What is the liver?

Structure and Functions

The liver, an accessory gland of the digestive system, is the largest organ in the human body. Located in the upper-right quadrant of the abdominal cavity, it abuts the diaphragm on the anterior surface. The liver is composed of two lobes of unequal size, with the large right lobe further divided into two smaller lobes. The organ is protected by the ribs, which cover nearly the entire surface. The liver contains only one type of functional cell, known as a hepatocyte. Closely associated with the organ is the gallbladder, a saclike structure that holds bile, a product of the hepatocytes. Bile is continually produced by the hepatocytes but is stored in the gallbladder until it is required for digestive products.

The liver is unique in that it receives blood from two different sources. The hepatic artery delivers blood to the liver from the systemic circulation. The liver also receives blood via the portal vein, which collects blood that has previously passed through the small intestine and has absorbed nutrients from the digestive system. As the blood enters the liver, it flows into dilated capillaries called sinusoids. Blood flow through sinusoids is much slower than through capillaries, and the exchange of materials between hepatocytes and the bloodstream is accomplished with little difficulty. This slower process also allows the liver to serve as a storage organ for blood, which gives the organ its characteristic dark red appearance.

The liver is essential to the normal functioning of the body. Its activities are many and varied: It regulates the metabolism of carbohydrates, lipids, and proteins; synthesizes proteins, particularly those of blood plasma that control clotting; serves as a storage site for some vitamins and iron; degrades steroid hormones; and inactivates and/or excretes certain drugs and toxins.

The liver plays a major role in carbohydrate metabolism. As
carbohydrates are absorbed from the small intestine, they are transported to the liver through the portal vein. The liver regulates blood sugar levels by removing excess quantities. If the diet includes too much glucose, this substance is stored in the liver or skeletal muscle as glycogen. If the blood sugar levels are low, the glycogen is broken down into glucose and released to the bloodstream. The liver is also capable of converting amino acids, lipids, or simple carbohydrates into glucose.

The principal functions of the liver in lipid metabolism are twofold. First, it is responsible for the breakdown of large fat molecules into small compounds that can be used for energy. Second, it synthesizes triglycerides, cholesterol, and phospholipids from other fats. All three of these compounds play important roles in cellular function.

The synthesis of proteins by the liver is of major importance for the body. The liver is capable of synthesizing not only a variety of proteins but also the nonessential amino acids that are the building blocks of proteins. Many of the proteins that the liver synthesizes are found in blood plasma, including those factors responsible for blood clotting. To protect the body against deficiencies in these substances, the liver stores vitamins A, D, and B12. It is also capable of storing iron, the mineral necessary for the production of hemoglobin.

Located in the smooth endoplasmic reticulum of hepatocytes are nonspecific enzymes called the mixed-function oxidases. They are capable of metabolizing a wide variety of hormones, including some polypeptide hormones and the steroid hormones, such as cortisol, estrogen, and testosterone. These same enzymes are responsible for the degradation of many foreign substances that enter the body, such as prescription medications, illegal drugs, and toxins. Most of the materials metabolized are made more water-soluble, and therefore more easily excreted, by the kidney. Others are removed from the hepatocytes in the bile that the cells produce.

Production of bile by the hepatocytes is of utmost importance to the digestive system. Bile is composed of lecithin, cholesterol, bile pigments, proteins, and bile acids, along with an isotonic solution similar to blood plasma. Bile is produced continually and stored in the gallbladder. Several minutes after a meal begins, the gallbladder releases bile to the duodenum of the small intestine. The highest rate of bile release occurs during the duodenal
digestion of food and is controlled by the hormone cholecystokinin. In the duodenum, bile acts as an emulsifier of fat in the diet. It breaks large lipid droplets into many small lipid droplets, which can more easily be digested by enzymes in the small intestine. About 95 percent of the bile is reabsorbed and returned to the liver, and the other 5 percent is excreted with the feces. This provides one mechanism for the body to use the digestive system for the removal of waste products. One important product that is excreted in this
manner is bilirubin, a by-product of the normal destruction of old red blood cells.

Disorders and Diseases

The liver is unique among body organs because it has the ability to regenerate in cases of injury or disease. It is estimated that in a young, healthy individual a liver that has suffered a physical injury could regenerate as much as 80 percent of the total organ. Many important organs are paired, such as the lungs and kidneys. Though the liver is a single organ, its ability to regenerate ensures normal function even in cases of severe injury.

The presence of liver disease is detectable in many ways. With some diseases, the liver becomes enlarged and can be felt below the ribs. This swelling may be associated with localized discomfort or pain in the region. In more severe cases of liver disease, the organ may actually shrink and recede further under the ribs, a condition easily detected by a physician.

The pathophysiology of the liver is characterized by certain physiologic events that occur regardless of the underlying cause. Within the liver, disease may result in portal hypertension, blockage of bile ducts, and cellular injury or death. Cellular injury may be manifest by fatty infiltration and by interference with cellular functions, including the synthesis of proteins necessary for blood clotting, the metabolism of drugs or toxins, the regulation of glucose, and the production of bile. Any or all of these physiologic changes can lead to effects in other parts of the body.

Disease of the liver is often detectable by routine blood tests that include liver function tests. The patient may show decreased levels in the blood serum of proteins that are normally produced by the liver, an increased blood-clotting time, or increased serum levels of enzymes that are normally found only in the liver. A yellow skin tone known as
jaundice has been associated with liver disease. This discoloration of skin and the sclera of the eye is a result of excessively high levels of bilirubin in the blood. Bilirubin is a by-product of the breakdown of red blood cells that are near the end of their 120-day life cycle.

The injury or death of liver cells may present a pathology unique to the liver, the disease cirrhosis. When hepatocytes are injured or diseased, they begin to accumulate lipids in vacuoles, giving the liver a whitish appearance. Associated with the development of a fatty liver, the cells may divide to produce more cells that will ensure normal function. Sometimes, however, this stimulation of cell division leads to an excess of hepatocytes, a condition that may result in abnormal patterns of blood flow through the liver. In addition, this phenomenon may include the production of large nodules of connective tissue to replace dead or dying cells, a condition comparable to scarring. The development of scars may cause increased blood pressure in the portal veins and may block bile ducts. Cirrhosis may be caused by a variety of conditions, including alcoholism, exposure to toxic substances, or infection. It
is irreversible and ultimately causes the death of the patient.

Diseases of the liver can be classified according to the following scheme: congenital liver disorders, viral and nonviral infections, drug-induced and toxin-induced disease, vascular disorders, metabolic disorders, iron accumulation, alcoholic liver disease, and tumors.

The most common types of congenital diseases of the liver involve abnormalities of the bile ducts or of the portal vein, which may be associated with portal hypertension. More important, however, are those diseases that lead to the formation of cysts, such as polycystic liver disease or hepatic fibrosis. Jaundice of the newborn, a discoloration of the skin at birth, usually clears within a week or so with no long-term effects.

Viral infections of the liver may be associated with the hepatitis viruses or other viruses less specific for the liver. The four most common hepatitis viruses are hepatitis A, hepatitis B, hepatitis C, and hepatitis D. Hepatitis can also be associated with yellow fever, infectious mononucleosis, cytomegalovirus infection, and herpes simplex.

Hepatitis A is also known as infectious hepatitis. It is generally transmitted via fecal contamination of milk, water, or seafood. It is most common in the areas of the world where untreated sewage may come into contact with the water supply or food sources. It has a short incubation period and is usually not fatal; it does not lead to chronic hepatitis. Hepatitis B, also known as serum hepatitis, is transmitted from persons with an active form of the disease or from carriers via contaminated blood or blood products. It is particularly prevalent among drug users who share needles. The threat of contraction of hepatitis B from a transfusion has been greatly reduced by the screening of blood products. Hepatitis B has a long incubation period, up to six months. The severity of the disease varies greatly from subclinical hepatitis (showing no symptoms) to chronic hepatitis and in some cases may result in death. The course of hepatitis C disease resembles that of hepatitis B and may lead to chronic hepatitis. Hepatitis D is believed to be a defective virus that is found only in the presence of hepatitis B. It is transmitted via the same route and can result in chronic hepatitis.

Hepatitis from any cause may show subclinical or mild, influenza-like symptoms. Acute hepatitis may cause loss of appetite, vomiting, fever, jaundice, and enlargement of the liver. The viruses that cause hepatitis replicate within the liver cells, which could be the cause of the injury to these cells. Hepatocyte injury could also be a result of the immune system’s attempt to fight the virus, which may injure the cells of the liver in the process. In either case, the damaged cells swell before they die. The liver can also be infected by bacterial cells, which usually reach the liver as a result of a systemic infection.

Many toxins or drugs can injure the liver, in a general pattern that is similar to the effects of infectious agents. The assault on the cell often leads to fatty infiltration, followed by swelling and finally by the death of the hepatocyte. Even in less severe cases of injury, those that do not lead to death of the hepatocyte, there is often impairment of the metabolic activities of the liver that can lead to diverse systemic effects. One of these effects is the ability to metabolize foreign compounds or naturally occurring steroids; the accumulation of these compounds throughout the body can have wide-ranging consequences.

The liver is adversely affected by the constant intake of excessive quantities of ethyl alcohol. In the early stages of alcoholism, the physiologic changes may be a result of improper nutrition or of vitamin deficiencies. During the more advanced stages of alcoholism, the patient is likely to suffer from a fatty liver and, ultimately, from cirrhosis. While those who stop drinking may slow down the advancement of cirrhosis, the disease appears to be irreversible.

There are more than five thousand metabolic enzymes in the liver, each of which is controlled genetically. Important in the treatment of metabolic disease is early diagnosis, which may prevent damage to other organs or to the liver. Dietary control may be used to minimize the effects of such conditions, leading to a near-normal life. Examples of treatable metabolic diseases are galactosemia, a condition that prevents the conversion of galactose to glucose; fructosemia, a condition that leads to the accumulation of fructose-1-phosphate; and Wilson disease, an accumulation of copper in vital organs as a result of a defect in copper metabolism. In each case, the accumulation of a certain substance can lead to cellular damage, but dietary control of the substance can minimize the effects. Hemochromatosis is a similar disease that leads to accumulation of iron in the liver. As with Wilson disease, the deposition of this element is not limited to the liver and can accumulate in other vital tissues of the body as well.

Cancer of the liver
is usually caused by its spread from another site. Primary liver cancers are rare and usually do not occur until late in life. Risk factors may include exposure to hepatotoxins, chronic liver disease, or hepatitis B. There are two types of primary carcinomas of the liver: hepatocellular carcinoma, which develops in hepatocytes, and cholangiocellular carcinoma, which develops in bile ducts.

Perspective and Prospects

The liver is a vital organ that plays a major role in the homeostasis of the body. Any condition that adversely influences the liver will have wide-ranging effects on other organs and the patient as a whole.

Because one of its functions is the metabolism of pollutants, drugs (including alcohol), and hormones, the liver is often exposed to substances that are toxic to its hepatocytes. When these compounds are encountered, the liver efficiently alters them for excretion. Sometimes, however, these substances may do damage to the cells before the liver can metabolize them.

When a liver cell is injured, the end result may be the death of the cell. Fortunately, liver cells are efficient at cell division and can replace those cells that have been injured or that have died. With continued damage to liver cells, however, the body can no longer replace them, and the resulting decrease in liver function leads to extensive complications throughout the body. A decrease in liver function will not only have an effect on the digestive system but will have wide-ranging effects on glucose and lipid metabolism (normal functions of the blood whose proteins are synthesized by the liver) and on the ability to remove certain foreign substances or toxins from the blood. For example, if the ability to metabolize medication is impaired by liver disease, the patient’s body may accumulate high, even toxic, levels of drugs. These substances can have pronounced effects, particularly on the nervous system. With liver injury, the once-simple act of determining a medication dosage can become a critical problem.

Despite the liver’s regenerative capacity, liver injury or disease can have permanent effects. However, some conditions previously thought incurable, such as chronic hepatitis B and C, can now be treated successfully in many cases with antiviral drugs and interferon. The medical community can treat the symptoms of hepatitis.

Cancer of the liver
is also difficult to treat. Because it is not easily detected, the diagnosis is rarely early. Unless the cancer is restricted to one lobe that can be removed, surgery is rarely the answer. Treatment is further complicated by the fact that the liver cells are particularly sensitive to radiation and that the doses needed to treat the cancer would be deadly to hepatocytes. Chemotherapy has been the mainstay of treatment for both metastatic and primary liver cancer, but transplantation is increasingly recommended for patients with primary liver cancer.

With the discovery of immunosuppressive drugs,
liver transplantation has become a positive procedure in the treatment of liver disease, and the results are promising. The availability of healthy livers for transplant, however, makes this an option limited to a small percentage of patients.

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