Home / Resources / Clinical Gems / International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #102: Pathogenesis of Nonalcoholic Fatty Liver Disease (NAFLD) Part 4

International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #102: Pathogenesis of Nonalcoholic Fatty Liver Disease (NAFLD) Part 4

Dec 5, 2017

Hypertriglyceridemia and low HDL cholesterol, increased risk of type 2 diabetes

Under fasting conditions, the liver of subjects with NAFLD overproduces triglyceride-enriched VLDL particles despite hyperinsulinemia when compared to equally obese subjects without NAFLD [68]. Insulin normally decreases production of VLDL by inhibiting adipose tissue lipolysis, and by directly suppressing hepatic production of VLDL [69]. In subjects with NAFLD, insulin fails to suppress both lipolysis [20] and production of triglyceride-rich VLDL particles from the liver [16]. This hepatic overproduction of large triglyceride-rich VLDL particles is another consequence of hepatic insulin resistance and the major contributory mechanism underlying the increase in serum triglycerides in subjects with the MetS and NAFLD [69] (Figure 19.4). The increase in VLDL leads to lowering of HDL cholesterol and also to generation of small dense LDL particles, which are known to be highly atherogenic (see [32] for review).

Markers of cardiovascular risk, increased risk of cardiovascular disease and thromboembolic complications

The liver in subjects with NAFLD overproduces multiple markers of cardiovascular risk. These include, in addition to liver enzymes, glucose, and VLDL, increased production of C-reactive protein (CRP), fibrinogen, coagulation factors (FVII-IX, XI-XII), and plasminogen activator inhibitor-1 (PAI-1), and decreased production of insulin-like growth factor binding protein 1 (IGFBP-1) and sex-hormone binding globulin (SHBG) [70]. Changes in these circulating markers could explain, at least partly why NAFLD predicts CVD (see [8] for review), also when adjusted for obesity [8]. The changes in the markers of fibrinolysis and coagulation could contribute to an increased risk of thromboembolic complications in NAFLD [17].

Other metabolic disease

NAFLD increases the risk of cholesterol gallstones [41]. The fatty liver overproduces cholesterol [71] and displays other alterations in cholesterol metabolism [72], which may contribute to formation of cholesterol gallstones and also hepatic damage (Figure 19.2).NAFLD is also associated with an increased prevalence of obstructive sleep apnea and polycystic ovary syndrome.


NAFLD is a new epidemic, which has important health consequences. The data summarized in this review support the idea that NAFLD, which is not due to genetic variation in PNPLA3 “metabolic NAFLD,” closely resembles the MetS with respect to its causes and consequences. For these subjects, liver fat content is an excellent marker of the metabolic abnormalities characterizing the MetS. Indeed, since NAFLD predicts type 2 diabetes, even independent of the MetS, it may be better than the MetS in predicting risk. In the absence of simple and reliable tools to diagnose NAFLD, screening for simple steatosis is not recommended at present [1]. However, an incidental finding of NAFLD should lead to careful evaluation of the presence of risk factors for diabetes and CVD as well as for NASH. NAFLD may also be encountered more often than by chance in patients with otherwise unexplained deep venous thromboembolism and gallstone disease. On the other hand, the possibility of NASH should be remembered in all patients with the MetS by calculating appropriate risk scores such as the NAFLD liver fibrosis score [73,74]. PNPLA3 genotyping may become a routine test in all subjects with NAFLD as these patients are at particularly high risk of NASH and even HCC but not diabetes and CVD. However, the clinical utility of such testing still warrants further evaluation.

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