Taking Charge of Your Health

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, unrelated to alcohol or viral causes. Typically, it affects individuals with metabolic
syndrome, which includes a combination of three of the following five diagnosis: 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 precise mechanism of nonalcoholic
fatty liver disease is not 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 pushing 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, shows
widespread steatosis which makes the liver appear large, soft, yellow, and greasy. Over time, the 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 particularly
vulnerable to initiators such as the reactive oxygen species like the hydroxy 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 will
react with non-radicals, including molecular oxygen and undamaged fatty acids. This goes on until one radical species reacts
with another radical species terminating 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. In addition to bloated and dying hepatocytes,
there may be additional histopathologic changes like the presence of Mallory-Denk bodies which
are tangles of intermediate filaments that can be seen in the cytoplasm of hepatocytes. The mechanism for how these form remains unclear. Hepatocyte damage also attracts neutrophils
into the liver tissues. Finally, chronic steatohepatitis can cause
liver stellate cells to lay down fibrotic tissue causing the disease to be classified
as fibrosis. As the process of fibrosis continues, the
overall architecture of the liver changes, to the point where the disease is classified
as cirrhosis. Even at the advanced stage of steatohepatitis,
an individual might have no symptoms. And when there are symptoms, they are often
vague – like fatigue or malaise. Once there is significant liver damage, there
can be hepatomegaly or enlargement of the liver, pain in the right upper quadrant of
the abdomen, jaundice, and even an accumulation of fluid in the peritoneal cavity called ascites. Because hepatocytes are being destroyed, there
can be an increase in liver enzymes such as aspartate transaminase (AST) and alanine transaminase
(ALT). Classically, progression of steatosis to steatohepatitis
and then to cirrhosis causes an increase in the ALT and sometimes AST. In contrast, alcoholic liver injury generally
causes the a big increase in AST and a more modest increase in ALT giving a AST:ALT ratio
generally>2. If nonalcoholic fatty liver disease is suspected,
a diagnosis can be made with imaging studies such as ultrasound, a CT scan, or an MRI to
look for fatty infiltrates. In addition, a biopsy of the liver can be
done to confirm the diagnosis and assess the severity of the disease. Generally speaking, a liver with more than
5% fat content is considered abnormal. Steatosis and to a lesser degree steatohepatitis
is generally reversible by addressing the underlying cause, however, that’s generally
not the case once fibrosis and cirrhosis have set in. The goal is to reverse the factors that contribute
to insulin resistance, primarily through a healthy diet and an active lifestyle, as well
as medications to control blood glucose levels if needed. OK, quick recap: nonalcoholic fatty liver
disease occurs when fat is deposited in the liver – a process called steatosis. Inflammation from steatosis can lead to steatohepatitis,
and chronic steatohepatitis can lead to fibrosis, and ultimately to cirrhosis. This spectrum of disease is thought to be
caused by insulin resistance, and depending on the stage of disease, it can be reversed
with careful attention to diet and exercise – as well as medications to help control blood
glucose levels. Thanks for watching, you can help support
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