Structure
and Function
Venous blood from the stomach and intestine flows into the portal vein and through the liver before entering the systemic circulation. The liver is the first organ to encounter absorbed materials from the gut, and is responsible for their catabolism, storage and or excretion into bile. Secretion into bile is a mayor toxicant clearance route, to be excreted in urine or feces. Exceptions occur when a compound is repeatedly reabsorbed in the intestinal lumen, a process known as enterohepatic circulation.
The liver is divided into hexagonal lobules around central hepatic venules. At the corners of the lobule are the portal triads, containing a branch of the portal vein, a hepatic arteriole and a bile duct. Blood flows from the portal venules and hepatic arteriole into sinusoids and percolates towards the central venule.
Sinusoids are lined by thin, discontinuous endothelial cells with numerous fenestrae. Very little if any base membrane separates endothelial cells from hepatocytes (space of Disse). Kupffer cells are the resident macrophages located in the sinusoidal lumen. Ito cells are located between endothelial cells and hepatocytes, and their functions include collagen synthesis and vitamin A storage.
The lobule is divided into three regions according to their position relative to the central venule and portal triad: centrolobular, midzonal and periportal. Hepatocytes in the periportal region are rich in mitochondria and are predominant in fatty acid oxidation, gluconeogenesis and urea synthesis. They also have high levels of glutathione. P450 is more abundant in centrolobular Hepatocytes
Canaliculae are channels formed by specialized regions of the plasma membrane of adjacent Hepatocytes Hepatocytes secrete the components of bile into the canaliculae, which then connect to larger bile ducts.
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Cool Web Site: Normal liver and gallbladder histology @ University of Delaware
Types of Injury
The most common types of liver injury are steatosis, hepatocyte death, cholestasis, bile duct damage, sinusoidal damage, cirrhosis and neoplasia.
Steatosis, or fatty liver, is an increase in hepatic lipid content. Hepatocytes appear to have multiple round vacuoles that displace the nucleus to the periphery of the cell. Steatosis is due to either oversupply of fatty acids (obesity), interference with lipid metabolism, or acute chemical injury. Compounds that produce steatosis include carbon tetrachloride, valproic acid and ethanol.
Hepatocyte necrosis can be detected by assaying plasma for liver cytosolic enzymes like alanine aminotransferase (ALT), a predominantly hepatocyte enzyme. Chemicals that produce hepatocyte necrosis include dimethylforamide, acetaminophen, copper, ethanol and Ecstasy. Cell death can occur in a focal (single cell or small clusters), zonal (usually centrolobular or periportal) or panlobular pattern (massive death of most cells in a lobule). Many toxins cause centrolobular necrosis, while fewer are known to damage the periportal or midzonal areas. Centrolobular necrosis may affect only a narrow rim of cells around the venule, or extend into the midzone.
Cholestasis is defined by a decrease in the volume of bile, and is characterized by elevated serum levels of bile components (bile salts, bilirubin, etc.). Structural changes are subtle and include dilation of canaculus, and the presence of bile plugs in bile ducts or canaliculi. This type of injury may be induced by chlorpromazine, cyclosporin A, 1,1-dichloroethane and estrogens.
Bile duct damage includes swollen biliary epithelium, debris of damage cells within the ductal lumen and inflammatory cell infiltration. Chemicals that damage bile ducts include amoxicillin and methylene dianiline.
Sinusoidal damage occurs by dilation or blockade of the sinusoidal lumen. Dilation occurs when the efflux of hepatic blood is impeded, as occurs in association with exposure to anabolic steroids. Blockade occurs when fenestrae enlarge and allow entrance of blood cells to the space of Disse, and is associated with acetaminophen overdose. Over accumulation of blood in the liver may lead the rest of the body into shock.
Cirrhosis is characterized by accumulation of excessive amounts of collagen fibers in response to damage or inflammation. With repeated chemical insults, hepatocytes are destroyed and replaced by fibrotic scars. With continuous deposition, the architecture of the liver is disrupted by interconnected scars. Cirrhosis is not reversible and is associated with overdose of vitamin A and chronic alcoholism.
Chemically induced neoplasia in the liver usually involves hepatocytes or bile duct cells, and rarely sinusoidal lining cells. Hepatocellular carcinomas are linked to androgen abuse, aflatoxin, hepatitis B and throrotrast. Angiosarcomas are associated with vinyl chloride, arsenic and throrotrast.
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Factors that Affect Damage
Factors that affect liver damage include uptake/concentration, bioactivation/detoxification, activation of sinusoidal cells and inflammatory/immune responses.
The membrane-rich liver concentrates lipophilic compounds. Other toxins are taken up by special transporters found predominantly in the liver. The mushroom toxin phalloidin and the blue-green algae micocystin are examples of toxins selectively taken up by the liver. Excessive metabolic concentrations of vitamin A and iron will cause liver toxicity because the liver is directly involved in the metabolic homeostasis of these substances.
Hepatocytes contain high activity of phase I enzymes that often toxicate xenobiotics to reactive electrophiles. Cytochrome P450 plays a specially important role in this mechanism, since some isoenzymes generate reactive oxygen species. P450 activation of carbon tetrachloride is a classic example. Normally there is also high activity of phase II enzymes detoxicate such a metabolite, but if phase II activity is less than normal the equilibrium will be shifted towards liver injury. In the case of ethanol, this balance may also be shifted by polymorphism of aldehyde dehydrogenase.
Acetaminophen is another important example of biotransformation-mediated toxicity, and balance between phase I and phase II enzymes. Typical therapeutic doses of acetaminophen are not hepatotoxic. The dominant biotransformation pathways are glucuronide or sulfate conjugation, with little drug activation. Toxicity is enhanced by fasting and other conditions that deplete glutathione, and is minimized by N-acetylcysteine treatment. Alcoholics are vulnerable to acetaminophen toxicity within the therapeutic dose range. Ethanol induction of CYP2E1 accelerates bioactivation to the electrophilic N-acetyl-p-benzoquinone imine. This reactive metabolite forms adducts with macromolecules in hepatocytes, altering their functional integrity.
Activation of Kupffer and Ito cells seems to modulate the toxic response of the liver. Activated Kupffer cells secrete soluble cytotoxins, including reactive oxygen and nitrogen species. Pretreatments that activate or deactivate Kupffer cells appropriately modulate the damage produced by toxicants like acetaminophen, carbon tetrachloride and ethanol. It is possible that signals from injured hepatocytes activate Kupffer cells to release cytotoxins and Ito cells to secrete collagen. Alcoholics have elevated systemic levels of Kupffer cell activating factors like tumor necrosis factor (TNF) and endotoxin from gut bacteria.
Migration of inflammatory cells to regions of liver damage causes hepatitis, or inflammation of the liver. Hepatitis may be caused by microorganisms, or chemicals like ethanol and halothane.
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