Cirrhosis pathophysiology On the Web
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Cirrhosis occurs due to long term liver injury which causes an imbalance between matrix production and degradation. Early disruption of the normal hepatic matrix results in its replacement by scar tissue, which in turn has deleterious effects on cell function.
- The liver plays a vital role in the synthesis of proteins (e.g. albumin, clotting factors and complement), detoxification, and storage (e.g. vitamin A). In addition, it participates in the metabolism of lipids and carbohydrates.
- Cirrhosis is often preceded by hepatitis and fatty liver (steatosis). If the cause is removed at this stage, the changes are still fully reversible.
- The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal parenchyma, blocking the portal flow of blood through the organ and disturbing normal function. The development of fibrosis requires several months, or even years, of ongoing injury.
- Recent research shows the pivotal role of the stellate cell, a cell type that normally stores vitamin A, in the development of cirrhosis. Damage to the hepatic parenchyma leads to the activation of the stellate cell, which becomes contractile (called myofibroblast) and obstructs blood flow in the circulation. In addition, it secretes TGF-β1, which leads to a fibrotic response and proliferation of connective tissue. The extracellular matrix around hepatocytes is composed of collagens (especially type I, III, IV), glycoprotein and proteoglycans.
- Sinusoidal endothelial cells are also important contributors of early fibrosis. Endothelial cells from a normal liver produces collagen, laminin and fibronectin.
- In addition, the liver responds to injury with new blood vessel formation. Platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF), nitric oxide, and carbon monoxide are the mediators involved in angiogenesis. Angiogenesis in cirrhosis results in the production of immature and permeable VEGF induced neo-vessels that fail to correct liver injury. ,
- Furthermore, it disturbs the balance between matrix metalloproteinases and the naturally occurring inhibitors (TIMP 1 and 2), leading tomatrix breakdown and replacement by connective tissue-secreted matrix.. Matrix metalloproteinase (MMP) are calcium dependent enzymes that specifically degrade collagen and non collagenous substrate. There are five categories of MMP based upon their specificity for the substrate. MMP-2 and stromyelysin-1 are produced from stellate cells. MMP-2 degrades collagen and stromelysin-1 degrades proteoglycan and glycoprotein.
- The fibrous tissue bands (septa) separate hepatocyte nodules, which eventually replace the entire liver architecture, leading to decreased blood flow throughout.
- The spleen becomes congested, which leads to hypersplenism and increased sequestration of platelets.
- Portal hypertension is responsible for the most severe complications of cirrhosis.
- Pathogenesis of cirrhosis based upon its individual cause is as follows:
- Alcoholic liver disease: Alcohol seems to injure the liver by blocking the normal metabolism of protein, fats, and carbohydrates. Patients may also have concurrent alcoholic hepatitis with fever, hepatomegaly, jaundice, and [[anorexia].
- Chronic hepatitis C: Infection with the hepatitis C virus causes inflammation of and low grade damage to the liver that over several decades can lead to cirrhosis.
- Non-alcoholic steatohepatitis (NASH): In NASH, fat builds up in the liver and eventually causes scar tissue. This type of hepatitis appears to be associated with diabetes, protein malnutrition, obesity, coronary artery disease, and treatment with corticosteroid medications.
- Primary sclerosing cholangitis: PSC is a progressive cholestatic disorder presenting with pruritus, steatorrhea, fat soluble vitamin deficiencies, and metabolic bone disease. There is a strong association with inflammatory bowel disease (IBD), especially ulcerative colitis.
- Autoimmune hepatitis: This disease is caused by the immunologic damage to the liver causing inflammation and eventually scarring and cirrhosis.
- Certain TERT (Telomerase reverese transcriptase)gene variants resulting in reduced telomerase activity has been found to be a risk factor for sporadic cirrhosis
- An uncharacterized nucleolar protein, NOL11, has a role in the pathogenesis of North American Indian childhood cirrhosis
- Loss of interaction between the C-terminus of Utp4/cirhin and other SSU processome proteins may cause North American Indian childhood cirrhosis
Macroscopically, the liver may initially be enlarged, but with progression of the disease, it becomes smaller. Its surface is irregular, the consistency is firm, and the color is often yellow (if associates steatosis). Depending on the size of the nodules there are three macroscopic types: micronodular, macronodular and mixed cirrhosis.
- In the micronodular form (Laennec's cirrhosis or portal cirrhosis) regenerating nodules are under 3 mm.
- In macronodular cirrhosis (post-necrotic cirrhosis), the nodules are larger than 3 mm.
- The mixed cirrhosis consists of a variety of nodules with different sizes.
Microscopically, cirrhosis is characterized by regeneration nodules surrounded by fibrous septa. In these nodules, regenerating hepatocytes are disorderly disposed. Portal tracts, central veins and the radial pattern of hepatocytes are absent. Fibrous septa are important and may present inflammatory infiltrate (lymphocytes, macrophages). If it is a secondary biliary cirrhosis, biliary ducts are damaged, proliferated or distended - bile stasis. These dilated ducts contain inspissated bile which appears as bile casts or bile thrombi (brown-green, amorphous). Bile retention may be found also in the parenchyma, as the so called "bile lakes".
Chronic active hepatitis - Cirrhosis
Primary biliary cirrhosis
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- Pathology atlas, "cirrhosis".