How to Approach a Patient With Nonalcoholic Fatty Liver Disease Herbert Tilg  Gastroenterology  Volume 153, Issue 2, Pages 345-349 (August 2017) DOI: 10.1053/j.gastro.2017.06.016 Copyright © 2017 AGA Institute Terms and Conditions

Figure 1 Nonalcoholic fatty liver disease (NAFLD). Diagnostic algorithm in the general population (A) and in type 2 diabetes (T2D) patients (B) (i). Diagnostic steps (from noninvasive toward invasive) are dependent on severity of disease. Abbreviations: CAP, controlled attenuation parameter; HbA1c, hemoglobin A1c; HDL, high-density lipoproteins; HOMA, homeostasis model assessment; IR, insulin resistance; MRE, magnetic resonance elastography; MS, metabolic syndrome; NASH, nonaloholic steatohepatitis; OGTT, oral glucose tolerance testing. Gastroenterology 2017 153, 345-349DOI: (10.1053/j.gastro.2017.06.016) Copyright © 2017 AGA Institute Terms and Conditions

Figure 2 Multiple hits drive the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and define potential treatment targets. All these pathways have been or are currently studied in numerous clinical trials (≥phase II studies). (1) Lipotoxicity. Drugs either suppress de novo lipogenesis (eg, aramchol, a conjugate of cholic and arachidic acid, or selective inhibitors of acetyl-coenzyme A-carboxylase) or increase lipid export from the liver (eg, peroxisome proliferator-activated receptor [PPAR]-γ agonists such as pioglitazone). (2) Insulin resistance. Hepatic or systemic insulin resistance is improved by various drugs such as PPAR-γ agonists (eg, pioglitazone, elafibrinor) or gastrointestinal hormones such as glucagon-like peptide-1 analogues (eg, liraglutide) or fibroblast growth factor 19/21 analogues. Induction of the potent anti-inflammatory adipokine adiponectin is one of the key functions of PPAR-γ agonists. (3) Oxidative stress. Affected by vitamin E. (4) Inflammation and apoptosis. Because inflammation commonly precedes fibrosis effective targeting of inflammation is of crucial importance in this disease. Currently, inhibitors of apoptosis signal-regulating kinase 1 (ASK1) or an oral antagonist of CCR2/5, chemokine receptors for MCP1 and RANTES are tested in phase III studies. (5) Fibrosis. A reduction of fibrosis reflects the main goal in treatment. Galectin-3 plays a key role in fibrosis development (galectin-3 inhibitors are currently being tested). (6) Bile acids. Blocking enterohepatic circulation of bile acids, for example, by inhibiting the ileal apical sodium-dependent bile acid transporter (ASBT) by sevelamer. (7) Farnesoid X receptor (FXR) agonists negatively regulate bile acid synthesis, decrease hepatic lipogenesis and gluconeogenesis, and improve peripheral insulin sensitivity thereby critically affecting various NAFLD pathways. Several FXR agonists eg, obeticholic acid have been tested in clinical trials. (8) Gut microbiota are targeted by antibiotics or probiotics and fecal microbial transfer. Several of the potential NAFLD drugs are able to affect various treatment targets (eg, hepatic fat content and insulin resistance), thereby acting in a pleiotropic manner. Considering its complex pathophysiology, it seems likely that a combination therapy might be the future treatment approach in patients with NASH. Gastroenterology 2017 153, 345-349DOI: (10.1053/j.gastro.2017.06.016) Copyright © 2017 AGA Institute Terms and Conditions