Non-alcoholic fatty liver disease (NAFLD) is now the most common chronic liver disease in the developed world and affects about 25% to 30% of adults in the US. Comprised of a spectrum of disease severity, NAFLD ranges from simple steatosis to nonalcoholic steatohepatitis (NASH). Patients with NAFLD have significantly increased mortality because of both hepatic complications, such as cirrhosis and hepatocellular carcinoma, and extrahepatic complications, such as metabolic syndrome, cardiovascular disease, nephrological disorders, and malignancy.

The relationship between NAFLD and metabolic alterations such as type 2 diabetes is well described and related to insulin resistance, with NAFLD being recognized as the hepatic manifestation of metabolic syndrome. NAFLD also is strongly associated with type 2 diabetes mellitus, chronic kidney disease, and obstructive sleep apnea. Experimental evidence suggests that chronic intermittent hypoxia is a triggering factor for liver injury, inflammation, and fibrogenesis, and, interestingly, OSAS is also believed to be one of the elements promoting the evolution of NAFLD from steatosis to NASH. Although these associations may result from shared risk factors, strong evidence suggests that for some of the factors at least, there is a bidirectional influence on the natural history of the other comorbidity. This means that the management of NAFLD can help improve the management of comorbidities and vice versa. However, NAFLD may also coincide with endocrine diseases such as polycystic ovary syndrome, hypothyroidism, growth hormone deficiency, or hypercortisolism. Hyperlipidemia, lipotoxicity, and impaired insulin secretion are among the possible mechanisms underlying the association of NAFLD with diabetes melltius type 2 and cardiovascular disease. Consistently, estrogen deficiency, by potentiating hepatic inflammatory changes, hastens the progression of disease in a dietary model of NASH developing in ovariectomized mice fed a high-fat diet. Fertile age may be associated with more severe hepatocyte injury and inflammation, but also with a decreased risk of liver fibrosis compared to men and postmenopausal status. Later in life, ovarian senescence is strongly associated with severe steatosis and fibrosis which may occur in postmenopausal women. Estrogen deficiency is deemed to be responsible for these findings via the development of postmenopausal metabolic syndrome. Some studies have shown that NAFLD patients may have early or subtle cognitive dysfunction, including in the visuospatial and executive function domains. Also, individuals with NAFLD have a higher prevalence of depression than general populations and depression was independently associated with NAFLD.

In this Special Issue, we invite investigators to contribute original research articles as well as review articles that will stimulate the continuing efforts to understand the widespread comorbidity of NAFLD. Of particular interest is the relationship between NAFLD and endocrine dysfunctions, as well as on NAFLD involvement with OSAS, risk estimation of NAFLD patients for cardiovascular diseases, psychological impairments in NAFLD patients, novelties in the diagnostics and therapy of NAFLD and concomitant diseases, prevention and early detection of NAFLD to avoid appearance of comorbid diseases or, at least to reduce the possible risk for extra-hepatic complications, etc.

Potential topics include but are not limited to the following:

• NAFLD as a multisystemic disease
• NAFLD and comorbidity in the general population
• NAFLD insulin resistance and diabetes mellitus type 2
• Endocrinological comorbidity and NAFLD
• Risk for cardiovascular diseases and complications
• Obstructive sleep apnea and NAFLD
• NAFLD and chronic kidney disease
• Psychiatric disorders and brain organic aftermaths in NAFLD
• Potential clashes between combined pharmacotherapy of NAFLD and comorbid disorders
• Preventive measures to avoid NAFLD and extra-hepatic manifestations