Non-alcoholic fatty liver disease

Nonalcoholic fatty liver disease is actually a spectrum of disease, going from least to most severe—steatosis, steatohepatitis, fibrosis, and finally cirrhosis.

Nonalcoholic fatty liver disease results from fat deposition in the liver, which is unrelated to alcohol or viral causes.

Typically, it affects individuals with metabolic syndrome, which includes a combination of three of the following five diagnoses: obesity, hypertension, diabetes, hypertriglyceridemia, and hyperlipidemia.

Given how common metabolic syndrome has become, it’s not surprising that the rate of nonalcoholic fatty liver disease has also increased dramatically.

It’s a massive problem growing in lock-step with expanding waistlines, affecting about three quarters of all obese individuals, including many children.

Although the exact mechanism of nonalcoholic fatty liver disease isn’t clear, insulin resistance seems to play an important role.

Over time, insulin receptors on various tissues including the liver become less responsive to insulin, and as a result the liver goes into a mode where it increases fat storage and decreases fatty acid oxidation.

That means decreased secretion of lipids into the bloodstream, in the form of lipoproteins, and increased synthesis and uptake of free fatty acids from the blood, a process called steatosis.

Steatosis causes fat droplets to form within hepatocytes, some of which become large enough to cause the hepatocytes to swell up with fat and push the nuclei to the edge of the cell.

You can see this on a histopathology slide of the liver.

All of these white circles are large deposits of fat.

Zooming out and looking at the liver, you see widespread steatosis which makes the liver appear large, soft, yellow, and greasy.

Over time, that fat in the hepatocytes is vulnerable to degradation.

Unsaturated fatty acids, or fatty acids that have at least one double bond in their carbon chain, have hydrogen atoms that are especially vulnerable to initiators such as the reactive oxygen species like the hydroxyl radical that have an unpaired electron.

In this example the hydroxyl radical pairs with the vulnerable lipid hydrogen to make water and a fatty acid radical.

The fatty acid radical is unstable and reacts with non-radicals, including molecular oxygen and undamaged fatty acids.

This goes on until one radical species reacts with another radical species, which terminates the reaction.

This process damages lipid membranes leading to things like mitochondrial dysfunction and eventually cell death.

Cell death generates inflammation, and together the process of steatosis and inflammation is referred to as steatohepatitis.

In the absence of alcohol this is called nonalcoholic steatohepatitis or NASH.