1.2. Pathophysiology of cirrhosis
There is an alteration in the architecture of the liver that leads to
the formation of dense fibers in tissues due to chronic inflammation and
restoration. The stellate cells of the liver release collagen in the
hepatic sinusoids causing blockade in the liver system which leads to
diminishing of synthetic and metabolic process (10). There is activation
of fibroblast and hepatic stellate cells during the progress of
cirrhosis. The myofibroblasts are formed due to differentiation of cells
derived from bone marrow. Formation of myofibroblasts and epithelial
cells of the bile duct leads to the chemotaxis activation of cells at
injury sites (11, 12). The inflammatory mediators lead to the
proliferation of cells resulting in collagen production that induces
hepatic fibrosis. This inhibits degradation of the matrix and programmed
cell death of myofibroblasts resulting in the progression of liver
injury-causing hepatic cirrhosis (13-15).
Hepatocytes (hepatic stellate cells, sinusoidal epithelial cells, and
kupffer cells) play a pivotal role in pathophysiological modification in
cirrhosis. The hepatic stellate cells present in the sinusoids help in
the storage of a fat-soluble vitamin i.e., of Vitamin A. When the
inflammatory mediators such as endothelin-1 and interleukins (IL-1,
IL-16) were released, the HSCs get activated and get converted to
myofibroblasts due to which collagen deposition occurs, resulting in
fibrosis. The sinusoidal epithelial cells form fenestrations present in
the wall and help in the extracellular exchange of nutrients between
liver cells and sinusoids (16). The damage in fenestrations upon chronic
inflammation contributes to fibrosis (17). Kupffer cells commonly known
as satellite macrophages located in the wall of sinusoids are
responsible for the release of harmful mediators and act as
antigen-presenting cells for foreign elements (18). Additionally,
physical injury to hepatocytes releases reactive oxygen species, free
radicals, and cytokines leading to the activation of hepatic stellate
cells and further causing cirrhosis.
The mortality in patients suffering from cirrhosis is mainly due to
hypertension and collateral vasoregulatory circulation development.
Pharmacologically, the sinusoidal epithelial cells release vasodilator
factors such as nitric oxide and endothelin-1 and restrict the
sinusoidal blood flow. Pathophysiologically in patients with cirrhosis,
the endothelin-1 levels rise and nitrous oxide level decline developing
portal hypertension. Due to the homeostatic phenomenon, the vascular
remodeling in hepatic stellate cells in sinusoids leads to vascular
resistance amplification. To remunerate this hike in vascular pressure,
the development of collateral circulation transpires (19). The counter
effect in systemic vascular resistance and splanchnic vasodilation
enhances the RAAS activation, resulting in natriuretic effect and
hyperdynamic circulation, which counterparts the rise in after loading
to the heart (20).