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B. Liver Functions The body depends on the liver to perform a number of vital functions (Figure 6), and although there is substantial overlap, they can be divided into three basic categories: Figure(6) ?regulation, synthesis, and secretion of many substances important in maintaining the body's normal state ?storage of important nutrients such as glycogen (glucose), vitamins, and minerals ?purification, transformation, and clearance of waste products, drugs, and toxins Disease or traumatic injury can greatly reduce the liver's ability to carry out these normal activities. Thus, most of the clinical manifestations of liver dysfunction (discussed later in this module) stem from cell damage and impairment of the normal liver capacities. For example, viral hepatitis causes damage and death of hepatocytes. In this case, manifestations may include increased bleeding (due to decreased synthesis of clotting factors), jaundice (yellow pigmentation due to decreased clearance of bilirubin ), and increased levels of circulating hepatocyte enzymes (released from dead liver cells). 1. Regulations, Synthesis, and Secretion. Hepatocytes are metabolically active cells that serve many functions. For example, they take up glucose, minerals, and vitamins from portal and systemic blood and store them. In addition, hepatocytes can produce many important substances needed by the body, such as blood clotting factors, transporter proteins, cholesterol, and bile components. Finally, by regulating blood levels of substances such as cholesterol and glucose, the liver helps maintain body homeostasis. a. Glucose. The liver plays a major role in maintaining blood concentrations of glucose, by storing or releasing glucose as needed. b. Proteins. Most blood proteins (except for antibodies) are synthesized and secreted by the liver. One of the most abundant serum proteins is albumin. Impaired liver function that results in decreased amounts of serum albumin may lead to edema, swelling due to fluid accumulation in the tissues. The liver also produces most of the proteins responsible for blood clotting, called coagulation or clotting factors. If the blood cannot clot normally due to a decrease in the production of these factors, excessive bleeding may result. c. Bile. Bile is a greenish fluid synthesized by hepatocytes and secreted into biliary ducts. It then leaves the liver to be temporarily stored in the gallbladder before emptying into the small intestine. The major components of bile include cholesterol, phospholipids, bilirubin (a metabolite of red blood cell hemoglobin), and bile salts. Importantly, bile salts act as "detergents" that aid in the digestion and absorption of dietary fats. Liver damage or obstruction of a bile duct (e.g., gallstone) can lead to cholestasis, (the blockage of bile flow, which causes the malabsorption of dietary fats), steatorrhea (foul-smelling diarrhea caused by non-absorbed fats), and jaundice. d. Lipids. Cholesterol, a type of lipid, is a substance found in cell membranes that helps maintain the physical integrity of cells. The liver synthesizes cholesterol, which is then packaged and distributed to the body to be sued or excreted into bile for removal from the body. Increased cholesterol concentrations in bile may predispose to gallstone formation. The liver also synthesizes lipoproteins, which are made up of cholesterol, triglycerides (containing fatty acids), phospholipids, and proteins. Lipoproteins circulate in the blood and shuttle cholesterol and fatty acids (an energy source) between the liver and body tissues. Most liver diseases do not significantly affect serum lipid levels, with the exception of cholestatic diseases, which may be associated with increased levels. 2. Storage. As mentioned above, the liver is designed to store important substances such as glucose (in the form of glycogen). The liver also stores fat-soluble vitamins (vitamins A, D, E and K), folate, vitamin B 12 , and minerals such as copper and iron. However, excessive accumulation of certain substances can be harmful. For example, patients with an inherited condition known as Wilson's disease cannot secrete copper into bile normally and usually have a low blood level of the copper-binding protein ceruloplasmin. Retained copper accumulates in the liver (leading to cirrhosis and in the central nervous system (resulting in neuropsychiatric symptoms). 3. Purification, Transformation, and Clearance. The liver removes harmful substances (such as ammonia and toxins) from the blood and then breaks them down or transforms them into less harmful compounds. In addition, the liver metabolizes most hormones and ingested drugs to either more or less active products. a. Ammonia. The liver converts ammonia to urea, which is excreted into the urine by the kidneys. In the presence of severe liver disease, ammonia accumulates in the blood because of both decreased blood clearance and decreased ability to form urea. Elevated ammonia levels can be toxic, especially to the brain, and may play a role in the development of hepatic encephalopathy. b. Bilirubin. Bilirubin is a yellow pigment formed as a breakdown product of red blood cell hemoglobin. The spleen, which destroys old red cells, releases "unconjugated" bilirubin into the blood, where it circulates in the blood bound to albumin (Figure 7). The liver efficiently takes up bilirubin and chemically modifies it to "conjugated," or water-solube, bilirubin that can be excreted into bile. Increased production or decreased clearance of bilirubin results in jaundice, a yellow pigmentation of the skin and eyes from bilirubin accumulation. Figure(7) c. Hormones. Since the liver plays important roles in hormonal modification and inactivation, chronic liver disease may cause hormonal imbalances. For example, the masculinizing hormone testosterone and the feminizing hormone estrogen are metabolized and inactivated by the liver. Men with cirrhosis, especially those who abuse alcohol, have increased circulating estrogens relative to testosterone derivatives, which may lead to body feminization. d. Drugs. Nearly all drugs are modified or degraded in the liver. In particular, oral drugs are absorbed by the gut and transported via the portal circulation to the liver. In the liver, drugs may undergo first-pass metabolism, a process in which they are modified, activated, or inactivated before they enter the systemic circulation, or they may be left unchanged. Alcohol is primarily metabolized by the liver, and accumulation of its products can lead to cell injury and death. In patients with liver disease, drug detoxification and excretion may be dangerously altered, resulting in drug concentrations that are too low or too high or the production of toxic drug metabolites. Therefore, medications that are metabolized by the liver must be used with caution in patients with hepatic disease; these patients may need lower doses of the drug. e. Toxins. The liver is generally responsible for detoxifying chemical agents and poisons, whether ingested or inhaled. Pre-existing liver disease may inhibit or alter detoxification processes and thus increase the toxic effects of these agents. Additionally, exposure to chemicals or toxins may directly affect the liver, ranging from mild dysfunction to severe and life-threatening damage. Summary From its sheltered position in the abdominal cavity, the liver filters blood from both the portal and systemic circulations. The body depends on the liver to regulate, synthesize, store, and secrete many important proteins and nutrients and to purify, transform, and clear toxic or unneeded substances. To carry out these functions, hepatocytes are organized for optimal contact with sinusoids (leading to and from blood vessels) and bile ducts. A special feature of the liver is its ability to regenerate, but this capacity can be exceeded by repeated or extensive damage.