Hepatic fibrosis is the accumulation of intrahepatic fibrous tissue due to an imbalance in the balance of extracellular matrix formation and degradation, which results from the collapse and coagulation of pre-existing fibrous tissue in the liver. Etiology Hepatic fibrosis is a common response to hepatocyte necrosis or injury. Fibrosis can be caused by a variety of factors: any process that destabilizes the liver’s internal environment, especially inflammation, toxic damage, altered hepatic blood flow, liver infections (viral, bacterial, fungal, parasitic). Many inborn metabolic disorders causing accumulation of substances in the liver are also associated with liver fibrosis, including abnormal lipid metabolism (Gaucher disease), glycogen storage disorders (especially types III, IV, VI, IX and X), alpha1-antitrypsin deficiency, accumulation of exogenous substances such as iron overload syndrome (hemochromatosis), copper deposition disorders (Wilson disease), diseases leading to accumulation of toxic metabolites (e.g., hypertyrosinemia, fungal, parasitic). hypertyrosinemia, fructosemia, galactosemia), peroxidase abnormalities (Zellweger’s syndrome). Many chemicals and drugs are associated with the development of hepatic fibrosis (especially alcohol, methotrexate, isoniazid, hydroxybenzindole, methyldopa, polyvinyl chloride, toluenesulfonylurea, ethamethoxazole). Intrahepatic circulatory disturbances (chronic heart failure, Budd-Chiari syndrome, veno-occlusive disease, portal vein embolism) and obstruction of bile flow can also lead to hepatic fibrosis. Finally, liver fibrosis can also be caused by congenital anomalies. The normal liver is composed of hepatocytes and hepatic sinusoids distributed in a matrix composed of collagen (mainly type I, type III and type IV) and non-collagenous proteins, the latter including glycoproteins (fibronectin, laminin) and some proteoglycans (heparan sulfate, chondroitin sulfate, keratin sulfate, hyaluronic acid). Fibroblasts of the portal vein lumen produce collagen, macromolecular glycoproteins and proteoglycans. Other hepatocytes (especially hepatocytes and lipid storage cells – Ito cells, Kupffer cells and endothelial cells) also produce extracellular matrix components. Lipid storage cells, located under the endothelial cells of the Disse lumen and sinusoids, are the precursors of fibroblasts and are capable of proliferating and producing large amounts of extracellular matrix. The exact fibrogenic factors released from these cells are unknown, but may be a variety of cytokines or lipid peroxidation products and inflammatory cytokines produced by Kupffer cells and activated macrophages. The necrotic hepatocytes are surrounded by new fibroblasts and collagen synthesis is increased leading to scar formation. Decreased active collagen production and degradation of normal or neoplastic collagen leads to liver fibrosis. Lipid storage cells, Kupffer cells, and endothelial cells play an important role in the removal of type I collagen, some proteoglycans, and degenerated collagen, and changes in the function of these cells can affect the extent of liver fibrosis. To the pathologist, fibrous tissue appears more pronounced in fibers that are passively collapsing and shrinking. Increased collagen synthesis and/or decreased degradation leads to deposition of excessive connective tissue, which affects liver function: (1) pericellular fibrosis affects cellular nutrition and causes hepatocyte atrophy; (2) in the lumen of the Disse, fibroblasts are deposited around the hepatic sinusoids, preventing the entry of substances from the blood into the hepatocytes; (3) fibrosis in the small hepatic veins and portal vein disturbs hepatic blood flow and intrahepatic venous resistance (3) fibrosis of the small hepatic veins and portal vein disturbs blood flow in the liver and increases intrahepatic venous resistance, involving all three pathways from the portal vein branches to the hepatic sinusoids and eventually to the hepatic veins. The fibrous cords connecting the portal lumen to the central vein cause anastomotic channels where arterial blood flows directly out of the hepatic vein without passing through normal hepatocytes, further impairing liver function and leading to hepatocyte necrosis, the degree to which some or all of these changes are present determines the degree of impaired liver function. For example, in congenital liver fibrosis, a large number of fibrous cords mainly involve the portal area, while the liver parenchyma is less involved, so congenital liver fibrosis manifests as portal hypertension, while liver function is better preserved. Diagnosis and treatment Although liver fibrosis can occur in many chronic liver diseases, the ultimate clinical reflection of liver fibrosis is portal hypertension. Histological diagnosis relies on liver biopsy. Fibrous tissue can be more easily visualized by special stains (aniline blue, trichrome, silver stain). Since liver fibrosis is a sign of liver injury, its treatment is usually specific to the causative agent.