Systemic Complications of Nonalcoholic Fatty Liver Disease: When the Liver Is Not an Innocent Bystander

Abstract

The top three leading causes of death in patients with nonalcoholic fatty liver disease (NAFLD) in descending order are cardiovascular disease, cancer, and liver disease. It is clear now that the increased risk of metabolic and macro- and microvascular complications in NAFLD stems from the associated features of metabolic syndrome. However, NAFLD itself may contribute to the spectrum of risk factors associated with insulin resistance. The primary focus of this review is to summarize the main systemic associations of NAFLD, as well as to discuss the mechanisms that link them to NAFLD. Hepatic lipid accumulation in NAFLD impairs hepatic glucose and lipid metabolism further increasing the risk of type 2 diabetes mellitus and of cardiovascular disease, independently of established risk factors. The incidence, prevalence, and severity of these complications are proportional to the histological severity of liver damage suggesting that NAFLD, but particularly nonalcoholic steatohepatitis, can also contribute to the low-grade inflammatory state through the systemic release of several markers of inflammation, oxidative stress, and of procoagulant factors. The clinical implication of these findings is that patients with NAFLD require a multidisciplinary evaluation, with a major focus on type 2 diabetes mellitus and cardiovascular disease complications and may benefit from more intensive surveillance and early treatment interventions to decrease the risk for cardiovascular and kidney complications.

Animal Models of Nonalcoholic Steatohepatitis: Eat, Delete, and Inflame

“…Hepatic triglyceride accumulation in turn contributes to impaired glucose metabolism and insulin sensitivity in muscle and in the liver [4]. NAFLD is now recognized as a predictor of future risk of type 2 diabetes mellitus [5,6]. Long-term follow-up studies in NASH suggest that the disease is usually slowly progressive, but can ultimately lead to cirrhosis in a subset of patients with its sequelae of portal hypertension, end-stage liver disease and hepatocellular carcinoma and an increase in overall mortality [7–9].…”

Nonalcoholic fatty liver disease: Updates on associations with the metabolic syndrome and lipid profile and effects of treatment with PPAR-γ agonists

“…However, this 111 hypothesis should be confirmed by specifically designed future cohort studies. 112 risk of T2DM and CVD [7]. Because of the multifactorial nature of the disease, a combined 231 treatment, simultaneously targeting more than one pathogenetic "hit", might represent a more 232 realistic management, as we previously suggested [28].…”

“…NAFLD is now among the leading causes of cirrhosis [3], hepatocellular carcinoma [4] 40 and liver transplantation [5]. Besides hepatic morbidity, NAFLD has been associated to extra-41 hepatic morbidity too [6], including metabolic complications, chronic kidney, malignancies 42 and cardiovascular disease (CVD), which all contribute to the higher mortality observed 43 among NAFLD patients [7]. Specifically, evidence from recent studies strongly emphasizes 44 the importance of assessing the global CVD risk in patients with NAFLD and that NAFLD 45 might be both a marker and an early mediator of CVD.…”

Low Birthweight Increases the Likelihood of Severe Steatosis in Pediatric Non-Alcoholic Fatty Liver Disease

“…Traditionally considered the hepatic manifestation of the metabolic syndrome (MetS), NAFLD is a multifactorial disease with a substantial inter-patient variability in terms of severity and rate of progression [5][6][7]. In obese children, NAFLD and NASH have a general prevalence of 70 and 30%, respectively [8].…”