I. NORMAL STRUCTURE AND FUNCTION OF THE LIVER

A. Structure

The liver is the largest visceral organ, located in the right upper quadrant and protected by the rib cage. There are right and left lobes. Most major vessels and ducts enter and exit at the porta hepatis on the posterior side of the liver. The gall bladder sits in its own compartment behind the liver and closely apposed to it.

The liver has a dual blood supply. The portal vein supplies 2/3 of the blood flow and 1/2 of the oxygen. The hepatic artery supplies 1/3 of the blood flow and 1/2 of the oxygen. The portal vein is made up of the confluence (joining) of veins that drain the GI tract. The blood is relatively poor in oxygen, but rich in nutrients that have been absorbed from the GI tract. These nutrients therefore travel directly to the liver; they do not go out into the general circulation. These nutrients can be extracted by the liver cells for further metabolism. The portal system is normally a low-pressure system. Branches of the portal vein and the hepatic artery generally are found running together in the liver. 

The liver cells (hepatocytes) are arranged in layers one cell thick. On one side, they are in contact with blood-carrying spaces called sinusoids.  The outlet system of bile canals, which serves to carry away bile secretions, is located on the other side. The liver is made up of hexagonal lobules. Branches of the portal vein, hepatic artery, and bile duct (which make up the portal triad) are located at the corners of the lobules. Blood flows from the portal vein and hepatic artery into the sinusoids, which then drain into a central venule (also called a hepatic venule) located in the center of the lobule. Eventually, the blood flows into the hepatic vein and the vena cava.

One of the major secretions of the liver is bile. Bile is made by the hepatocytes and is collected in small ducts. These smaller ducts empty into larger ducts that are part of the portal triad. Within the liver, branches of the bile duct run alongside branches of the portal vein and hepatic artery. However, the direction of flow of bile is opposite to that of blood. Eventually, bile leaves the liver at the area of the hilum to enter the common hepatic duct. Some bile enters the cystic duct for storage in the gallbladder, and some passes through the common bile duct into the duodenum. The opening of the common bile duct into the duodenum is shared by the opening of the pancreatic duct. Under the influence of hormones, bile can be released from the gallbladder into the duodenum through the common bile duct. The production of hormones that stimulate release is triggered by ingestion of a fatty meal.

B. Function

The liver has a great many functions.

1. Synthetic functions: The liver makes many essential substances.

• Albumin, which is extremely important for maintaining proper oncotic pressure in the blood and acts as a carrier protein for other molecules.
• Bile
• Enzymes

• Aspartate aminotransferase (AST): formerly called SGOT. Not specific to the liver.
• Alanine aminotransferase (ALT): formerly called SPGT. ALT is more specific to the liver than is AST, but it, too, is found in other tissues. An elevated level of ALT in the blood is a sensitive indicator that liver cells have been damaged (thus releasing their internal stores of the enzyme). Both AST and ALT are enzymes that are important in the metabolism of proteins.

• Clotting factors, including Factors II, VII, IX, and X
• Lipids, including some components of bile

• Cholesterol
• Phospholipids
• Triglycerides

2. Storage functions

• Glycogen, which is stored when glucose is present in excess.
• Vitamin A

3. Detoxification

• Drugs, which can be metabolized to less toxic forms, to water-soluble forms, or even to more active forms.
• Poisons, such as carbon tetrachloride or alcohol
• Endogenous toxins that are produced within the body can be converted to less injurious substances by the liver.

4. Secretion

• Bile, which is also synthesized by the liver

Bile is made by liver cells and is composed of water, salts, cholesterol, and bile salts, which are needed for absorption of fats in the GI tract. Bile salts are largely resorbed in the ileum and recycled back to the liver. A minor but important component of bile is bilirubin, which is derived from heme groups and gives bile its color.  These heme groups come from hemoglobin, which is broken down when old red blood cells are destroyed by macrophages, largely in the spleen. The heme is first converted to biliverdin and then to bilirubin. The bilirubin is released into the blood and taken up by liver cells, which then conjugate (join) it to glucuronic acid. The conjugated bilirubin is then secreted into the bile, transported to the intestine, and ultimately eliminated in the stool.

Conjugated bilirubin is also called direct bilirubin; the unconjugated form is called indirect bilirubin. Conjugation of bilirubin increases its solubility in water, which makes it less toxic to cells and facilitates its excretion in the bile and eventually in the urine.

II. JAUNDICE

The normal level of bilirubin in the blood is 1 mg/dL. If the concentration increases to 2 mg/dL, yellowing of the skin, sclera, and mucous membranes will become evident. Yellowing due to increased levels of bilirubin in the blood (hyperbilirubinemia), which then deposits in the tissues of the body, is called jaundice or icterus. Depending on the site of the problem, hyperbilirubinemia is usually dominated by either the unconjugated or conjugated type. Jaundice can be classified according to the mechanism that produced it:

1. Hemolytic (prehepatic) jaundice: occurs when the liver cells are normal, but so much bilirubin is present that the capacity of the liver to take it up and/or conjugate it is exceeded. A typical cause is excessive breakdown of red blood cells (i.e., hemolytic anemia). In prehepatic jaundice, the type of bilirubin seen in the blood is largely unconjugated.

2. Hepatocellular jaundice: usually occurs when production of bilirubin is normal, but damage to the liver cells interferes with uptake, conjugation, or excretion of bilirubin. Depending on which factors predominate, bilirubin may be conjugated or unconjugated.

3. Posthepatic (obstructive): is due to obstruction in the biliary drainage system, rather than to any problem with the hepatocytes themselves. Strictures or stones in the extrahepatic biliary tract, as well as tumors, may produce this type of jaundice. This "backed-up" bilirubin, which is conjugated, can get into the blood.

In young people, jaundice is most frequently due to viral hepatitis or alcohol abuse. In older people, malignancies are a more common cause. Premature infants may develop jaundice due to increased hemolysis and immature liver cells that contain insufficient enzymes to process bilirubin properly. Jaundice itself is not toxic except in newborns. Since their blood-brain barrier is not fully functional, bilirubin can pass into the brain and cause damage.

III. HEPATITIS

Hepatitis is inflammation of the liver. It can arise from many causes, but it is usually due to infections with hepatotropic viruses that specifically target the liver. There are at least five hepatotropic viruses: hepatitis viruses A, B, C, D, and E. These are completely distinct viruses.  A, B, and C cause the majority of disease in the US. The latest statistics show the order of incidence as B>A>C, but it is difficult to be certain as many cases of hepatitis A go unreported. Hepatitis D virus is rare and can cause infection only when Hepatitis B virus is also present.  Hepatitis E is very rare in the US.

The clinical symptoms are similar no matter which of these viruses is the cause. However, the prognosis and outcomes vary greatly depending on the causative virus. Symptoms include malaise, fever, fatigue, and nausea. These symptoms are quite nonspecific; only the presence of jaundice (which is not always seen) points to the liver as the problem. Perhaps half the population has had hepatitis A, but many of these people may have been unaware of the infection.  Also, it is important to note that patients may be infectious before the onset of symptoms.

A. Hepatitis A

Hepatitis A is also called infectious hepatitis or short incubation hepatitis. The incubation period is generally from 15 to 60 days. It is caused by an RNA virus that is relatively simple in structure. Hepatitis A is transmitted by the ever-popular oral-fecal route, and the virus can appear in the stool before any symptoms are observed. Dumping of sewage can result in infection of shellfish, which can then transmit the disease if eaten raw. Very rarely, transmission by transfusion occurs, since there is a brief period of viremia (presence of virus in the blood). Greater than 99% of cases recover without incident, usually within 2 to 3 months. Unless jaundice develops, many of these people never realize that they are infected since the symptoms are so nonspecific. Infected people first make IgM antibodies directed against the virus, followed by IgG, which confers life-long immunity. Life-long immunity is also seen for those who recover from hepatitis B, but this is not the case for hepatitis C. Fewer than 1% of patients with hepatitis A (usually those over 60 years old) develop massive inflammation leading to necrosis of liver cells and death. For the vast majority who recover, no chronic carrier state ever develops.  A highly effective vaccine that confers life-long protection is available and is recommended for food handlers and health-care workers.

B. Hepatitis B

Hepatitis B is also called serum hepatitis or long-incubation hepatitis. It is caused by a DNA virus with a complex structure, and the incubation period is generally 1 to 6 months (average is ~2 months).

The hepatitis B virus is composed of a DNA core surrounded by a capsid containing a protein called hepatitis B surface antigen. When the virus infects liver cells, the core and capsid are produced separately and then joined together. The capsid is produced in excess of the core, and the excess is released by the infected cell into the blood. Capsids containing hepatitis B surface antigen can be detected in the blood by clinical tests to diagnose the disease.  Tests to detect the viral DNA in the blood are also now available and are commonly used.

Hepatitis B is transmitted parenterally (by a route other than through the gastrointestinal tract), e.g., through blood, semen, saliva, or tears. Hepatitis B is often spread through IV drug abuse, accidental needle sticks, or sexual intercourse. Before effective means of screening blood were developed, transfusion was the most common mode of transmission. In about 1/3 of cases, the source of infection is unknown.

Surface antigen appears in the blood before symptoms are seen. The patient makes antibody to surface antigen; as the levels of antibody increase, the levels of surface antigen decrease. About 95% of patients recover and have immunity for life. However, the immune systems of the remaining 5% do not clear the virus. The surface antigen is seen in the blood for > 6 months, which is the definition of chronic hepatitis. This is referred to as a carrier state, since active virus remains present. Chronic hepatitis can lead to cirrhosis (see next section), end-stage liver disease, and death. The chronically infected liver cells may also become malignantly transformed, giving rise to hepatocellular carcinoma, which is very deadly.

C. Hepatitis C

Hepatitis C was called non-A, non-B hepatitis before the causative RNA virus was identified. Tests that detect antibodies to hepatitis C or viral RNA have been developed to screen donor blood, which has greatly decreased the spread of this disease through transfusion. It is the major cause of hepatitis in IV drug abusers. The source of infection for a third or more of cases is unknown. The virus can be spread by close household contact, but most transmission is via contaminated blood in drug abusers. Sexual transmission is rare.  Hepatitis C virus does not get into the stool, so transmission by the oral-fecal route does not occur.  The incubation period, like that of hepatitis B, is generally long, but ranges from 14 to 180 days. A whopping 50% of victims develop chronic hepatitis, and 10% develop cirrhosis (which may not appear for a decade or two). Chronic carriers are at risk for hepatocellular carcinoma.  The chances of developing cancer are increased if the initial infection occurs during childhood.   The incidence of hepatocellular carcinoma has doubled over the past 15 years, probably due to increased incidence of infections with Hepatitis C virus.  An antibody response to the virus does not necessarily protect against a second round of infection; it may be that there are variants of the virus.

The following chart summarizes treatment and prevention of the three major types of hepatitis:

IV. CIRRHOSIS

Cirrhosis is end-stage liver disease. It is defined as a diffuse structural disorganization of the liver characterized by necrosis, fibrosis (scarring), and nodular regeneration. Necrosis of liver cells leads the liver to attempt to repair itself, which causes both regeneration of liver cells and scarring. The combination of these two processes occurring simultaneously results in formation of nodules surrounded by dense fibrous bands. Profound abnormalities in the function of the liver may result. The cirrhotic liver is often smaller than normal.

In the US, the major causes of cirrhosis are hepatitis B and hepatitis C (not A), and, even more commonly, alcohol abuse. Some cases have no known cause, and certain rare metabolic diseases may result in cirrhosis.

Micronodular cirrhosis, which is characterized by small, diffuse nodules and fatty changes in the liver, is typically related to alcohol abuse. Macronodular cirrhosis, with variable damage to different areas of the liver, is more typical of hepatitis-related cirrhosis.  In hepatitis-related cirrhosis, much of the damage may be due to the action of lymphocytes that are attempting to destroy the virally infected cells.

Cirrhosis is an irreversible condition; the length of its course is variable. Cirrhosis affects nearly all normal functions of the body. The marked fibrosis in advanced cirrhosis provides resistance to the flow of blood from the portal vein, resulting in portal hypertension (increased pressure in the portal vein). Major pathophysiological consequences of cirrhosis include:

• Splenomegaly (enlargement of the spleen), anemia, and thrombocytopenia (decreased number of circulating platelets): The increased pressure in the portal vein is reflected back into other normally low pressure veins that flow into the portal vein. One of these is the splenic vein. In response to the elevated pressure, the spleen enlarges and increases its functional activity (hypersplenism). The spleen is responsible for clearing aged and damaged red blood cells and platelets from the circulation. In hypersplenism, the red cells and platelets are removed too rapidly, leading to anemia and thrombocytopenia. The diminished number of platelets contributes to abnormal bleeding.
• Varices: In cirrhosis, abnormal connections may develop between the portal vein and the veins of the systemic circulation. Portal hypertension then causes varices (regions of abnormal enlargement and dilation) to develop. Commonly affected are veins in the rectum, leading to formation of hemorrhoids, and in the distal esophagus. In the esophagus, the veins may become very enlarged and tortuous, making them highly susceptible to rupture. Rupture in turn may lead to massive hemorrhage. The rupture of esophageal varices is the second most common cause of death from cirrhosis, the first being liver failure itself.
• Ascites refers to an abnormal collection of fluid in the peritoneal cavity. It is a difficult condition to treat. In cirrhosis, ascites form in response to a variety of factors. These include an abnormal flow of blood and lymph in the liver, which causes fluid to ooze off of its surface into the peritoneal cavity. Because the liver is not functioning at full capacity, plasma levels of albumin are decreased, meaning that there is decreased oncotic pressure in the blood. This contributes to formation of both ascites and edema. Levels of aldosterone and antidiuretic hormone also increase, due to lack of their normal metabolism by the liver. As a consequence, there is increased retention of both water and salts.
• Encephalopathy: Normally, ammonia that is produced in the colon and released into the blood is removed by the liver. In cirrhosis, blood is shunted past the scarred liver, so that the ammonia is not removed. Ammonia and other toxic compounds that build up in the systemic circulation can cause slowing of mental processes and seizures.
• Bleeding tendencies: The liver normally produces clotting factors. Their lack, along with reduced numbers of platelets (see above), result in bleeding problems in patients with cirrhosis.

• Jaundice: occurs because the liver cells are not functioning well and are therefore not processing bilirubin normally.

• Testicular atrophy, gynecomastia (development of breasts in men): can occur in males with cirrhosis, since estrogen is not metabolized properly by the liver.

V. ALCOHOLIC LIVER DISEASE

Manifestations of alcoholic liver disease include fatty liver (steatosis), alcoholic hepatitis, and cirrhosis. About 10 to 50% of people drinking the equivalent of 8 shots of liquor a day will develop alcoholic liver disease. However, for unknown reasons, some people who consume that amount of alcohol are unaffected. 

Fatty liver develops because alcohol causes both an increase in the synthesis of fatty acids and a decrease in the transport of fats within the liver, resulting in accumulation of fats in hepatocytes. Anyone who drinks gets fatty changes in the liver. This is a completely reversible condition and does not damage cells. However, ethanol is directly toxic to liver cells, and, with prolonged exposure, some people (not all) will develop hepatitis and necrosis of liver cells. Why only some drinkers develop hepatitis, etc., is unclear. It is not related to the dose of alcohol or the length of exposure, and it is variable from person to person in an unpredictable way. Some people who develop hepatitis will progress to cirrhosis and full-blown liver disease. Alcohol-related cirrhosis is a leading cause of death in both men and women from 30 to 50 years old.

VI. LIVER TUMORS

World-wide, primary liver tumors are mostly the result of infection with hepatitis B or C viruses. In the US, most liver cancers are metastatic. Because of anatomical considerations, the most common tumor to spread to the liver is colon carcinoma (i.e., the veins from the colon drain to the liver). Multiple, variably sized nodules of metastatic tumor often develop. The liver can be rather massively involved before liver function is completely impaired. Other GI tumors (e.g., pancreatic carcinoma) and breast cancers also tend to metastasize to the liver.  Unfortunately, some liver tumors may be present for a long time before causing symptoms, since only a third of the liver is required for its normal function. 

VII. THE GALLBLADDER AND ITS DISEASES

The main function of the gallbladder is to store bile and release it via the common bile duct into the duodenum when appropriately stimulated by hormones. Release of the stimulatory hormones is triggered by ingestion of a fatty meal. The bile duct often shares a common lumen with the pancreatic duct.

The term cholelithiasis refers to the presence of stones or concretions in the gallbladder. This is a very common condition in the US. It is most common in obese females greater than 30 to 40 years old, although its incidence in younger people is rising. It is thought that stones form due to an imbalance of components in the bile. Normally, cholesterol is kept soluble by bile salts and lecithin. If there is an increase in cholesterol and/or a decrease in bile salts or lecithin, the cholesterol will precipitate and form crystals. These small crystals can enlarge to form stones. Stones can form either in the gall bladder itself or in the cystic or bile ducts, leading to obstruction. Stones may also move from the gall bladder into ducts.  Obstruction may cause bile to back up in the liver, where high concentrations can cause damage.

Stones may be asymptomatic. If they are causing obstruction, however, they typically produce a sharp, spasmodic pain in the right upper quadrant. The pain usually occurs after a fatty meal, which triggers contraction of the gallbladder and ducts. Stones can also impair blood flow in the gallbladder, leading to ischemia and predisposing to infection with bacteria (cholecystitis). Nearly everyone with cholecystitis has stones. It is usually recommended that anyone who has had a bout with cholecystitis have his or her gallbladder removed to prevent future complications, such as rupture.

Stones can be removed by laparoscopic or conventional surgery, dissolved by injecting chemicals, or broken up using shock wave therapy.

VIII. THE PANCREAS AND ITS DISEASES

The pancreas has both exocrine and endocrine functions, the latter of which are discussed in the lecture on the endocrine system. The exocrine function of the pancreas is to produce digestive enzymes. These enzymes are transported along the pancreatic duct and released into the duodenum under hormonal stimulation. Obstruction of the duct can lead to pancreatitis, as the pancreatic juices back up and digest surrounding tissues.

The incidence of pancreatic cancer is rising in the US. It is the fifth most common cancer and the fourth leading cause of death from cancer. It is a highly deadly cancer, often proving fatal within a couple of months of diagnosis. The one-year survival rate is < 10%, and there is no effective screening or treatments. The etiology is not clear. It is usually seen in people over the age of 50, and smoking and a diet high in fat are risk factors. Pancreatic tumors can grow large and spread without causing symptoms, especially those that arise in the body or tail of the organ. These do not usually cause jaundice, at least early on. Most often, cancers develop in the head of the pancreas, where they may obstruct the common bile duct, leading to post-hepatic jaundice (which, as you know, is characterized by conjugated hyperbilirubinemia). The pancreatic circulation drains into that of the liver, so spread to the liver is common.