The fat that defines NAFLD accumulates because of insulin resistance and disordered fatty-acid handling, but the step that turns steatosis into steatohepatitis is a second injury.
A multiple-hit process
Steatosis develops first, in a patient with dysregulation of fatty acid metabolism, which alters pathways inside the cell and leaves the hepatocytes vulnerable to further injury. Current understanding frames NAFLD as a multiple-hit disease rather than the two-hit model that was once proposed: several parallel insults act together, and the additional hits can be one or more environmental or genetic perturbations that predispose the hepatocytes to inflammation and necrosis. One common way of describing the sequence is:
- hepatic steatosis due to insulin resistance
- oxidative stress and inflammation
- activation of stellate cells and accumulation of extracellular matrix (ECM)
Why insulin resistance causes fat accumulation
Hepatic steatosis is the hallmark histological feature of NAFLD, and it is the result of the accumulation of free fatty acids inside the hepatocytes.
One of the main causes of NAFLD, and of hepatic steatosis in general, is insulin resistance, the kind present in type 2 diabetes mellitus. In type 2 diabetes mellitus there is alteration of, and resistance to, the intracellular signalling of insulin, which has a great effect on the metabolism of lipids. Insulin has an inhibitory effect on the lipolysis of adipose tissue, so when there is resistance to this hormone, free fatty acids (FFAs) increase in the circulation and accumulate inside the hepatocyte, which is the hallmark of NAFLD. In addition, most patients with type 2 diabetes mellitus are also affected by obesity, especially visceral obesity, and this is associated with the production of pro-inflammatory adipokines such as leptin and with lower production of anti-inflammatory adipokines such as adiponectin, giving a net inflammatory state in the body, including the liver, that forms the basis of hepatic fibrosis.
From steatosis to steatohepatitis
It is worth mentioning an important difference in terminology between steatosis and steatohepatitis. Steatosis simply indicates the accumulation of free fatty acids inside the hepatocytes, whereas steatohepatitis is an inflammatory condition that develops on top of steatosis when the protective mechanisms are overwhelmed and can no longer prevent lipotoxicity. Certain lipids, such as ceramides, are potentially harmful to the intracellular organelles and can lead to activation of autophagy, inflammation, activation of hepatic stellate cells and finally fibrosis.
One of the most important signalling pathways involved in steatohepatitis and the pathogenesis of NAFLD is the hedgehog signalling pathway, which is activated in these patients and leads to the conversion of stellate cells into myofibroblast cells, fibrosis and periportal inflammation.
Dysbiosis and increased LPS production by the gut microbiota, especially in small intestinal bacterial overgrowth (SIBO), is associated with NAFLD, and especially with NASH.