Fatty Liver (cont.)
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How does insulin resistance relate to NASH?
Almost all patients with NASH are
insulin resistant to some degree. However, only a minority of patients who are
insulin resistant develop NASH. While an increased amount of fat in the liver
may in itself lead to inflammation (see below), no evidence suggests that
insulin resistance alone can lead to NASH.
What else besides insulin resistance contributes to NASH?
The process whereby
liver inflammation and death of liver tissue develop in NASH remains to be
clearly explained. Several theories, however, have been advanced.
First, it is possible that the accumulation of fat in the liver alone could
lead to the development of NASH. According to this theory, the large quantity of
fat in the liver is thought to be a source of peroxidation (removal of electrons
from molecules). Peroxidation thereby generates so-called free radicals. These
free radicals then damage proteins and organelles (small structures within a
cell) in the liver cells. Finally, this damage leads to cell death and/or an
inflammatory cell cascade that removes the afflicted cells. In other words, the
fat could be thought of as potential fuel waiting to be ignited.
However, a growing body of work in animal models of fatty liver suggests a
two-hit hypothesis. With this theory, the first hit is the fatty liver
(steatosis). Then, a second event, or second hit, leads to the development of
NASH. Multiple potential second hits have been suggested.
- Small hormones
(cytokines), such as tumor necrosis factor-alpha, which is secreted by
cells and involved in inflammation, may induce cell death and even increase
insulin resistance.
- Intracellular organelles (mitochondria) that provide
energy to the cell may malfunction and thereby cause a decrease in cell energy
and lead to cell death.
- Enzymes (cytochromes) that are involved in multiple
metabolic pathways may lead to increased peroxidation and its consequences, as
described above.
- Receptors in the cell nucleus that are involved in triggering the
effects of insulin (peroxisome proliferator activating receptors, PPAR) may fail
and thus lead to insulin resistance, inflammation of the liver, and scarring of
the liver.
Finally, recent research suggests that
leptin resistance may contribute to
the development of NASH. Think of this theory as analogous to the process of
insulin resistance. Leptin is a very small hormone that is secreted by the
brain, fat, and stomach cells in response to eating. Its main effect is to curb
the appetite. Patients with NASH have abnormally elevated levels of leptin but
experience no loss of appetite. That is, they are resistant to the
appetite-curbing effect of leptin. The leptin also helps control the processes
of inflammation and scarring within the liver cells. Furthermore, interestingly
enough, leptin also increases insulin sensitivity. But the fact that patients
with NASH are insulin resistant supports the idea that the leptin receptors are
malfunctioning.
The development of severe, irreversible scarring of the liver (cirrhosis) in
NASH is even more poorly understood than the development of liver inflammation
and death of liver tissue, as discussed above. Cirrhosis may simply develop over
time as a result of chronic inflammation and repair, or may be due to yet a
third hit.
As with chronic viral hepatitis and alcoholic liver disease (ALD), not all
patients with NAFLD are at equal risk of developing substantial liver injury.
Thus, not all diabetic and obese patients will develop a fatty liver, and not
all patients with a fatty liver will develop NASH. Finally, not all patients
with NASH will develop cirrhosis. This varying susceptibility of individuals to
these diseases coupled with multiple disease-producing pathways suggests that
the cause of primary NASH is a multi-faceted process. The cause is thought to
involve altered lipid metabolism that results from environmental factors and
genetic predisposition. Many more years of research will be required to fully
understand the cause of NASH.
Next: What are the symptoms of NAFLD and NASH? »
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