Non-alcoholic fatty liver disease: pathophysiological concepts and treatment options

Abstract

The prevalence of non-alcoholic fatty liver disease (NAFLD) is continually increasing due to the global obesity epidemic. NAFLD comprises a systemic metabolic disease accompanied frequently by insulin resistance and hepatic and systemic inflammation. Whereas simple hepatic steatosis is the most common disease manifestation, a more progressive disease course characterized by liver fibrosis and inflammation (i.e. non-alcoholic steatohepatitis) is present in 10-20% of affected individuals. NAFLD furthermore progresses in a substantial number of patients towards liver cirrhosis and hepatocellular carcinoma. Whereas this disease now affects almost 25% of the world's population and is mainly observed in obesity and type 2 diabetes, NAFLD also affects lean individuals. Pathophysiology involves lipotoxicity, hepatic immune disturbances accompanied by hepatic insulin resistance, a gut dysbiosis, and commonly hepatic and systemic insulin resistance defining this disorder a prototypic systemic metabolic disorder. Not surprisingly many affected patients have other disease manifestations, and indeed cardiovascular disease, chronic kidney disease, and extrahepatic malignancies are all contributing substantially to patient outcome. Weight loss and lifestyle change reflect the cornerstone of treatment, and several medical treatment options are currently under investigation. The most promising treatment strategies include glucagon-like peptide 1 receptor antagonists, sodium-glucose transporter 2 inhibitors, Fibroblast Growth Factor analogues, Farnesoid X receptor agonists, and peroxisome proliferator-activated receptor agonists. Here, we review epidemiology, pathophysiology, and therapeutic options for NAFLD.

Keywords: Cardio vascular disease; Diagnosis; NAFLD; Non-alcoholic liver disease; Pathophysiology; Treatment.

Graphical Abstract

Figure 1

The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is multifactorial. Diet and dietary components effect intestinal microbiota and influence hepatic inflammation and steatosis. FFAs, reactive oxygen species (ROS), and low-grade inflammation mediate insulin resistance by altering IKK-β. Increased lipogenesis and free cholesterol further add cellular stress (lipotoxicity). LPS activates hepatic Kupffer cells to produce pro-inflammatory cytokines. SCFAs and TMAO are metabolites derived from diet components through the intestinal microbiota. Together, different mechanisms induce inflammation (e.g. production of pro-inflammatory cytokines), which activates stellate cells to produce collagen and induce fibrogenesis. FFA, free fatty acids; FXR, Farnesoid X receptor; IKK-β, inhibitor of nuclear factor kappa-B kinase subunit beta; IL-1b, interleukin 1 beta; LPS, lipopolysaccharide; MST-3 and MST-4, GCKIII kinases Mammalian sterile 20-like 3 and 4; NF-κB, nuclear factor of activated B cells; ROS, reactive oxygen species; SCFA, Short chain fatty acids; TAG, triacylglycerol; TGFβ, transforming growth factor beta; TMAO, trimethylamine-N-oxide; TNF-α, tumour necrosis factor alpha.

Figure 2

Diagnostic algorithm adapted from Kanwal et al. and the EASL CPG. A1AT, alpha 1 antitrypsin; ALT, alanin aminotransferase; AST, aspartat aminotransferase; CVD, cardio vascular disease; HDL-c, high-density lipoprotein cholesterol; IgG, immunoglobulin G; VCTE, vibration controlled transient elastography.