other shared risk factors. The OSA–NAFLD association is related to the degree of nocturnal hypoxaemia in OSA. Animal models have largely focused on intermittent hypoxia, a key manifestation of OSA, to shed light on the mechanisms by which OSA may give rise to the complex metabolic disturbances that are seen in NAFLD.

Mechanisms involving obstructive sleep apnea and NAFLD are under increasing assessment. In this prospective study by GK Krolow et al. (Porto Alegre, Brazil), patients with at least one of metabolic syndrome criteria were initially assessed by the NAFLD fibrosis score and according to the outcome underwent liver biopsy. All patients performed polysomnography.

A multivariate analysis adjusted for obesity level, found that patients with moderate to severe OSA had an increased risk of hepatic fibrosis (odds ratio 1.22).

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.