Visceral Surface

bare area area

• Prothrombin and fibrinogen, important components of the blood-clotting cascade.

• Nonimmune a- and {¡-globulins, which also help maintain plasma colloid osmotic pressure and serve as carrier proteins for various substances (see Chapter 9, page 216).

The liver stores and converts several vitamins and iron

Several vitamins are taken up from the bloodstream and are then stored and/or biochemically modified by the liver. They include

• Vitamin A (retinol), an important vitamin in vision. Vitamin A is the precursor of retinal, which is required for the synthesis of rhodopsin in the eye. The liver plays a major role in the uptake, storage, and maintenance of circulating levels of vitamin A. When the vitamin A levels in the blood decrease, the liver mobilizes its storage sites in the hepatic stellate cells (see page 541). Vitamin A is then released into the circulation in the form of retinol bound to retinol-binding protein (RBP). The liver also synthesizes RBP; RBP synthesis is regulated by plasma levels of vitamin A. Night blindness and multiple skin disorders are related to vitamin A deficiency.

• Vitamin D (cholecalciferol), an important vitamin in calcium and phosphate metabolism. Vitamin D is acquired from dietary vitamin D3 and is also produced in the skin during exposure to ultraviolet light by conversion of 7-dehydrocholesterol. Unlike vitamin A, vitamin D is not stored in the liver but is distributed to skeletal muscles and adipose tissue. The liver plays an important role in vitamin D metabolism by converting vitamin D, to 25-hydroxycholecalciferol, the predominant form of circulating vitamin D. Further conversion takes place in the kidney to 1,25-hydroxycholecalciferol, which is 10 times more active than vitamin D3 Vitamin D is essential for development and growth of the skeletal system and teeth. Deficiency of vitamin D is associated with rickets and disorders of bone mineralization.

• Vitamin K, which is important in hepatic synthesis of prothrombin and several other clotting factors. Like vitamin D, it is derived from two sources: dietary vitamin K and synthesis in the small intestine by intestinal bacterial flora. Vitamin K is transported to the liver with chylomicrons, where it is rapidly absorbed, partially used, and then partially secreted with the VLDL fraction. Vitamin K deficiency is associated with hypopro-thrombinemia and bleeding disorders.

In addition, the liver functions in the storage, metabolism, and homeostasis of iron. It synthesizes almost all of the proteins involved in iron transport and metabolism, including transferrin, haptoglobin, and hemopexin. Transferrin is a plasma iron-transport protein. Haptoglobin binds to free hemoglobin in the plasma, from which the entire complex is removed by the liver to preserve iron. He mopexin is involved in the transport of free heme in the blood. Iron is stored within the hepatocyte cytoplasm in the form of ferritin or may be converted to hemosiderin granules. Recent studies indicate that hepatocytes are the major sites of long-term storage of iron. Iron overload (as in multiple blood transfusions) may lead to hemochromatosis, a form of liver damage characterized by excessive amounts of hemosiderin in hepatocytes.

The liver degrades drugs and toxins

Hepatocytes are involved in degradation of drugs, toxins, and other proteins foreign to the body (xenobiotics). Many drugs and toxins are not hydrophilic; therefore, they cannot be eliminated effectively from the circulation by the kidneys. The liver converts these substances into more soluble forms. This process is performed by the hepatocytes in two phases:

• Phase I, called oxidation, includes hydroxylation (adding an —OH group) and carboxylation (adding a —COOH group) to a foreign compound. This phase is performed in the hepatocyte smooth endoplasmic reticulum (sER) and mitochondria. It involves a series of biochemical reactions with proteins collectively named cytochrome P450.

• Phase II, or conjugation, includes conjugation with glucuronic acid, glycine, or taurine. This process makes the product of phase I even more water soluble so that it can be easily removed by the kidney.

The liver is involved in many other important metabolic pathways

The liver is important in carbohydrate metabolism as it maintains an adequate supply of nutrients for cell processes. In glucose metabolism, the liver phosphorylates absorbed glucose from the gastrointestinal tract to glucose-6-phosphate. Depending on energy requirements, glucose-6-phosphate is either stored in the liver in the form of glycogen or used in the glycolytic pathways. During fasting, glycogen is broken down by glycogenolysis, and glucose is released into the bloodstream. In addition, the liver functions in lipid metabolism. Fatty acids derived from plasma are consumed by hepatocytes using (3-oxidation to provide energy. The liver also produces ketone bodies that are used as a fuel by other organs (the liver cannot use them as an energy source). The involvement in cholesterol metabolism (synthesis and uptake from the blood) is also an important function of the liver. Cholesterol is used in formation of bile salts, synthesis of VLDLs, and biosynthesis of organelles. The liver synthesizes most of the urea in the body from ammonium ions derived from protein and nucleic acid degradation. Finally, the liver is involved in the synthesis and conversion of nonessential amino acids into essential amino acids.

Bile production is an exocrine function of the liver

The liver is engaged in numerous metabolic conversions involving substrates delivered by blood from the digestive tract, pancreas, and spleen. Some of these products are involved in the production of bile, an exocrine secretion of the liver. Bile contains conjugated and degraded waste products that are returned to the intestine for disposal, as well as substances that bind to metabolites in the intestine to aid in absorption. (Table 17.1) Bile is carried from the parenchyma of the liver by bile ducts that fuse to form the hepatic duct. The cystic duct then carries the bile into the gallbladder where it is concentrated. Bile is returned, via the cystic duct, to the common bile duct, which delivers bile from the liver and gallbladder to the duodenum (see Fig. 17.15).

The endocrine-like functions of the liver are represented by its ability to modify the structure and function of many hormones

The liver modifies the action of hormones released by other organs. The liver's endocrine-like actions involve

• Vitamin D, which is converted by the liver to 25-hydroxycholecalciferol, the predominant form of circulating vitamin D (page 534).

• Thyroxine, a hormone secreted by the thyroid gland as tetraiodothyronine (T4), which is converted in the liver to the biologically active form, triiodothyronine (T}), by deiodination.

• Growth hormone (GH), a hormone secreted by the pituitary gland. The action of GIT is modified by liver-produced growth hormone-releasing hormone (GHRH) and inhibited by somatostatin, which is secreted by enteroendocrine cells of the gastrointestinal tract.

• Insulin and glucagon, both pancreatic hormones. These hormones are degraded in many organs, but the liver and kidney are the most important sites of their degradation.

Blood Supply to the Liver

To appreciate the myriad functions of the liver introduced above, one must first understand its unique blood supply and how blood is distributed to the hepatocytes. The liver has a dual blood supply consisting of a venous (portal) supply via the hepatic portal vein and an arterial supply via the hepatic artery. Both vessels enter the liver at a hilum or porta hepatis, the same site at which the common bile duct, carrying the bile secreted by the liver, and the lymphatic vessels leave the liver.

The liver receives the blood that initially supplied the intestines, pancreas, and spleen

The liver is unique among organs because it receives its major blood supply (about 75%) from the hepatic portal vein, which carries venous blood that is largely depleted of oxygen. The blood delivered to the liver by the hepatic portal vein comes from the digestive tract and the major abdominal organs, such as the pancreas and spleen. The portal blood carried to the liver contains

• Nutrients and toxic materials absorbed in the intestine

• Blood cells and breakdown products of blood cells from the spleen

• Endocrine secretions of the pancreas and enteroendocrine cells of the gastrointestinal tract

Thus, the liver stands directly in the pathway of blood vessels that convey substances absorbed from the digestive tract. While the liver is the first organ to receive metabolic

TABLE 17.1. Composition of Bile Component

Water

Phospholipids (i.e., lecithin) and cholesterol

Bile salts (also called bile acids): primary (secreted by liver): cholic acid, chenodeoxycholic acid; secondary (converted by bacterial flora in the intestine): deoxycholic acid, lithocholic acid

Bile pigments, principally the glucuronide of the bilirubin produced in the spleen, bone marrow, and liver by the breakdown of hemoglobin

Function

Solute in which other components are carried

Metabolic substrates for other cells in the body; precursors of membrane components and steroids; largely reabsorbed in the gut and recycled

Emulsifying agents that aid in the digestion and absorption of lipids from the gut and help to keep the cholesterol and phospholipids of the bile in solution, largely recycled, going back and forth between the liver and gut

Detoxify bilirubin, the end product of hemoglobin degradation, and carry it to the gut for disposal

Electrolytes: Na+, K+, Ca2\ Mg2', CI", and HCOr

Establish and maintain bile as an isotonic fluid; also largely reabsorbed in the gut terminal hepatic venule (central vein)

terminal hepatic venule (central vein)

Central And Hepatic Vein

Blood supply to the liver: the portal triad. The portal triad is composed of the branches of the hepatic artery, portal vein, and bile duct. Blood from the terminal branches of the hepatic artery and portal vein enters the hepatic sinusoids. The mixture of venous and arterial blood is transported by the sinusoids toward the terminal hepatic venule (central vein). From here, blood drains into the sublobular veins, the tributaries of the hepatic vein. Note the small vessels and

Blood supply to the liver: the portal triad. The portal triad is composed of the branches of the hepatic artery, portal vein, and bile duct. Blood from the terminal branches of the hepatic artery and portal vein enters the hepatic sinusoids. The mixture of venous and arterial blood is transported by the sinusoids toward the terminal hepatic venule (central vein). From here, blood drains into the sublobular veins, the tributaries of the hepatic vein. Note the small vessels and capillary network in the perivascular connective tissue surrounding each hepatic triad within the portal canal. Also note the periportal space of Mall, located between the portal canal and the outermost hepatocytes. This space is also filled with a small amount of connective tissue in which lymph drainage begins. From here, blind-ended lymphatic capillaries form larger lymphatic vessels that accompany branches of the hepatic artery.

substrates and nutrients, it is also the first exposed to toxic substances that have been absorbed.

The hepatic artery, a branch of the celiac trunk, carries oxygenated blood to the liver, providing the remaining 25% of its blood supply. Because blood from the two sources is mixed just before it perfuses the hepatocytes of the liver parenchyma, the liver cells are never exposed to fully oxygenated blood.

Within the liver, the distributing branches of the portal vein and hepatic artery, which supply the sinusoidal capillaries (sinusoids) that bathe the hepatocytes, and the draining branches of the bile duct system, which lead to the common hepatic duct, course together in a relationship termed the portal triad. Although a convenient term, it is a misnomer because one or more vessels of the lymphatic drainage system of the liver always travel with the vein, artery, and bile duct. (Fig. 17.2)

The sinusoids are in intimate contact with the hepatocytes and provide for the exchange of substances between the blood and liver cells. The sinusoids lead to a central vein that in turn empties into the sublobular veins. Blood leaves the liver through the hepatic veins, which empty into the inferior vena cava.

Structural Organization of the Liver

As introduced above, the structural components of the liver include

• Parenchyma, consisting of organized plates of hepatocytes, which in the adult are normally one cell thick and are separated by sinusoidal capillaries. In young individuals up to 6 years of age, the liver cells are arranged in plates two cells thick.

• Connective tissue stroma that is continuous with the fibrous capsule of Glisson. Blood vessels, nerves, lymphatic vessels, and bile ducts travel within the connective tissue stroma.

• Sinusoidal capillaries (sinusoids), the vascular channels between the plates of hepatocytes.

• Perisinusoidal spaces (spaces of Disse), which lie between the sinusoidal endothelium and the hepatocytes.

With this information as background, one can now consider several ways to describe the organization of these structural elements in order to understand the major functions of the liver.

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