• Synthesis of various protiens, carbohydrates, and lipids (albumin, globulins, vitamins, and coagulation factors)
• Metabolizing (detoxification) of exogenous and endogenous compounds
• Storage of nutrients
• Formation and secretion of bile  

Exogenous Factors:

Chemical (toxins)

Physical (radiation)

Biological (virus)

 Endogenous Factors:

Circulatory

Metabolic/hereditary

Immune

Mechanical

Mildest form of liver injury

Usually affecting the mitochondria

Lack of ATP inhibits the activity of the ATP pump that maintains water homesostasis across the cell membrane.  This leads to water retention and intracellular swelling.

The cell body is enlarged, the cytoplasm become pale due to diluted contents

Further reduciton in the cells ability to produce energy leads to decreased synthesis of lipoproteins

Drives the metabolism of fatty acids towards increased TG formation

Net result is increased retention of lipids inside the hepatocytes

Acute intoxications have small vesicles:microvesicular steatosis

Chronic intoxications have larger vesicles:macrovesicular steatosis

Rapid accumulation of fat in microvesicular steatosis can lead to rapid hepatoceullular failure and death

Slow accumulation of fat in microvesicular steatosis can persist for a long time with no significant loss of hepatocellular function or evidence of cellular necrosis.

Asprin intoxication in predisposed children following mild viral illness.

Example of microvesicular steatosis

Involves the entire organ

Liver undergoes parenchymal collapse

Liver grossly appears as having infoldings or wrinkling of the hepatic fibrous capsule

Any amount of cell necrosis provokes an inflammatory response aimed at cleaning the dead cell debris and promoting cell regeneration.

This usually leads to full structural and functional recover in acute cases of less than submassive or massive necrosis.

Healing by primary intention

Kupffer cells are activated and secrete multiple cytokines.

Platlet derived growth facor (PDGF) and Tumor necrosis factor (TNF) activate stellate cells.

Contraction of the activated stellate cells is stimulated by Endothelin-1 (ET-1)

Fibrogenesis is stimulated by transforming growth factor-beta (TGF-B)

Chemotaxis of activated stellate cells to areas of injury is promoted by PDGF and Monocyte chemotatic protein-1 (MCP-1)

Fibrosis proceeds simultaneously with hepatocyte regeneration.  If the original liver reticulin framework is destroyed and the haphazard scar formation preculde a fully functional architectural recovery.  This results in patchwork regeneration of hepatocyte nodules and intervening (bridging) fibrosis septa are produced. This is the hallmark of end-stage liver disease or cirrhosis.

Fibrous septa can be seen throughout the liver but they do not enclose regenerative nodules.

The lobular organization within the enclosed liver parenchyma is preserved

Biliary Cirrhosis: Initial damage and subsequent fibrosis take place around the bile ductules. The portal areas become bridged with fibross and the central vein remains visible in the middle of the residual parenchymal nodule.

Cardiac Cirrhosis: Passive congestion of the liver. Initial injury is around the central vein (congested area) zone 3.  Fibrous septa would run between central veins leaving portal triads in the middle.

Alcoholic cirrhosis: The fibrosis is mostly pre-isinusoidal, bridging portal tracts with central veins and thus leaving no landmarks in the middle.

Post-necrotic cirrhosis: After chronic viral hepatitis.  Damage and resulting fibrosis do not follow any particular pattern.

Cryptogenic (unknown etiology)

Post-hepatitic (viral, toxic)

Metabolic (Fe, Cu, alpha-1-antitrypsin)