Figure 1713

Electron micrographs of a hepatocyte. a. This election micrograph shows organelles and other cytoplasmic structures near the nucleus (N). These include a peroxisome (P), mitochondrion (M), glycogen inclusions (CI), smooth endoplasmic reticulum (sER), and rough endoplasmic reticulum (rER). In the lower left, the membranes of the rER

activity, certain drugs and hormones induce synthesis of new sER membranes and their associated enzymes. The sER undergoes hypertrophy following administration of alcohol, drugs (i.e, phénobarbital, anabolic steroids, and progesterone), and certain chemotherapeutic agents used to treat cancer.

Stimulation of the sER by ethanol enhances its ability to detoxify other drugs, certain carcinogens, and some pesticides. On the other hand, metabolism by the sER can actually increase the hepatocyte-damaging effects of some toxic compounds, such as carbon tetrachloride (CCIJ and 3,4-benzpyrene.

The large Golgi apparatus in hepatocytes consists of as many as 50 Golgi units

Examination of hepatocytes with the TEM shows the Golgi to be much more elaborate than those seen in rou

have been cut in a tangential plane showing the ribosomes (encircled by a dashed line) on the cytoplasmic face of the membrane, x 12,000. b. This micrograph shows a region of cytoplasm near a bile canaliculus (C). It includes a lysosome (L), mitochondria (M), and both sER and rER. Note the microvilli in the bile canaliculus, x 18,000.

tine histologic specimens. Heavy-metal preparations (Golgi stains) of thick sections of liver give an indication of the extent of the Golgi network. As many as 50 Golgi units, each consisting of three to five closely stacked cis-ternae, plus many large and small vesicles, are found in hepatocytes. These "units" are actually branches of the tortuous Golgi apparatus seen in heavy-metal preparations. Elements of the Golgi apparatus concentrated near the bile canaliculus are believed to be associated with the exocrine secretion of bile. Golgi cisternae and vesicles near the sinusoidal surfaces of the cell, however, contain electron-dense granules 25 to 80 nra in diameter that are believed to be VLDL and other lipoprotein precursors. These substances are subsequently released into the circulation as part of the endocrine secretory function of the hepatocytes. Similar dense globules are seen in dilated portions of the sER and, occasionally, in the dilated ends of rER cisternae where they are synthesized.

Lipoproteins are multicomponent complexes of proteins and lipids that are involved in the transport of cholesterol and triglycerides in the blood. Cholesterol and triglycerides do not circulate free in the plasma because lipids, on their own, would be unable to remain in suspension. The association of the protein with the lipid-containing core makes the complex sufficiently hydrophilic to remain suspended in the plasma.

Lipoproteins serve a variety of functions in cellular membranes and in the transport and metabolism of lipids. Lipoprotein precursors are produced in the liver. The lipid component is produced in the sER; the protein component is produced in the rER of the he-patocytes. The lipoprotein complexes pass to the Colgi, where secretory vesicles containing electron-dense lipoprotein particles bud off and are then released at the cell surface bordering the perisi-nusoidal space to reach the bloodstream. Several hormones, such as estrogen and thyroid hormones, regulate the secretion of lipoproteins.

In general, four classes of lipoproteins have been defined by their characteristic density, molecular weight, size, and chemical composition: chylomicrons, VLDLs, LDLs, and HDLs. These lipoproteins differ in chemical composition and can be isolated from plasma according to their flotation properties, from largest and least dense to smallest and most dense.

Chylomicrons, the lightest of all lipoproteins, are made only in the small intestine. Their main function is to transport the large amount of absorbed fat to the bloodstream.

VLDLs are denser and smaller than chylomicrons; they are synthesized predominately in the liver and to a lesser extent in the small intestine. VLDLs are rich in triglycerides. Their function is to transport most of the triglycerides from the liver to other organs. Liver VLDLs are associated with circulating apolipoprotein B-100, also synthesized in the liver, which aids in secretion of VLDLs. In congenital liver disease, such as abetalipoproteinemia, and to a lesser degree in acute and chronic disorders, the liver is unable to produce apolipoprotein B-100, leading to blockage in the secretion of VLDLs. In liver biopsy specimens from these individuals, large lipid droplets occupy most of the hepatocyte cytoplasm.

LDLs and HDLs are produced in the plasma; however, small amounts of these fractions are produced by the liver. LDLs are denser than VLDLs, and HDLs are denser than LDLs. The function of LDLs is to transport cholesterol esters from the liver to the peripheral organs. The HDLs are involved in the transport of cholesterol from the peripheral tissues to the liver. High levels of LDL are directly correlated with increased risk of cardiovascular disease; high levels of HDL or low levels of LDL are associated with decreased risk.

Lysosomes concentrated near the bile canaliculus correspond to the peribiliary dense bodies seen in histologic sections

ITepatocyte lysosomes are so heterogeneous that they can only be positively identified, even at the TEM level, by histochemical means. In addition to normal lysosomal enzymes, TEM reveals other components:

• Pigment granules (lipofuscin)

• Partially digested cytoplasmic organelles

• Myelin figures

Hepatocyte lysosomes may also be a normal storage site for iron (as a ferritin complex) and a site of iron accumulation in certain storage diseases.

The number of lysosomes increases in a variety of pathologic conditions, ranging from simple obstructive bile stasis to viral hepatitis and anemia. However, although the range of normal liver function—particularly the rate of bile secretion—is quite wide, no statistically significant morphologic changes take place in the Golgi apparatus or lysosomes of the peribiliary cytoplasm to correlate with the rate of bile secretion.

Biliary Tree

The biliary tree is the system of conduits of increasing diameter that bile flows through from the hepatocytes to the gallbladder and then to the intestine. The smallest branches of this system are the canaliculi into which the hepatocytes secrete bile.

The bile canaliculus is a small canal formed by apposed grooves in the surface of adjacent hepatocytes

Bile canaliculi form a complete loop around four sides of the idealized six-sided hepatocytes (Fig. 17.14). They are approximately 0.5pm in luminal diameter and are isolated from the rest of the intercellular compartment by tight junctions, which are part of junctional complexes that also include zonulae adherentes and desmosomes. Microvilli of the two adjacent hepatocytes extend into the canalicular lumen. Adenosine triphosphatase (ATPase) and other alkaline phosphatases can be localized on the plasma membranes of the canaliculi, suggesting that bile secretion into this space is an active process. Bile flow is centrifugal, i.e., from the region of the central vein toward the portal canal (a direction opposite to the blood flow). Near the portal canal but still within the lobule, bile canaliculi join to form the short intrahepatic ductules, the canals of Hering (see Fig. 17.11a), which are lined with cuboidal nonhepatocytic cells. This ductule epithelium is subtended by a complete basal lamina, as is the rest of the distal biliary tree.

Intrahepatic bile ductules carry bile to hepatic ducts

The ductules have a diameter of about 1.0 to 1.5 pm and carry bile through the boundary of the lobule to the interlobular bile ducts that form part of the portal triad (see Fig. 17.11b). These ducts range from 15 to 40 p,m in di-

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