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LIVER DISEASE OVERVIEW

"Liver disease is an important cause of morbidity and mortality in the United States, affecting persons of all ages, but most frequently individuals in the productive years of life, between the ages of 40 and 60 years. Liver disease also disproportionately affects minority individuals and the economically disadvantaged".* Liver disease is a broad term that includes any genetic or acquired condition which impairs normal liver function. The American Liver Foundation recognizes over 100 types of liver disease.* Familiar forms of liver diseases include viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease, autoimmune liver disease, drug induced liver injury, cholelithiasis and Wilson's disease.

The liver has tremendous functional reserve which often masks minor liver damage. Liver disease becomes apparent when injury exceeds the liver's capacity to compensate. Liver injury can result from a variety of causes, including: toxins, infectious agents, diet, ischemic events, inherited conditions or medical treatment.

The liver responds to injury in several ways:

Accumulation of bile, fat (steatosis), proteinaceous debris (mallory bodies), minerals (iron-hemochromatosis) (copper-Wilson disease)
Cell death by apoptosis and/or necrosis. Necrosis may be zonal, bridging, submassive (lobular) or massive (total)
Inflammation (hepatitis) is initiated when stressed or dead hepatocytes spill contents causing the release of proinflammatory cytokines and chemokines
Regeneration differs depending on the type of injury
- regeneration following massive acute necrosis depends on proliferation and differentiation of stem cells originating in the canals of Hering.*
- regeneration following surgical partial hepatectomy or submassive necrosis, results from proliferation of remaining hepatocytes.* After a 70% partial hepatectomy the remnant liver can recover its original mass and function.
Fibrosis is the result of the healing process out of balance. Hepatocyte death or injury cause inflammatory mediators to activate hepatic stellate cells (HSC). Activated HSCs secrete: collagen, elastin, glycoproteins, proteoglycans and hyaluronan to replace or strengthen areas of extracellular matrix (ECM) damaged by necrosis. The fibers provide a scaffolding that holds sinusoidal endothelial cells (SEC) together and close to the remaining hepatocytes. SECs secrete Hepatocyte Growth Factor (HGF) which stimulates regeneration. Proliferating hepatocytes produce protease which degrades excess ECM. Chronic injury results in prolonged activation of HSCs and their fiber deposition. Fibrosis is the over growth of the scaffolding. Fibrosis and cirrhosis are common results of most chronic liver diseases.*
Cirrhosis is the result of progressive fibrosis. Normally, after injury, a fibrous scaffolding is erected, hepatocytes proliferate, HSC fiber production is down regulated and the scaffolding is degraded. In cirrhosis, HSC fiber production is not down regulated, the fibrous layers thicken and cross-linked, making them resistant to protease degradation. Chronic injury causes more fiber deposition leading to encapsulation of hepatocyte nodules, derangement of circulatory architecture, portal hypertension and eventual liver failure. Cirrhosis is also known to be associated with hepatocellular carcinoma.*