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).