Non-alcoholic fatty liver disease (NAFLD) increasingly afflicts a large sector of our community and, beyond its transformation into cirrhosis and end-stage liver disease, is now recognized as a barometer of cardiometabolic risk. This relates to the close link of NAFLD with obesity, insulin resistance, type 2 diabetes and the metabolic syndrome, as well as with oxidative stress, inflammation and endothelial dysfunction; NAFLD is also associated with ectopic toxic fat deposition in the heart, arteries, skeletal muscle and kidney that compound the systemic effects of hepatic steatosis.
NAFLD reflects triglyceride (TG) storage in the liver resulting from an imbalance between lipid uptake/synthesis and oxidation/secretion. Adipose tissue insulin resistance increases the rate of FFA uptake and TG synthesis and availability in the liver. Insulin resistance and excess dietary sugars upregulate SREBP1-c and ChREBP pathways enhancing hepatic lipogenesis, which contributes to VLDL production and TG accumulation in the liver. If secretion of VLDL particles is not able to adequately compensate for excess hepatic TG availability liver fat accumulation ensues, reflecting the imbalance between the total import and export of lipids. Recent evidence has invoked a role for defects in NOX4 and FOX01 signalling and free cholesterol and oxysterols in the pathogenesis of NAFLD, hepatic insulin resistance and dyslipidaemia. Increased hepatic secretion of large VLDL particles is a feature of hepatic insulin resistance and this results in the generation of small dense LDLs and HDLs in the circulation, which together with the accumualtion of chylomicron remnants in the postprandial state accelerates atherothromobsis; a defect in apoC-III metabolism may play a central role.
The initial progression of NAFLD to steatohepatitis (NASH) may be critically dependent on steroyl-CoA desaturase activity, which determines the balance between the accumulation of satutrates (toxic) versus monounsatuartes; subsequent progression to apoptosis involves lysosomal permeation, mitochondrial dysfunction, ER stress, and activation of Death and Toll-like receptors. As NAFLD progresses it potentially enhances systemic inflammation, thrombosis and oxidative stress, which accelerates the development of atherosclerosis. Susceptibility to NAFLD and NASH is under genetic control.
The management of NAFLD is underpinned by dietary and lifestyle measures that regulate obesity, dyslipidaemia and dysglycaemia; intake of saturated fat and sugars must be curtailed, a Mediterranean diet promoted and exercise prescribed. There may be value in using n3-PUFAs supplementation, orlistat and ezetimibe. NASH may improve with pioglitazone and Vitamin E supplementation, but not with metformin or UDCA. Foregut bariatric surgery may benefit NASH, but definitive evidence is lacking. Specific therapies that merit further research include PPAR α/δ agonists, GLP-1 analogues, FXR agonsits, probucol and probiotics. At present, given the panoply of cardiometabolic risk factors associated with NAFLD and NASH, a multiple risk factor approach should be employed, but the clinical trial evidence for the recomendation in this specific group of patients is also lacking.