Liver

Introduction

The liver acts as a vast biosynthetic chemical factory, synthesizing large complex molecules from substances brought to it in the blood, particularly substances recently absorbed by the intestine and transported by a portal blood system.

All of the biochemical functions of the liver are carried out by the epithelial parenchymal cells of the liver, the hepatocytes, and are dependent on close interrelationships between:

• The vasculature (hepatic artery and portal vein branches, sinusoids and central veins)

• The hepatocytes

• The bile drainage systems (the canaliculi and intrahepatic bile ducts; Fig. 12.1 ).

  

Bile synthesis and secretion. The liver produces bile, an alkaline secretion containing water, ions, phospholipids, bile pigments (mainly bilirubin glucuronide) and bile acids (glycocholic and taurocholic).

Excretion of bilirubin. Bilirubin is produced in the spleen from the breakdown of the haem component of haemoglobin. In the liver the bilirubin is conjugated with glucuronic acid, and the conjugate (bilirubin glucuronide) is excreted in the bile and thence the faeces.

Protein metabolism. The liver is centrally involved in protein metabolism. It brings about deamination of amino acids; it produces urea from circulating ammonia; it also interconverts amino acids and produces the so-called nonessential amino acids. The liver synthesizes many proteins, including most of the plasma proteins such as albumin, and blood clotting factors, such as fibrinogen and prothrombin.

The profile of proteins secreted by the liver can be influenced by cytokines circulating in the blood. In patients with inflammatory disorders, circulating cytokines can increase the concentration of several liver-produced proteins in the blood, such as fibrinogen, transferrin and serum-amyloid A protein. The production of some other proteins is downregulated, for example, albumin. This is called an acute-phase response .

Carbohydrate metabolism. Lipids and amino acids are converted into glucose in the liver by gluconeogenesis. The liver makes and stores glycogen and forms intermediary compounds in carbohydrate metabolism.

Lipid metabolism. The liver is involved in the synthesis of cholesterol, lipoproteins and phospholipids. It synthesizes fat from other precursors. It also oxidizes fatty acids to provide energy.

Storage. The liver acts as a store for vitamins A, D and B ₁₂ . It stores iron as ferritin.

Conjugation and elimination of metabolites and toxins. The smooth endoplasmic reticulum of the liver possesses large numbers of enzymes that break down or conjugate metabolites or toxic substances (e.g. alcohol and barbiturates). Certain hormones are eliminated by the liver.

Liver vasculature

The liver receives blood from two sources:

• The hepatic artery perfuses the liver with oxygenated blood from the coeliac axis branches of the aorta.

• The hepatic portal vein carries blood from the digestive tract and spleen to the liver, the blood from the digestive tract being rich in amino acids, lipids and carbohydrates absorbed from the bowel and that from the spleen being rich in haemoglobin breakdown products.

In the liver, the two input circulations (hepatic artery and hepatic portal vein) discharge their blood into a common network of anastomosing small vascular channels, the sinusoids ( Fig. 12.2 ). The terminal parts of the hepatic portal and arterial systems run together in a connective tissue framework called portal tracts, which also contain bile ductules.

After entering the liver at the porta hepatis, the portal vein divides within the liver into progressively smaller branches (interlobar, segmental and interlobular branches), which then branch further, eventually forming an extensive anastomosing network of terminal portal venules. Lateral side branches (inlet venules) of the terminal portal venules empty blood into the sinusoids, where it blends with blood from the terminal hepatic artery branches.

The hepatic artery divides into successively smaller branches, with the terminal elements running with the terminal branches of the hepatic portal vein before emptying into the hepatic sinusoids by short side branches (the arteriosinusoidal branches). A peribiliary plexus of small arterial branches supplies oxygenated blood into the large intrahepatic bile ducts before draining into the sinusoids, where it blends with blood from the portal venous system.

The sinusoids are surrounded on all sides by hepatocytes. In this way, blood flowing through the liver is exposed to a massive surface area of liver cells.

The hepatic sinusoids permeate the whole of the liver. They are lined by a thin, discontinuous, highly fenestrated endothelium, which is closely related externally to plates and cords of hepatocytes ( Fig. 12.3 ), albeit separated from them by a space. This perisinusoidal space of Disse is the main site where material is transferred between the blood-filled sinusoids and hepatocytes. This transfer is in both directions, with some material being taken up by hepatocytes in addition to being secreted.

The hepatic sinusoids are partly lined by phagocytic cells ( Küpffer cells ), which are a form of macrophage and are derived from circulating blood monocytes.

Within the perisinusoidal space is a population of small cells with scant cytoplasm called hepatic stellate cells (formerly called perisinusoidal cells and Ito cells ). These represent around 5% of the total liver cell population. In conventional histological preparations they are hard to see and are best identified using special staining with immunohistochemical methods ( Fig. 12.4 ).

Stellate cells are located between the lateral surface of hepatocytes and the sinusoidal endothelial cells with an elongated spindle and multiprocessed ramified shape. Cell processes bear protrusions termed spines, which have a functional role as chemosensing structures. A characteristic feature of stellate cells is the presence of cytoplasmic lipid vacuoles at the site of intracellular storage of vitamin A.

Stellate cells have several roles, including acting as support cells in the developing liver, acting as support cells for hepatocytes, in liver cell regeneration and as an immunomodulator regulating local inflammatory responses.

In response to liver damage stellate cells can transform to a myofibroblast-like cell with contractile and collagen-secreting properties. In these circumstances stellate cells become activated by cytokines and change their morphology to develop more cytoplasm along with expression of alpha smooth muscle actin. Stellate cells are understood to be responsible for the production of collagen in the process of fibrous scarring in the liver (see Fig. 12.9 ).

Blood which has passed through the functioning liver parenchyma enters terminal hepatic venules (central veins of the lobules; discussed later on p. 240), which in turn unite to form intercalated veins; these then fuse to form larger hepatic vein branches. Hepatic veins are devoid of valves and open separately into the inferior vena cava.

The liver produces a large volume of lymph. Fluid drains from the space of Disse into the portal tracts, in which it travels in fine channels. These lymphatic channels increase in size as portal tracts merge toward the hepatic hilum. Finally, lymph drains into the thoracic duct. Such is the extent of lymph production by the liver that it comprises about half of the total lymph flow in the body under resting conditions.

Hepatocytes

Hepatocytes (liver cells), which are intimately associated with the network of blood vessels (sinusoids), are polarized polyhedral cells with three identifiable types of surfaces (see later). As would be expected in cells that are so metabolically active, their cytoplasm is packed with a wide range of organelles.

The nuclei are large, spherical and central and contain scattered clumps of chromatin and prominent nucleoli. Many cells are binucleate, and nuclei are frequently polyploid; progressively more tetraploid nuclei develop with age.

The Golgi is either large and active or small and multiple and is mainly seen near the nucleus, with an extension lying close to the canalicular surface.

There are numerous free ribosomes in the cytosol, along with large glycogen deposits and some lipid droplets, the glycogen being closely related to the smooth endoplasmic reticulum.

Lysosomes (see p. 31) of various sizes are numerous, some containing lipofuscin and lamellated lipoprotein. They are particularly large and numerous near the canalicular surface.

Peroxisomes (see p. 33) usually number 200–300 per cell.

Mitochondria are abundant, numbering more than 1000 per cell, and scattered randomly. This vast mitochondrial component gives the hepatocyte cytoplasm its eosinophilic granular appearance in haematoxylin and eosin (H&E)–stained sections.

The hepatocyte surfaces are important because they are involved in the transfer of substances between hepatocyte, blood vessels and bile canaliculi.

The three types of surfaces are sinusoidal, canalicular and intercellular ( Figs. 12.5 and 12.6 ).

Sinusoidal surfaces account for approximately 70% of the total hepatocyte surface. They are covered by short microvilli, which protrude into the space of Disse. Between the bases of the microvilli are coated pits (see Fig. 2.5 ), which are involved in endocytosis.

The sinusoidal surface is the site where material is transferred between the sinusoids and the hepatocyte.

These account for approximately 15% of the hepatocyte surface and are closely apposed, except at the site of a canaliculus, which is a tube formed by the exact opposition of two shallow gutters on the surface of adjacent hepatocytes.

Canaliculi are about 0.5–2.5 μm in diameter, being smaller close to the terminal hepatic venule, and are lined by irregular microvilli arising from the canalicular surfaces of the hepatocytes.

Hepatocyte cytoplasm close to the canaliculi is rich in actin filaments, which are possibly capable of influencing the diameter of the canaliculus and thus the rate of flow.

The cell membrane around the canalicular lumen is rich in alkaline phosphatase and adenosine triphosphatase, and the canalicular lumen is isolated from the rest of the canalicular surface by junctional complexes ( Fig. 12.7 b).

Intercellular surfaces account for about 15% of the hepatocyte surface. They are comparatively simple but specialized for cell attachment and cell-to-cell communication via communicating junctions (see Fig. 3.7 ).

KEY FACTS

Hepatocytes

• Metabolically highly active and rich in cytoplasmic organelles

• High energy requirement with numerous mitochondria

• Much of the cell surface is related to sinusoids, where exchange of materials with blood takes place

• Part of the surface is in contact with bile canaliculi, where bile excreted from hepatocytes enters the biliary drainage system

Functional organization of hepatocytes

All hepatocytes are not equal, having different metabolic profiles depending on their distance from portal tracts.

Hepatocytes close to the portal tracts are exposed to blood that contains the highest oxygen concentration and contain enzymes involved in oxidative reactions. These cells make and store glycogen and produce and secrete proteins.

Hepatocytes farthest from the portal tracts – those adjacent to the central venules – are most distant from the oxygenated arterial blood supply. These hepatocytes have little capacity for oxidative activities and contain many esterases, being involved in conjugating and detoxifying reactions.

Hepatocytes in-between these extremes have intermediate metabolic properties.

These different metabolic profiles partly explain why different sets of hepatocytes are susceptible to different disease processes, especially responses to certain toxins.

The microanatomy of the liver has been described in two ways, termed the lobular and acinar concepts, respectively.

The components of the liver (i.e. the hepatocytes, terminal hepatic venules, portal triads and sinusoids) are arranged in a fairly constant pattern, which has been described as lobular ( Fig. 12.8 ). The classic lobule is a roughly hexagonal structure in cross-section, being composed of:

• A central terminal hepatic venule, into which drains a converging series of sinusoidal channels like the spokes of a bicycle wheel

• Interconnecting plates of hepatocytes which surround sinusoidal channels and run between the central terminal hepatic venule and the periphery of the lobule

• Peripherally arranged portal tracts, each containing terminal branches of the hepatic artery and portal vein and a small tributary of the bile duct

Thus a ring of portal tracts forms the outer limit of each classic lobule.

The channels within each portal tract are surrounded by a small amount of fibrocollagenous tissue, and in some animals, particularly the pig, fibrocollagenous septa extend from one portal triad to another, clearly outlining the limits of each lobule. In humans, however, these fibrous septa are absent and so the lobule is less clearly defined.

In the lobule, three main zones of hepatocytes are identified, termed centrilobular, periportal and mid-zones. Most of the nomenclature used in the descriptions of disease processes (e.g. centrilobular necrosis) is based on the lobular concept.

The outer layer of periportal hepatocytes adjacent to the portal tract is called the limiting plate; it is the first group of hepatocytes to be damaged in inflammatory liver disorders that primarily involve the portal tracts.

The lobule concept has stood the test of time; however, it has also been proposed that the structure of the liver is best considered in terms of another structural unit, the acinus (see Fig. 12.8 ). The proposal is based on observations made on injection studies of the microcirculation of the liver; the acinus concept is based on the volume of liver receiving its blood supply from a single terminal branch of the hepatic artery contained within a portal tract. In this structural unit, the periphery of the acinus is the central vein, whereas the centre is the portal tract. In the acinar model, hepatocytes are divided into three zones:

• Zone I: Those hepatocytes closest to the portal tract, which synthesize glycogen and proteins

• Zone II: Hepatocytes between zones I and III

• Zone III: Those hepatocytes adjacent to the central venule, which contain esterases and conjugating enzymes

The lobular and acinar concepts are simply two different ways of looking at the structure of the liver. In humans, neither lobules nor acini have a clearly visible outline in histological sections.

CLINICAL EXAMPLE

Cirrhosis

Many slowly progressive diseases destroy hepatocytes and lead to distortion of liver architecture, particularly the relationships between the sinusoids, the portal venous system and the bile ducts.

Death of hepatocytes is followed by scarring, and although hepatocytes can regenerate and produce a new population of cells, their connections with the portal system and the biliary drainage are destroyed. This pattern of liver disorder, known as cirrhosis ( Fig. 12.9 ), is a common cause of chronic liver failure.

Cirrhosis is characterized by:

• Continuing death of hepatocytes.

• Collapse of normal architecture.

• Increased production of fibrocollagenous tissue, leading to irregular scarring.

• Attempted regeneration of surviving hepatocytes, which form irregular nodules and have abnormal relationships with the microvasculature and bile drainage system. Regenerating hepatocytes can continue some synthetic functions but eventually fail to keep pace with normal demands, and the symptoms of liver failure begin to develop.

Cirrhosis produces chronic liver failure and symptoms appear progressively over a period of some years, usually culminating fatally in coma or as a result of the complications of portal hypertension.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here