FUNCTIONS OF THE LIVER
The liver plays a major role in the metabolism of glucose and the regulation of blood glucose concentration. After a meal, glucose is taken up from the portal venous blood by the liver and con-verted into glycogen, which is stored in the hepatocytes. Subse-quently, the glycogen is converted back to glucose and released as needed into the bloodstream to maintain normal levels of blood glucose. Additional glucose can be synthesized by the liver through a process called gluconeogenesis. For this process, the liver uses amino acids from protein breakdown or lactate produced by ex-ercising muscles (Bacon & Di Bisceglie, 2000).
Use of amino acids from protein for gluconeogenesis results in the formation of ammonia as a byproduct. The liver converts this metabolically generated ammonia into urea. Ammonia produced by bacteria in the intestines is also removed from portal blood for urea synthesis. In this way, the liver converts ammonia, a potential toxin, into urea, a compound that can be excreted in the urine.
The liver also plays an important role in protein metabolism. It synthesizes almost all of the plasma proteins (except gamma globulin), including albumin, alpha and beta globulins, blood clotting factors, specific transport proteins, and most of the plasma lipoproteins. Vitamin K is required by the liver for syn-thesis of prothrombin and some of the other clotting factors. Amino acids serve as the building blocks for protein synthesis.
The liver is also active in fat metabolism. Fatty acids can be bro-ken down for the production of energy and the production of ke-tone bodies (acetoacetic acid, beta-hydroxybutyric acid, and acetone). Ketone bodies are small compounds that can enter the bloodstream and provide a source of energy for muscles and other tissues. Breakdown of fatty acids into ketone bodies occurs pri-marily when the availability of glucose for metabolism is limited, as during starvation or in uncontrolled diabetes. Fatty acids and their metabolic products are also used for the synthesis of choles-terol, lecithin, lipoproteins, and other complex lipids. Under some conditions, lipids may accumulate in the hepatocytes, re-sulting in the abnormal condition called fatty liver.
Vitamins A, B, and D and several of the B-complex vitamins are stored in large amounts in the liver. Certain substances, such as iron and copper, are also stored in the liver. Because the liver is rich in these substances, liver extracts have been used for therapy for a wide range of nutritional disorders.
The liver metabolizes many medications, such as barbiturates, opioids, sedative agents, anesthetics, and amphetamines. Metab-olism generally results in loss of activity of the medication, although in some cases activation of the medication may occur. One of the important pathways for medication metabolism in-volves conjugation (binding) of the medication with a variety of compounds, such as glucuronic or acetic acid, to form more sol-uble substances. The conjugated products may be excreted in the feces or urine, similar to bilirubin excretion. If an oral medication (absorbed from the GI tract) is metabolized by the liver to a great extent before it reaches the systemic circulation (first-pass effect), the amount of medication actually reaching the systemic circula-tion (oral bioavailability) will be decreased. Bioavailability is the fraction of the administered drug that reaches the systemic circu-lation. Some medications have such a large first-pass effect that their use is essentially limited to the parenteral route, or oral doses must be substantially larger than parenteral doses to achieve the same effect.
Bile is continuously formed by the hepatocytes and collected in the canaliculi and bile ducts. It is composed mainly of water and electrolytes such as sodium, potassium, calcium, chloride, and bi-carbonate, and it also contains significant amounts of lecithin, fatty acids, cholesterol, bilirubin, and bile salts. Bile is collected and stored in the gallbladder and is emptied into the intestine when needed for digestion. The functions of bile are excretory, as in the excretion of bilirubin; bile also serves as an aid to digestion through the emulsification of fats by bile salts.
Bile salts are synthesized by the hepatocytes from cholesterol. After conjugation or binding with amino acids (taurine and glycine), they are excreted into the bile. The bile salts, together with cholesterol and lecithin, are required for emulsification of fats in the intestine, which is necessary for efficient digestion and absorption. Bile salts are then reabsorbed, primarily in the distal ileum, into portal blood for return to the liver and are again ex-creted into the bile. This pathway from hepatocytes to bile to in-testine and back to the hepatocytes is called the enterohepatic circulation. Because of the enterohepatic circulation, only a small fraction of the bile salts that enter the intestine are excreted in the feces. This decreases the need for active synthesis of bile salts by the liver cells.
Bilirubin is a pigment derived from the breakdown of hemoglo-bin by cells of the reticuloendothelial system, including the Kupf-fer cells of the liver. Hepatocytes remove bilirubin from the blood and chemically modify it through conjugation to glucuronic acid, which makes the bilirubin more soluble in aqueous solutions. The conjugated bilirubin is secreted by the hepatocytes into the adjacent bile canaliculi and is eventually carried in the bile into the duodenum.
In the small intestine, bilirubin is converted into urobilino-gen, which is in part excreted in the feces and in part absorbed through the intestinal mucosa into the portal blood. Much of this reabsorbed urobilinogen is removed by the hepatocytes and is se-creted into the bile once again (enterohepatic circulation). Some of the urobilinogen enters the systemic circulation and is excreted by the kidneys in the urine. Elimination of bilirubin in the bile represents the major route of excretion for this compound.
The bilirubin concentration in the blood may be increased in the presence of liver disease, when the flow of bile is impeded (ie, with gallstones in the bile ducts), or with excessive destruc-tion of red blood cells. With bile duct obstruction, bilirubin does not enter the intestine; as a consequence, urobilinogen is absent from the urine and decreased in the stool.
The Gerontologic Considerations Box outlines age-related changes in the liver. The most common change in the liver in the elderly is a decrease in its size and weight, accompanied by a decrease in total hepatic blood flow. In general, however, these decreases are pro-portional to the decreases in body size and weight seen in normal aging. Results of liver function tests do not normally change in the elderly; abnormal results in an elderly patient indicate abnormal liver function and are not the result of the aging process itself.
The immune system is altered in the aged, and a less respon-sive immune system may be responsible for the increased inci-dence and severity of hepatitis B in the elderly and the increased incidence of liver abscesses secondary to decreased phagocytosis by the Kupffer cells. With the advent of hepatitis B vaccine as the standard for prevention, the incidence of hepatic diseases may de-crease in the future.
Metabolism of medications by the liver appears to decrease in the elderly, but such changes are usually accompanied by changes in intestinal absorption, renal excretion, and altered body distri-bution of some medications secondary to changes in fat deposition. These alterations necessitate careful medication administration and monitoring; if appropriate, reduced dosages may be needed to prevent medication toxicity.