From the Literature

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.