Normal Liver Histology 101

Basic Architecture

The Capsule

The outer surface of the liver is composed of a fibrous / connective tissue capsule (Figure 1). The outermost surface is covered by a thin layer of mesothelial cells that arises from the peritoneum (Figure 2).

The Parenchyma

The capsule surrounds the liver parenchyma, which is composed of hepatocytes. Hepatocytes are large polygonal cells with eosinophilic (pink) cytoplasm, round nuclei, and prominent nucleoli (Figure 1). Hepatocytes are discussed in more detail in later sections.

Figure 1. Subcapsular liver biopsy showing the fibrous capsule surrounding hepatocytes.
Figure 2. Subcapsular liver biopsy with mesothelial cells lining the outermost layer of the capsule.

Organization: Lobules & Acini

Microscopically, the organization of liver parenchyma can be represented by three different schematics: (1) the classic (hepatic) lobule, (2) the portal lobule, and (3) the hepatic acinus.

The Lobules

Classic (hepatic) lobules are based upon blood flow. They are organized as “hexagons,” with the central vein (CV) in the center of the lobule and portal tracts (PTs) at the periphery of the lobule (corners of the hexagon) (Figures 3 and 4). The PT consists of the hepatic artery (HA), portal vein (PV), and bile duct (BD). Blood enters the liver via the PV and HA, drains into the CV, and exits the liver via the hepatic vein to the inferior vena cava.

Portal lobules are based upon bile flow. They are organized as “triangles,” with a PT at the center of the lobule and CVs at the periphery of the lobule (corners of the triangle) (Figure 3). Hepatocytes produce bile that drains from the bile canaliculi > canals of Hering > bile ductules > interlobular bile ducts > intrahepatic ducts > right and left hepatic ducts > common hepatic duct > joins with cystic duct to form the common bile duct > duodenum). The flow of bile is in the opposite direction of blood flow (Figure 4).

The Hepatic Acinus (Acinus of Rappaport)

The hepatic acinus is based upon blood perfusion throughout the liver parenchyma. The acinus is organized as a “diamond,” with PTs at the corners of the short axis and CVs at the corners of the long axis (Figure 3). The acinus is arbitrarily divided into three zones based upon perfusion. Zone 1 receives the most oxygenated blood and nutrients, while zone 3 receives the least.

Figure 3.  Organizational units of the liver including the (1) classic (hepatic) lobule (2) portal lobule and (3) hepatic acinus. [Fontana, Josef, et al. “Functions of Cells and Human Body: Multimedia Textbook.” Liver and Biotransformation of Xenobiotics, http://fblt.cz/en/skripta/ix-travici-soustava/5-jatra-a-biotransformace-xenobiotik/]
Figure 4. Classic (hepatic) lobule with PTs at the periphery of the lobule and CV in the center of the lobule. The PTs and CV are evenly spaced throughout the hepatic parenchyma. Blood flows from the PTs to the CV (red arrow), while bile flows in the opposite direction (green arrow). The acinus is represented by the thicker curved lines and is composed of zones 1-3. (H&E photo courtesy of Dr. Jennifer Findeis-Hosey, URMC)

Key Structures

The Portal Tract

The PT consists of the HA, PV, and BD (Figure 5). The HA and PV are lined by endothelial cells. The HA is small with thick walls, while the PV is larger with thin walls. The BD is roughly the same size as the hepatic artery and is lined by a single layer of cuboidal (square-shaped) epithelium. Occasionally, lymphatic ducts may also be seen. The structures in the portal tract are surrounded by fibrous connective tissue. Although it is normal to see a few scattered inflammatory cells (ex. lymphocytes), no neutrophils or plasma cells should be present. The single layer of hepatocytes immediately adjacent to the portal tract delineates the limiting plate.

Figure 5. The portal tract consists of branches of the hepatic artery (HA), portal vein (PV), and bile duct (BD), which are surrounded by connective tissue (CT). The limiting plate (black dashed line) is delineated by the layer of hepatocytes immediately adjacent to the portal tract.
The Central Vein

The CV is lined by a single layer of endothelial cells and drains blood coming from the PTs via sinusoids. Plates of hepatocytes radiate outward from the CV toward the PTs (Figure 6).

Figure 6. Plates of hepatocytes radiate out from the central vein (CV) toward the PTs. The CV drains blood coming from the PT via the sinusoids.

Parenchyma

Hepatocytes

Hepatocytes are polygonal cells (20-30µm) with abundant granular eosinophilic (pink) cytoplasm, centrally placed round to ovoid nuclei, and prominent nucleoli (Figure 7). Normal hepatocytes can also show binucleation and pleomorphism (differences in size). Hepatocytes are arranged in plates that are 1 cell thick. Hepatocyte plasma membranes are separated into sinusoidal, canalicular, and apicolateral domains. The sinusoidal (basal) domain contains microvilli and faces the space of Disse, while the canalicular (apical) domain forms the bile canaliculus. The apicolateral domain is between the sinusoidal and canalicular domains (Figure 8).

Figure 7. Hepatocytes with abundant granular, eosinophilic cytoplasm and centrally placed, round nuclei with prominent nucleoli. Occasional binucleate forms are present.
Figure 8. Hepatocytes are separated into sinusoidal (basal), canalicular (apical), and apicolateral domains. Tight junctions (blue rectangles) separate the canalicular domain from the apicolateral domain. L = lumen, N = nucleus. [C. L. Slim et al., “Par1b Induces Asymmetric Inheritance of Plasma Membrane Domains via LGN-Dependent Mitotic Spindle Orientation in Proliferating Hepatocytes,” PLoS Biol., 2013, doi: 10.1371/journal.pbio.1001739.]
Sinusoids

Hepatocytes are separated by sinusoids (Figures 9 and 10), which are spaces lined by fenestrated endothelial cells that transport blood from the PTs to the CVs. Sinusoids contain macrophages called Kupffer cells.

Space of Disse

The space of Disse (SoD) is the space between the endothelium and the hepatocytes (Figure 9), which transports lymphatic fluid to lymphatic capillaries in the portal tract and contains reticulin fibers. The SoD also contains stellate (Ito) cells that store lipids (vitamin A) and are involved in fibrinogenesis.

Figure 9. Hepatocytes are separated by sinusoids, which are lined by fenestrated endothelial cells. The space of Disse lies between the endothelial cells and hepatocytes. [D. H. Adams and B. Eksteen, “Aberrant homing of mucosal T cells and extra-intestinal manifestations of inflammatory bowel disease,” Nature Reviews Immunology. 2006, doi: 10.1038/nri1784.]
Figure 10. Sinusoids are lined by a single layer of endothelial cells and transport blood from the PT to the CV. (H&E photo courtesy of Dr. Jennifer Findeis-Hosey, URMC)

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