From the Literature

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.