1. Liver Structure and Function / R.J. Hilsden and E.A. Shaffer

1.1 Liver Morphology

The liver is the largest and most metabolically complex organ in humans. Anatomically, it consists of two main lobes, right and left, separated by the round and falciform ligaments, plus two smaller lobes, the caudate lobe located on the posterior surface and the quadrate lobe on the inferior surface. The liver is functionally divided into eight segments based on the distribution of the portal and hepatic veins. Each segment receives a pedicle of the portal vein and is an independent functional unit. The caudate lobe (segment 1) differs from other segments in that it receives blood from both the right and left branches of the portal vein and drains directly into the inferior vena cava.

At a microscopic level, the liver consists of myriads of individual functional units, traditionally called lobules. Each lobule is bounded by four to five portal triads (supplied from the portal vein and hepatic artery) and has a central terminal hepatic venule (central vein). A more physiologically sound concept is the unit termed the acinus. At the center is the portal triad, while the terminal hepatic venules are at the periphery. The acinus is divided into three zones based upon the distance from the feeding vessels (Figure 1).

The liver receives a dual blood supply. The portal vein drains the splanchnic circulation and provides 75% of the total blood flow (1,500 mL/min). The hepatic artery provides the remaining 25%. Small branches of each blood vessel (the terminal portal venule and the terminal hepatic arteriole) enter the acinus at the portal triad (zone 1). Blood then flows through sinusoids between plates of hepatocytes toward the terminal hepatic venule (zone 3), where blood from several adjacent acini merges. The sinusoidal lining is fenestrated; this porosity allows nutrients to gain access to the intervening space of Disse and from it to the hepatocyte. The terminal hepatic venules coalesce to form the hepatic vein, which carries all efferent blood to the inferior vena cava. A rich supply of lymphatic vessels also drains the liver.

Hepatocytes make up the bulk of the organ. They are arranged in plates that radiate out from each portal triad toward adjacent central veins. Those hepatocytes surrounding the portal tract form an interface between the connective tissues of the portal tract and the hepatic parenchyma, termed the limiting plate.

The bile canaliculus is formed by grooves on the contact surface of adjacent liver cells. Bile forms in these canaliculi and progressively flows into ductules, interlobular bile ducts and then larger hepatic ducts. Outside the porta hepatis, the hepatic duct joins the cystic duct from the gallbladder to form the common bile duct, which drains into the duodenum.

Sinusoidal lining cells comprise at least four distinct populations: endothelial cells, Kupffer's cells, perisinusoidal fat-storing cells and pit cells. Endothelial cells differ from the vascular endothelium elsewhere in the body in that they lack a basement membrane and contain numerous fenestrae that permit hepatocytes to have ready access to nutrients and macromolecules in plasma. Endothelial cells are also responsible for endocytosis of molecules and particles, and play a role in lipoprotein metabolism.

Spindle-shaped Kupffer's cells are tissue macrophages. They form an important part of the body's reticuloendothelial system. Their major functions include phagocytosis of foreign particles, removal of endotoxins and other noxious substances, and modulation of the immune response through the release of mediators and cytotoxic agents.

Perisinusoidal fat-storing cells (Ito cells) store vitamin A. They transform into fibroblasts in response to hepatic injury, contributing to hepatic fibrosis.

Pit cells, the least common sinusoidal lining cells, are large, granular lymphocytes, which function as natural killer cells.

The extracellular matrix of the liver includes its reticulin framework and several molecular forms of collagen, laminin, fibronectin and other extracellular glycoproteins.

1.2.1 METABOLISM

The liver plays a central role in carbohydrate, protein and fat metabolism. It stabilizes glucose level by taking up and storing glucose as glycogen (glycogenesis), breaking this down to glucose (glycogenolysis) when needed, and forming glucose from noncarbohydrate sources such as amino acids (gluconeogenesis). Hypoglycemia occurs only late in the course of severe liver disease because the liver has a large functional reserve; glucose homeostasis can be maintained with only 20% of the liver functioning. The liver synthesizes the majority of proteins that circulate in the plasma, including albumin and most of the globulins other than gamma globulins. Albumin provides most of the oncotic pressure of plasma and is a carrier for drugs and endogenous hydrophobic compounds such as unconjugated bilirubin. Globulins include the coagulation factors: fibrinogen, prothrombin (factor II), and factors V, VII, IX and X. Factors II, VII, IX and X are vitamin K-dependent. Availability of vitamin K, a fat-soluble vitamin, requires adequate bile salts for the vitamin's absorption. These factors decrease with fat malabsorption (as with prolonged cholestasis) and with the reduced synthetic function of hepatocellular disease. (In hepatocellular diseases, deficiency of these coagulation factors is not corrected by parenteral vitamin K administration.) The liver is also the site of most amino acid interconversions and catabolism. Amino acids are catabolized to urea. During this process ammonia, a product of nitrogen metabolism and a possible neurotoxin, is utilized and therefore detoxified. Fatty acids are taken up by the liver and esterified to triglycerides. The liver packages triglycerides with cholesterol, phospholipids and an apoprotein into a lipoprotein. The lipoprotein enters blood for utilization or storage in adipocytes. Most cholesterol synthesis takes place in the liver. Bile salts are the major product of cholesterol catabolism.

The liver's rich enzyme system allows the metabolism of many drugs, including alcohol. The liver detoxifies noxious substances arriving from the splanchnic circulation, preventing them from entering the systemic circulation. This particularly makes the liver susceptible to drug-induced injury. The liver converts some lipophilic compounds into more water-soluble agents, which are then easily excreted in the urine or bile. Others are metabolized to less active agents.

Bile provides the main excretory pathway for toxic metabolites, cholesterol and lipid waste products. Bile is also necessary for the efficient digestion and absorption of dietary fats. Bile salts are synthesized exclusively in the liver from cholesterol and are the driving force behind bile formation. After excretion by the liver, bile is stored in the gallbladder during periods of fasting.

Cholecystokinin (CCK), released from the small intestine during digestion by fatty acids and amino acids, stimulates gallbladder evacuation. When the bile reaches the duodenum it aids in fat absorption by acting as a biologic detergent. Bile salts are reabsorbed predominantly in the ileum and return to the liver via the portal vein to be taken up and secreted once again. This is the enterohepatic circulation (intestine-to-liver).