The primary characteristic of<unk>  is the accumulation of lipids in the<unk> , largely in the form of triglycerides. However, the mechanisms by which triglycerides accumulate and the reasons that accumulation can lead to<unk>  dysfunction are complex and incompletely understood.<unk>  can include steatosis along with varied signs of<unk>  injury: either lobular or portal inflammation (a form of<unk>  injury) or ballooning degeneration. Similarly, NASH can include histological features such as portal inflammation, polymorphonuclear cell infiltrates, Mallory bodies, apoptotic bodies, clear vacuolated nuclei, microvesicular steatosis, megamitochondria, and perisinusoidal fibrosis. NASH increases hepatocyte death via apoptosis or necroptosis is increased in NASH compared with simple steatosis, and inflammation is a hallmark of NASH. One debated mechanism proposes that hepatic steatosis progresses to steatosis with inflammation following some further injury, or second hit. Oxidative stress, hormonal imbalances, and mitochondrial abnormalities are potential causes of this "second hit" phenomenon. A further nutrigenomics model named multiple hit extends the second hit model, suggesting that multiple disease biomarkers and factors such as genes and nutrition influence<unk>  and NASH progression. This model attempts to use these factors to predict the impact of lifestyle changes and genetics for the evolution of the<unk>  pathology. Many researchers describe<unk>  as a multisystem disease, as it impacts and is influenced by organs and regulatory pathways other than the<unk> . The accumulation of senescent cells in the<unk>  is seen in persons with<unk> . In mice,<unk>  senescent hepatocytes result in increased<unk>  fat deposition. Treatment of<unk>  mice with senolytic agents has been shown to reduce hepatic steatosis. Based on gene knockout studies in murine models, it has been suggested that, among many other pathogenic factors, TGF beta signals may be crucially involved in promoting the progression of NASH. Fructose consumption<unk><unk>  and<unk><unk><unk>  disease share similar histological features, which suggests that they might share common pathogenic pathways. Fructose can cause<unk>  inflammation and addiction similarly to ethanol by using similar metabolic pathways, unlike glucose. Therefore, some researchers argue that<unk><unk>  and<unk><unk><unk>  diseases are more alike than previously thought. Furthermore, high fructose consumption promotes fat accumulation in the<unk>  by stimulating de novo lipogenesis in the<unk>  and reducing the beta-oxidation of fat. Unlike the sugar glucose, the enzyme fructokinase rapidly metabolizes fructose. This leads to a decreased level of intracellular adenosine triphosphate (ATP). The decrease in ATP increases oxidative stress and impairments in proper protein synthesis and mitochondrial function in the<unk> . Insulin resistance Insulin resistance contributes to the accumulation of toxic fat in the<unk>  in several ways. First, it promotes the release of free<unk>  acids (FFAs) from adipose tissue into the blood. Typically, adipose tissue stores lipids in the form of triglycerides, slowly releasing them into the bloodstream when insulin is low. In insulin-resistant adipose tissue, such as in people with obesity and type 2 diabetes, more triglycerides are broken down into FFAs and released into the bloodstream, promoting uptake by the<unk> . Second, insulin promotes the production of new FFAs in the<unk>  via de novo lipogenesis; this production of<unk>  fats continues to be stimulated by insulin, even when other tissues are insulin-resistant. These FFAs are combined back into triglycerides in the<unk> , forming the major constituent of the accumulated fat in the<unk> . The three sources of free<unk>  acids that contribute to<unk>  triglyceride accumulation include FFAs circulating in the bloodstream (59%), FFAs derived from carbohydrates such as fructose and glucose (26%), and diet (14%). Despite the accumulation of triglycerides in the<unk> , they are not directly toxic to<unk>  tissue. Instead, alteration of the profile of the other lipid subtypes present in the<unk> , such as diacylglycerols, phospholipids, ceramides, and free cholesterol, have a more significant role in the pathogenesis of<unk> . Once<unk>  progresses in severity to the point of NASH, this promotes further insulin resistance in the adipose tissue and<unk> , which results in a harmful cycle of insulin resistance,<unk>  fat accumulation, and inflammation. Adipose tissue dysfunction also decreases secretion of the insulin-sensitizing adipokine adiponectin in people with<unk> . Adiponectin has several properties that protect the<unk> . These properties include improved<unk>  fat metabolism, decreased de novo lipogenesis, decreased glucose production in the<unk> , anti-inflammatory properties, and anti-fibrotic properties. Skeletal muscle insulin resistance may also play a role in<unk> . Insulin-resistant skeletal muscle is not as efficient at taking up glucose from the bloodstream after a meal. This inefficient glucose uptake promotes the redistribution of consumed carbohydrates from glucose destined for use in glycogen stores in the skeletal muscles to being used as a substrate for de novo lipogenesis in the<unk> . Dysbiosis Disruptions in the intestinal microbiota seem to influence<unk>  risk in several ways. People with NASH can have elevated levels of blood ethanol and proteobacteria (which produce alcohol), with dysbiosis proposed as a mechanism for this elevation. Alterations in the composition of the intestinal microbiota may influence<unk>  risk in several ways. These changes appear to increase the permeability of intestinal tissue, thereby facilitating increased<unk>  exposure to harmful substances (e.g., translocated bacteria, bacterial toxins, and inflammatory chemical signals). The increased transport of these harmful substances to the<unk>  promotes<unk>  inflammation, enhances nutrient and calorie absorption, and alters choline metabolism. Higher levels of intestinal bacteria that produce butyrate may be protective. Excessive macronutrient intake contributes to gut inflammation and perturbation of homeostasis, and micronutrients may also be involved. In addition to reducing weight and risk factors, lifestyle changes may prompt positive changes in the gut microbiota. In particular, diet<unk> sity may play a role that was overlooked in animal studies, since they often compare a Western high-fat, low-diversity diet against a low-fat but higher-diversity chow. The health benefits after bariatric surgery may also involve changes in the gut microbiota by increasing gut permeability. File:Mallory_body_high_mag_cropped_annotated.Mallory-Denk body File:Ballooning_degeneration_high_mag_cropped_annotated.Ballooning degeneration File:6_Nash_8_680x512px.NASH (inflammation) and fibrosis stage 1 File:2_NASH_09_680x512px.NASH (inflammation) and fibrosis stage 2 File:Lobular_necro-inflammation_--_high_mag.Lobular inflammation
Non-alcoholic fatty liver disease
Metabolic syndrome
Alcoholic liver disease
Alcoholic hepatitis
Fatty liver disease
Autoimmune hepatitis
Viral hepatitis
Polycystic liver disease