Hepatitis

Hepatitis Glossery Albumin [al BYOO min]: a protein in the serum that transports substances Such as drugs and prevents leakage of fluid into the surrounding tissues. Alkaline phosphatase [AL kuh lin FAHS fah tays]: protein found in bile duct cell membranes; blood levels may be increased in any liver disease, but more markedly with cholestasis. Alpha 1 - antitrypsin [AL fah -1 an tigh TRIP sin]: plasma protein produced by the liver that inhibits the activity of trypsin and other proteolytic enzymes; inherited deficiency leads to emphysema and sometimes cirrhosis. Aminotransferase [ah MEE noh TRANS fir ays]: hepatocyte enzyme that modifies proteins; blood levels increase in the setting of hepatocellular necrosis (hepatocyte death). The two aminotransferases important in liver disease are AST (aspartate aminotransferase) and ALT (alanine aminotransferase). Antibodies: proteins produced in response to a specific antigen, which can then combine with that antigen and neutralize it. Antigens: a molecule with a specific configuration that is recognized by the immune system; usually part of a protein or sugar. It stimulates the formation of a specific antibody and can elicit an allergic reaction, or otherwise trigger an immune response. Ascites [uh SIGH teez]: accumulation of fluid in the abdominal cavity, usually secondary to liver scarring and increased sinusoidal pressure. Intractable ascites is unresponsive to treatment and continually recurs. Autoimmunity [AW toh im MEWN it ee]: a state or disease in which the body's immune system attacks the body's own tissues. Bile: greenish fluid formed by the liver and emptied into the small intestine via the bile ducts; contains bilirubin, bile salts, phospholipids, and cholesterol. Bilirubin [BIL ee roo bin]: a bile pigment cleared from the bolld by the liver; formed as a breakdown product of old red blood cells; marked increase in blood levels can lead to jaundice from deposition of bilirubin in skin, mucous membranes, and whites of the eyes. Caput medusae [KAP medusae [KAP ut muh DOO see]: literally "Medusa's head"; dilated, varicose veins around the umbilicus, which may be seen in patients with cirrhosis of the liver. Ceruloplasmin [suh ROO loh PLAZ min]: copper transporter protein; blood levels are usually decreased in Wilson's disease. Cholestasis [hoh luh STAY sis]: blockage or suppression of bile flow, from either intrahepatic or extrahepatic causes. Cirrhosis [sur ROH sis]: pathologically-defined disease characterized by diffuse, irreversible fibrosis of the liver surrounding regenerative nodules. Coagulopathy [koh AG yoo LAH puh thee]: increased bleeding tendency due to decreased hepatic synthesis of clotting factors. Decompensation: failure of the liver to compensate for damage or injury, resulting in a decrease in liver functions. Dysplasia [dis PLAY zhuh]: alteration in size, shape, and organization of cells; may be precursor of cancer. Encephalopathy [en SEF uh LAH puh thee]: alteration in sleep patterns and mental status, ranging from forgetfulness and mild confusion to coma; may be caused by circulating gut-derived brain-toxic proteins not cleared by a dysfunctional liver. Fibrosis [figh BROH sis]: the formation of fibrous tissue, or scarring. Fulminant: running a speedy course, with rapid worsening. Hemochromatosis [HEE moh KROH mah TOH sis]: toxic accumulation of iron in organs leading to dysfunction, including cirrhosis; may be genetic (inherited increase in gut iron absorption) or a result of massive blood transfusions. Hepatitis [HEP uh TIGH tis]: inflammation and damage to the liver; generally considered acute if duration is less than 6 months, chronic if greater than 6 months. Hepatocellular necrosis: localized tissue death of hepatic cells. Hepatocellular carcinoma (HCC): a primary liver tumor more common in patients with cirrhosis. Hepatocytes: liver cells. Hepatorenal [HEP uh togh REE nahl] syndrome: poorly understood terminal kidney failure in the setting of hepatic disease. Homeostasis [HOH mee oh STAY sis]: tendency of the body to maintain a stable internal environment, using a variety of counterbalancing control systems. Hyperbilirubinemia [HIGH pur BIL ee roo bin EE mee uh]: abnormally high levels of bilirubin in the blood. Icterus: see Jaundice. Idiopathic [ID ee oh PATH ik]: autoimmune chronic active hepatitis (IACAH): chronic hepatitis of unknown origin; associated with a variety of anti-self antibodies; progresses to cirrhosis and decompensation unless treated with corticosteroids. Jaundice [JAHN dis]: hyperbilirubinemia, with deposition of bile pigment in the skin, mucous membraes, and sclerae (whites of eyes), resulting in a yellow appearance of the patient; also called icterus. Kayser-Fleischer rings: golden-brown rings in the corneas due to copper deposition in Wilson's disease. Kupffer cells: "scavenger" cells that remove foreign matter, worn-out blood cells, and bacteria from the liver. Limiting plate: layer of hepatocytes surrounding each portal triad and separating it from the surrounding sheets of hepatocytes. Lobule [LAHB yool]: "structural" unit of the liver; shaped like a hexagon on cross section, with six portal triads at the periphery and a central vein. Portal hypertension [POR tahl HIGH per TEN shun]: abnormal increase in portal blood pressure, usually due to obstruction of, or increased resistance to, portal blood flow. Portal system: includes all the veins that drain the small and large intestines, stomach, and spleen and that converge into the portal vein to drain into the liver. Portal triad (or tract): consists of three components: branch of the hepatic artery, branch of the portal vein, and a biliary duct, all held tightly together by a limiting plate of hepatocytes at the periphery of the lobule. Portosystemic [POR toh sis TEM ick] shunting: development of blood vessels that connect the portal and systemic circulation while bypassing the liver. Prognosis: prediction as to the probable outcome of a disease. Prothrombin [proh THRAHM bin] time (PT): laboratory test that measures the clotting of blood in seconds; abnormally increased PT signifies bleeding risk due to deficient synthesis of clotting proteins. Pruritus: itching. Seroconversion: appearance of specific antibodies in the blood, indicating recovery from infection or successful vaccination. Sinusoids: tunnels through hepatic tissue allowing exchange of nutrients and other substances between blood and hepatocytes. Spider angiomas: red capillary tufts in the skin that blanch on pressure; often found in patients with cirrhosis. Spontaneous bacterial peritonitis (SBP): bacterial infection of ascitic fluid. Steatorrhea [STEE uh toh REE uh]: decreased absorption of dietary fats, resulting in their passage to the distal bowel which causes foul-smelling diarrhea; can be caused by deficiency of bile salts. Transaminase: see Aminotransferase. Varices [VAYR ih seez]: dilated veins; lower esophageal varices form as collaterals from portal hypertension and can rupture, leading to massive bleeding. Wilson's disease: inherited metabolic disorder in which copper accumulates in the liver and in the central nervous system, causing hepatitis, cirrhosis, and neuropsychiatric symptoms. Key Concepts The liver is located in the right upper quadrant of the abdominal cavity and comprises right and left lobes. . The liver receives a unique dual blood supply: systemic (body) via the hepatic artery and portal (gut) via the portal vein. 3. Microscopically, the liver is organized into structural units, or lobules, with six peripheral portal triads and a central vein. 4. One of the unique capacities of the liver is its ability to regenerate after partial removal or damage, although severe damage can lead to irreversible scarring. 5. The liver is important in the synthesis and secretion of key proteins (such as albumin and blood clotting proteins) and the storage of glucose and many vitamins and minerals. 6. Bile, which is important for the digestion and absorption of fats, is synthesized by the liver and enters the intestine via the bile ducts. 7. The liver plays a major role in the purification, transformation, and clearance of waste products (such as ammonia), drugs, and toxins. A. Structure The liver, the largest organ in the body, is located below the diaphragm in the right upper quadrant of the abdominal cavity, as shown in Figure 1; it is sheltered by the rib cage. In an adult, the liver normally weights about 3 pounds and extends approximately from the right fifth rib to the lower border of the rib cage (along an imaginary line extending down from the middle of the collar bone). When the patient inhales, the liver edge may be felt 1 to 2 cm below the right edge of the rib cage. Liver structure has several unique aspects. This section discusses its gross anatomy and blood supply, its cellular organization, and its capacity to regenerate. 1. Gross Anatomy. Figure 2 shows the gross anatomy of the liver. Visual examination reveals that the liver is separated into two lobes, the right and the left (Figure 2a), separated by the falciform ligament. The right lobe is about six times the size of the left and contains two lesser lobes (Figure 2b). The porta hepatis is the entry way for supplying blood vessels (the portal vein and the hepatic artery) as well as the exit site of ducts that drain bile formed in the liver. Bile leaves the liver via the right and left hepatic ducts, which then unite to form the common hepatic duct. The common hepatic duct in turn joins with the cystic duct from the gallbladder to form the common bile duct. Bile is stored in the gallbladder (a pear-shaped bag), and then it flows through the cystic duct into the common bile duct and empties into the intestine. 2. Hepatic Circulation. Figure 3 summarizes the blood flow to and from the liver. As mentioned above, the liver receives a dual blood supply. The portal vein supplies blood (from the portal system, the network of veins and capillary beds draining the intestines and spleen) that is rich in nutrients and absorbed dietary substances but poor in oxygen. This provides 75% of the liver's blood supply. The hepatic artery supplies oxygenated blood from the systemic circulation (aorta) and provides the remaining 25% of the liver's blood supply. Within the liver, both the portal vein and the hepatic artery branch within the lobes and eventually converge together into tunnels, or sinusoids Figure 4, that run parallel to rows of hepatocytes (liver cells). Sinusoids allow the exchange of substances between the blood and hepatocytes and merge to form central veins, which drain blood from the liver into the hepatic vein and then back to the right heart and lungs via the inferior vena cava. 3. Cellular Architecture. The most abundant and metabolically active cells in the liver are the hepatocytes. They lie together in cords, or sheets, in close association with bile ducts and sinusoids Figure 4. The sinusoids are lined by a single layer of endothelial cells, where oxygen, nutrients, and poisons are removed from the blood, and products made by hepatocytes for use elsewhere in the body are secreted into the blood. Kupffer cells, found in the sinusoids, are specialized "scavengers" that can engulf foreign particulate matter, worn-out blood cells, and bacteria. Microscopically, the liver is organized into polyhedral units called lobules. When viewed on a cut section, a lobule is hexagonal with six portal triads at the periphery see Figure 5. Each portal triad contains a branch of the portal vein, a branch of the hepatic artery, and a bile duct, all held tightly together by a layer of hepatocytes, called a limiting plate, that surrounds the portal triad and separates it from the sheets of hepatocytes that radiate outward. In the center of the hexagon is a central vein. Blood flows through sinusoids from portal triads toward the central veins (peripheral to central), while bile flows outward toward the peripheral portal triads. 4. Regenerative Capacity. Hepatocytes rarely divide, but they have a unique capacity to reproduce in response to an appropriate stimulus, such as the removal of a portion of liver. This process involves controlled hyperplasia, or increased cell division, that usually restores the liver to within 5 to 10% of its original weight. Hepatic injury or partial removal leads to both systemic (e.g., in the blood and other tissues) and local (within the liver) release of growth factors that stimulate hepatocyte replication. Because all hepatocytes can perform the necessary hepatic functions and all have an equal ability to replicate, the liver can undergo compensatory growth and restore its size. Liver regeneration plays an important role after surgical removal of a portion of liver (partial hepatectomy) and after injuries that destroy portions of the liver, such as viral, toxic, or ischemic damage. However, excessive damage can reach a "point of no return," and normal tissue will be replaced with scar tissue. The liver's ability to regenerate is also compromised by pre-existing or repeated liver damage or disease Figure 1 Figure 2 Figure 3 The Liver in Health The characteristic structure and organization of the liver enables it to perform vital roles in regulating, synthesizing, storing, secreting, transforming, and breaking down many different substances in the body. In addition, the liver's ability to regenerate lost tissue helps maintain these functions, even in the face of moderate damage. This section of the module focuses on the structural aspects of the liver and its ability to regenerate. 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: · 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. 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 lifethreatening 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. Figure 6 Figure 7 The Liver in Disease Key Concepts 1. Hepatitis, or inflammation of the liver, has numerous potential causes: infections with viruses, bacteria, fungi, or protozoa; exposure to toxins such as alcohol, drugs, or chemical poisons; and autoimmunity. 2. Portal hypertension involves an increase in portal blood pressure due to obstruction of, or increased resistance to, blood flow, and it can lead to ascites, rupture of esophageal varices, and portosystemic shunting. 3. Metabolic diseases such as Wilson's disease, hemochromatosis, and alpha 1 - antitrypsin deficiency can lead to liver damage. 4. The liver can compensate for a significant amount of damage, but eventually liver function will decline markedly (decompensation), as manifested by diminished synthesis, abnormal clearance and excretion, ascites, and portal hypertension. 5. Acute hepatitis may resolve without significant sequelae, but unresolved inflammation that persists for longer than six months is termed chronic hepatitis. Chronic hepatitis may be caused by ongoing infection and associated inflammation or by repeated exposure to toxins, such as alcohol. Whatever the offending agent, chronic inflammation may lead to irreversible liver scarring and fibrosis, a condition known as cirrhosis of the liver. Occasionally, acute infection results in massive tissue destruction and high risk of death (fulminat hepatitis). 6. Chronic persistent hepatitis and chronic active hepatitis are histologic designations developed for autoimmune chronic hepatitis; they do not carry any prognostic value in chronic viral hepatitis. 7. Jaundice is related to increased levels of serum bilirubin (hyperbilirubinemia) that lead to a yellow appearance of the skin and whites of the eyes. 8. Jaundice may involve unconjugated or conjugated hyperbilirubinemia; the latter may be due to hepatocellular or cholestatic disorders. 9. Cirrhosis is pathologically defined as irreversible, diffuse fibrosis (or scarring) of the liver that is a common endpoint for many chronic liver diseases; it carries an increased risk of liver decompensation, hepatic failure, and the development of hepatocellular carcinoma. 10. Hepatocellular carcinoma is often associated with cirrhosis and with chronic viral hepatitis; it is usually diagnosed at an advanced stage, with very poor prognosis. 11. Hepatic failure is marked by severe impairment of liver functions and is usually accompanied by encephalopathy; death occurs in over 50% of cases. 12. Cirrhosis, hepatocellular cancer, and hepatic failure can all occur as a result of chronic viral hepatitis. A. Causes of Liver Dysfunction Liver disease has numerous causes, ranging from microbial infections and neoplasms (tumors) to metabolic and circulatory problems. I. Inflammatory Disorders (Hepatitis). Hepatitis involves inflammation and damage to the hepatocytes. This type of insult may result from infectious agents, toxins, or immunologic attack see Figure 8. In addition, other disorders such as Wilson's disease can cause hepatitis, and some diseases such as alpha 1 -antitrypsin deficiency can imitate hepatitis. However, the most common cause of hepatitis is viral infection. a. Infection. Infection is a very important cause of hepatitis, since primary viral infection of the liver is common and viruses cause the majority of liver infections. Three major viruses cause hepatitis in the United States: hepatitis viruses A, B, and C. Together, they infect nearly 500,000 people in the United States every year. Viral hepatitis will be discussed in detail in Module 2. In addition, bacteria, fungi, and protozoa can infect the liver, and the liver is almost inevitably involved to some extent in all blood-borne infections. b. Toxins. Toxins such as alcohol, drugs, or poisons can cause hepatitis directly (by damaging liver tissue) or indirectly (by reducing defenses or stimulating an autoimmune response), but the exact mechanism is not always clear. Alcohol. Alcohol is primarily metabolized by the liver, and these metabolites can cause liver damage. The risk of hepatic toxicity increases if more than 40 grams, or about four drinks, are consumed per day. Drugs. Numerous medications can damage the liver, ranging from mild, asymptomatic alteration in liver chemistries to hepatic failure and death. Liver toxicity may or may not be dose-related. Dilantin (an anti-convulsant) and isoniazid (an anti-tuberculosis agent) are examples of drugs that can cause "viral-like" hepatitis. Chemicals/Poisons. Both environmental and industrial toxins can cause a wide variety of changes in the liver. Hepatic damage is not necessarily dose-dependent and can range from mild, asymptomatic inflammation to fulminant failure or progressive fibrosis and cirrhosis. c. Immunologic mechanisms. The immune system functions primarily to recognize "foreign" or 'non-self" antigens, for example, invading viruses, bacteria, and their proteins. These antigens may be recognized by antibodies, proteins that can specifically bind to them and help remove them from the body. Occasionally, autoimmunity develops, whereby the immune system incorrectly reacts against "self" antigens, (one's own cells). This occurs in autoimmune hepatitis and primary biliary cirrhosis, two diseases in which the immune system attacks and destroys portions of the liver. If unchecked, persistent inflammation can eventually lead to cirrhosis. 2. Vascular Disorders. Obstruction of portal blood flow that drains the intestines, stomach and spleen results in portal hypertension (elevation in portal blood pressure). Think of the liver as a sieve that filters portal blood; with scarring from repeated injury, the holes of the sieve become progressively smaller, resisting flow. Resistance to blood flow can also occur before the portal blood reaches the liver, or after leaving the liver see Figure 9. Portal hypertension can lead to ascites, an accumulation of fluid that fills and distends the abdomen. Two serious consequences of portal hypertension include: · rupture of dilated esophageal blood vessels ( varices) causing massive bleeding · portosystemic shunting, in which substances from the gut (including drugs, bacteria, and toxic substances such as ammonia) bypass the liver and thus have access to other body tissues (for example, hepatic encephalopathy due to brain exposure to ammonia or other nitrogen-containing materials) 3. Metabolic Disorders. Problems with metabolic processes in the liver can be either congenital (present at birth) or acquired. Some of these disorders, such as Wilson's disease and hemochromatosis, can present as hepatitis or cirrhosis and must be distinguished from other causes of these forms of liver disease. As explained earlier, Wilson's disease is a rare inherited condition, mostly affecting young people, that is characterized by an inability to excrete copper into bile, resulting in the toxic accumulation of copper in the liver and nervous system. Manifestations include liver disease (including fulminant hepatitis, chronic active hepatitis, and cirrhosis) and neuropsychiatric symptoms. Hemochromatosis is an iron overload syndrome causing iron deposits and consequent damage to various organs, including the liver (cirrhosis), heart (heart failure), pancreas (diabetes), and pituitary gland (decreased sex drive and impotence). The disease may be due to an inherited increase in gut absorption of iron or to multiple blood transfusions, since iron is normally found in circulating red blood cells. Alpha 1 - antitrypsin deficiency is an inherited disease that predisposes the affected person toemphysema (or lung destruction), especially predisposes the affected person toemphysema (or lung destruction), especially with smoking. Alpha 1 - antitrypsin inactivates other enzymes, causing damage to organs if left unchecked. The lung is the most severely affected organ in patients with this disease, but approximately 10% of adult patients will also develop cirrhosis. 4. Neoplastic Disorders. Benign (non-cancerous) hepatic tumors are generally asymptomatic. The most common are hemangiomas, blood-filled vascular channels which occur more often in women and are present in about 5% of the population. The liver is the most frequent site for blood-borne malignant tumor metastases, including colorectal, breast, lung, stomach, pancreas, and ovarian cancers, and malignant melanoma (a skin cancer), among others. Primary malignant liver cancer - hepatocellular carcinoma (HCC) most commonly occurs in patients with cirrhosis from viral infection, alcoholism, hemochromatosis, or alpha 1 - antitrypsin deficiency. Men are affected more frequently than women, and the prognosis is dismal, with an average survival of about six months after symptoms begin. Hepatocellular carcinoma will be discussed in more detail later in Section II - B5. 5. Liver Involvement in Extrahepatic Disorders. The liver may be affected by numerous conditions, particularly autoimmune disorders, in which the immune system attacks the body's own normal tissues. Some examples include rheumatic diseases (such as systemic lupus erythematosus and rheumatoid arthritis) and inflammatory bowel diseases (such as ulcerative colitis and Crohn's disease). Systemic infections, such as tuberculosis, candidiasis, and toxoplasmosis, may spread to the liver. In addition, heart failure can lead to liver congestion, scarring, and ascites, because blood cannot drain from the liver properly when the heart is not pumping effectively. Clinical Manifestations of Liver Dysfunction A variety of insults can damage the liver, but their signs and symptoms are similar and may be due to hepatic dysfunction and/or obstruction to blood or bile flow. These manifestations include symptoms and signs of hepatitis, jaundice, cirrhosis, hepatocellular carcinoma, and hepatic failure. 1. Natural History of Hepatic Disease. Hepatocyte injury, such as occurs in acute viral hepatitis infection, stimulates an inflammatory response designed to try to eliminate the cause of the injury. Hepatocytes are frequently damaged and destroyed during the course of the inflammation; the death of these cells is termed hepatocellular necrosis. This type of injury may be initially well tolerated due to a large reserve of functioning hepatic tissue (compensated liver disease), and the injury may be repaired by regeneration with minimal loss. However, with severe, continuing, or repeated damage, such as in chronic hepatitis, compensatory regeneration eventually fails to repair the whole injury (it may be too large and/or the framework may have been destroyed), and the destroyed hepatocytes are replaced by scar tissue (fibrosis), leading to cirrhosis. The liver is a resilient organ and can tolerate a certain amount of cell loss, but eventually a threshold is reached and liver function declines markedly. Such decompensation may be manifested by the following: · synthetic defect - fewer normally functioning liver cells reduce the amounts of serum albumin and coagulation factors (a marked abnormality in blood clotting is associated with a poor prognosis) · abnormal clearance - decreased hepatic clearance of gut-absorbed proteins and ammonia can produce hepatic encephalopathy, a poisoning of the brain with symptoms ranging from confusion to coma · abnormal excretion - accumulation of serum bilirubin, which is normally taken up by the liver and excreted into bile, resulting in jaundice · ascites - increased sinusoidal pressure, as with severe inflammation or scarring of the liver, leads to fluid accumulation in the abdomen that becomes more difficult to control with progressive decompensation · portal hypertension - scarred liver tissue acts as a barrier to blood flow and causes increased portal blood pressure; a major risk is the rupture of esophageal varices, resulting in massive bleeding that may be fatal 2. Inflammation/Hepatitis. As described previously, hepatitis involves inflammation and damage of normal liver cells and is most commonly associated with viral and toxic insults. In general, the diagnosis is often made by excluding various viral, toxic, and metabolic etiologies until only one remains. For hepatitis B and hepatitis C, however, tests are available that may definitively detect the presence of virus in the blood. a. Acute hepatitis. Clinically, patients with hepatitis may be completely asymptomatic and without jaundice. More commonly, they complain of such symptoms as anorexia (loss of appetite), nausea, weakness, headache, muscle aches, altered small or taste, aversion to foods or tobacco, fever, abdominal pain, and jaundice. Hepatitis is generally considered acute if it resolves without sequelae (long-term changes) within six months. Serological tests for hepatitis A IgM should be positive if the person has acute hepatitis A. If the person has acute hepatitis B, the serological markers that may be positive include hepatitis B surface antigen, hepatitis B e antigen or hepatitis B IgM core antibody. b. Fulminant hepatitis. Rarely, a severe hepatitis results in acute, massive destruction of large portions of the liver or the entire organ. The most common causes are viruses and drug reactions. Decompensation rapidly occurs, manifested by encephalopathy, fever, marked jaundice, and either an enlarged tender liver or a shrunken liver, with a severe decline in liver function. The risk of death is high, and survival depends on the ability of the liver to regenerate. If patients recover, they do so fully. Hepatitis B is most likely to cause fulminant hepatitis; hepatitis C is a less frequent cause, while A causes fulminant hepatitis only rarely. c. Chronic hepatitis. Chronic hepatitis implies ongoing liver inflammation that has existed for more than six months. Chronic hepatitis is most likely caused by hepatitis B or C, if there is an infectious etiology. The anti-HCV test will be positive in the case of the latter, and HBsAg test positive in the former. The presence of HBEAG is indicative of ongoing hepatitis B infection. Symptoms vary greatly and may include fatigue, abdominal pain, and jaundice. A symptomatic or mildly symptomatic patients may escape diagnosis until a routine checkup reveals abnormal liver chemistries or an enlarged liver. Importantly, such persistent inflammation may lead to progressive liver scarring and cirrhosis. Historically, histologic patterns such as chronic persistent hepatitis (CPH) and chronic active hepatitis (CAH) were used to predict disease progression and prognosis. These classifications were originally developed to describe types of idiopathic autoimmune chronic active hepatitis (IACAH). It has since been recognized that in chronic viral hepatitis, histological activity is not directly related to prognosis. Instead, the presence and replicative activity of the virus are most important in determining disease progression. Although histologic examination is still important in clinical assessment, it has been proposed that chronic hepatitis be classified primarily by etiology see Figure 10., without using histology to imply prognosis. d. Carrier state. Carriers are completely asymptomatic individuals who harbor the virus without evidence of liver inflammation or damage. Liver chemistries and tissue biopsies are normal. Lifespan is considered normal, barring additional independent insults to the liver. The carrier state most commonly occurs with hepatitis B infection, in about 5% of those infected as adults. 3. Jaundice. A patient with jaundice has a yellow appearance, due to increased serum bilirubin (hyperbilirubinemia) , with deposition of bile pigment in the skin, mucous membranes, and sclera (whites of the eyes). Jaundice does not occur until the serum bilirubin exceeds 2 to 2.5 mg/dL and is generally asymptomatic. However, a jaundiced person may complain of pruritus , or itching of the skin; this is more common with chronic cholestasis. In addition, stools may be "clay-colored" (due to decreased biliary pigment excreted into the gut) and urine may be dark (due to increased bilirubin excreted in the urine). 4. Cirrhosis. Cirrhosis is the common endpoint of many chronic liver diseases, since inflammation and cell death eventually yield to fibrosis, or scar formation. Cirrhosis involves irreversible damage to the lobular architecture, with diffuse fibrous bands of scar tissue surrounding nodules of regenerating hepatocytes. A pathologic diagnosis based on liver biopsy, cirrhosis is described as micronodular if the nodule diameter is less than 3 mm and macronodular if it is more than 3 mm. Patients with cirrhosis have significantly shortened life spans and are at risk for decompensation decompensation and hepatic failure, as well as the development of hepatocellular carcinoma. Chronic viral hepatitis, chronic autoimmune hepatitis, and alcoholic liver disease are the predominant causes of cirrhosis in the United States. Viral infection can be investigated by checking specific blood tests, such as serum antigens or antibodies (discussed in Section III). Autoimmune liver disease may be detected by discovering certain autoimmune antibodies in the blood. Alcoholic cirrhosis can usually be inferred from a history of chronic alcohol consumption. A liver biopsy may be helpful in distinguishing causes, but in some patients, an exact etiology cannot be determined (cryptogenic cirrhosis). Cirrhosis may also be caused by metabolic diseases (Wilson's disease, hemochromatosis, and alpha 1 - antitrypsin deficiency, all of which can be diagnosed by laboratory tests and/or liver biopsy) or toxins (diagnosed by positive history for drugs, environmental or industrial toxins, and confirmatory lab investigation). Cirrhosis may be clinically silent for many years except for progressive weight loss, fatigue, and chronic jaundice. Eventually, liver failure and portal hypertension develop, with deepening jaundice, bleeding from esophageal varices, intractable ascites, and encephalopathy. Death usually occurs as a result of bleeding, hepatic coma, infections (such as spontaneous bacterial peritonitis, or infection of ascitic fluid), or kidney failure. 5. Hepatocellular Carcinoma. Primary malignant Primary malignant cancer of the liver, or hepatocellular carcinoma (HCC), is associated with a dismal prognosis since it is usually diagnosed at a late stage. Cirrhosis often progresses to the development of this tumor; in fact, about 75% to 95% of patients who develop HCC have cirrhosis. This tumor is also associated with certain hepatitis viruses (B and C), as indicated by its prevalence in certain areas of the world where the incidence of viral hepatitis is high. a. Etiology/epidemiology. HCC is most common in Africa, the Far East (Taiwan, southeast China, Japan), and southern Europe, probably due to the high incidence of chronic viral hepatitis in these areas. In the United States, approximately 3 people per 100,000 develop HCC each year. HCC is more common in men, particularly in their 50s and 60s. It generally occurs in those with long-standing cirrhosis associated with alcoholism, post-viral hepatitis B and and C, hemochromatosis, or alpha 1 - antitrypsin deficiency. HCC rarely develops in patients with cirrhosis due to Wilson's disease or primary biliary cirrhosis. b. Pathogenesis. Chronic inflammatory diseases of the liver, as in other tissues, may increase the risk of developing cancer. Nodular regeneration in cirrhotic livers may lead to cellular dysplasia (alteration in shape, size, and organization of cells), since errors are more likely to be made in more actively dividing cells. This is most likely an intermediate step in the progression to carcinoma, the proliferation of mutated cells. Additionally, excessive cell turnover probably increases the susceptibility to carcinogens (agents that may induce cancer) and may promote the expression of oncogenes ("cancer geners"). Hepatitis B genomic material (fragments of hepatitis B virus DNA) has been found integrated in cancer cells, but the significance of this finding is not clear. c. Clinical features and prognosis. Hepatocellular carcinoma is usually well advanced by the time patients present with symptoms, which include right-upper quadrant pain (often a "dull ache"), weight loss, anorexia, nausea, fever, or sudden worsening of jaundice or ascites. Severe pain may be associated with bleeding into the liver or abdomen. On physical exam, the liver may be stony hard. Unfortunately, the prognosis is dismal, primarily because the disease is at an advanced stage at diagnosis (extensive hepatic enlargement and/or metastatic spread to the lungs). Complete surgical removal of the affected tissue offers the only potential cure. Chemotherapy is ineffective, and most patients die within 3-6 months of presentation (primarily from liver failure or bleeding). 6. Hepatic Failure. Hepatic failure involves the systemic complications associated with severe liver injury and dysfunction. It may occur in a patient without pre-existing liver disease or may be superimposed on chronic liver injury. The diagnosis of acute liver failure requires the presence of symptoms, including jaundice and encephalopathy. Mortality exceeds 50%, even in the best circumstances. Management involves general supportive measures until the liver can regenerate and resume function. In acute liver failure without pre-existing disease, liver transplant may be life-saving. a. Underlying conditions. About 2000 patients a year develop fulminant hepatic failure in the United States. The most common cause is viral hepatitis, followed by hepatotoxic drugs. b. Clinical features. Fulminant hepatic failure impairs all liver functions, causing decreased bilirubin metabolism (jaundice), decreased clearance of ammonia and gut-derived proteins (encephalopathy), and decreased clotting factor production (coagulopathy ). It may also cause kidney failure (such as hepatorenal syndrome respiratory failure (due to infection, water accumulation, or inflammation of the lungs), shock (severe fall in blood pressure), and sepsis (systemic infection, probably a result of decreased clearance of portal bacteria by the liver). Without a liver transplant, more than 50% of patients will die, usually from a combination of the above conditions. However, if patients survive without transplantation, their livers may regenerate to normal functional capacity, especially if the liver was healthy before failure began. Summary Liver disease may have a variety of origins. Inflammation, or hepatitis, may be caused by infection (especially viral infection), exposure to toxins (including alcohol and drugs), or autoimmune reactions. Portal hypertension and metabolic diseases, such as Wilson's disease and hemochromatosis, can also cause significant liver problems. In addition to benign primary tumors and malignant metastases, the liver may develop hepatocellular carcinoma, which carries a dismal prognosis. The liver may also become involved in a number of systemic conditions, including autoimmune disorders, infections, and heart failure. Regardless of the specific cause, liver disease frequently presents similar clinical manifestations. Initially, symptoms may be mild, since this resilient organ can compensate for a certain amount of damage. However, eventually decompensation occurs, characterized by a marked decline in liver functions and the development of ascites and portal hypertension. Hepatitis may be acute (with recovery within six months), fulminant (acute critical illness with high mortality rate), or chronic (persistent disease for more than six months). Manifestations of hepatic desease include jaundice (hyperbilirubinemia), cirrhosis (irreversible fibrosis and scarring), hepatocellular carcinoma (primary malignant cancer of the liver), and hepatic failure (severe decline in all liver functions). Figure 8 Figure 9 Click on image to go back to paper. Figure 10 Types of hepatitis : Hepatitis A : what is it ? Hepatitis A is the most prevalent type of hepatitis. Hepatitis A and hepatitis E are mainly transmitted through the fecal-oral route, while hepatitis B, C, and D are spread through blood or other body fluids. Source: PR Newswire Hepatitis A (HAV) is a highly contagious virus that attacks the liver. It is the seventh most commonly reported infectious disease in the United States (behind gonorrhea, chicken pox, syphilis, AIDS, salmonellosis, and shigellosis). HAV accounts for as many as 65 percent of all viral hepatitis cases in the U.S. each year. In 1996, approximately 29,000 cases of HAV were reported in the U.S. However,the Federal Centers for Disease Control for Disease Control and Prevention (CDC) estimate that there are approximately 143,000 HAV infections in the United States each year. Worldwide, there are an estimated 1.4 million cases reported annually. There are several types of hepatitis. Hepatitis A is the . Hepatitis A is the most prevalent. Hepatitis A and hepatitis E are mainly transmitted through the fecal-oral route, while hepatitis B, C, and D are spread through blood or other body fluids. Common Symptoms of Hepatitis A -- fatigue -- nausea -- vomiting -- fever/chills -- jaundice -- pain in the liver area -- dark urine -- light-colored stools -- abdominal pain There is currently no treatment for hepatitis A, although rest and proper nutrition can relieve some symptoms. The most important factor affecting the severity of the disease is age. Children less than a year old rarely show clinical signs of the illness. This means that parents and child-care workers handling soiled diapers can catch or transmit the disease without knowing they have been exposed. Clinical manifestations of hepatitis A often pass unrecognized in children younger than two years of age. Overt hepatitis develops in the majority of infected older children and adults. In adults, approximately 22 percent will be hospitalized. An estimated 100 deaths occur in the U.S. each year from hepatitis A. In out breaks, three people died in northern California in December, 1995, and another person died in Canada in January, 1996. The incubation period for hepatitis A ranges from 20 to 50 days , which means that infectious patients, such as food handlers or children, can spread the disease well before they are even aware they have it. Incubation is shorter with increasing age. Most patients begin recovery within three weeks, although some have prolonged or relapsing symptoms for up to six months. How Is Hepatitis A Spread? The hepatitis A virus is transmitted by the fecal-oral route, through close person-to-person contact, or by ingesting contaminated food or water. Infection has been shown to be spread by: -- close personal contact with someone infected with hepatitis A. -- eating foods contaminated by infected food handlers. -- contact with infected children (who do not usually show symptoms), who can then infect nonimmune children or adults at home or in child-care centers. -- ingesting raw or undercooked shellfish (e.g. oysters, clams, mussels) from waters contaminated with the hepatitis A virus. -- ingesting contaminated food or water during travel to underdeveloped areas. -- transmission through blood transfusions or sharing needles with infected people using injectable drugs. In the United States and other developed countries, people potentially susceptible to catching hepatitis A include: -- those who travel to less developed areas of the world where hepatitis A is common. These areas include Africa, Asia (except Japan), the Mediterranean basin, Eastern Europe, the Middle East, Central and South American, Mexico andparts of the Caribbean. -- military personnel -- individuals living in areas where hepatitis A is endemic -- certain ethnic and geographic populations that experience cyclic epidemics -- male homosexuals and others who engage in high-risk sexual activity -- hemophiliacs and other recipients of therapeutic blood products -- youngsters in child-care facilities, their families, and facility staff -- food handlers -- healthcare workers who treat patients infected with the virus -- institutionalized persons and their caregivers -- laboratory workers who handle live hepatitis A virus -- handlers of primates that may harbor hepatitis A. Also at risk are people who live in frequently affected communities with poor sanitation or overcrowded living conditions. Why Worry About Children? The highest incidence of hepatitis A is in children. Nearly 30 percent of the reported cases occur in children younger than 15. Many very young children do not show symptoms, so the unreported number is likely much higher. Many health experts suggest that children are a silent source in spreading the disease. Approximately 45% of persons with HAV cannot identify a recognized risk factor associated with their disease, but about half of them have children under five years of age living in their households. How Can Hepatitis A Be Prevented? Historically, the most common preventative has been immune globulin administration, which is effective for about three to six months. Now, however,there are two vaccines that provide longerterm protection and eliminate the need for repeated shots. These vaccines typically are administered as oneinitial shot followed by a booster shot in about six to 18 months. Prior infection with hepatitis A confers lifetime protection against a second attack. If in doubt, a blood test can determine if an individual has had hepatitis A in the past or needs protection. What Is The Economic Impact Of Hepatitis A? The annual direct and indirect costs of treating cases and controlling outbreaks of hepatitis A in the United States are estimated to be $200 million. Additional economic costs are incurred when adults who contract the disease miss an average of 27 days of work, which translates into approximately $2600 in lostwages for each adult case ($2600 x 150,000 cases annually = $390 million in losttime). These estimates do not include business losses in the restaurant ortourist industries related to outbreaks of the disease. Question: Is the new hepatitis A vaccine effective and who needs it? : Yes, the new hepatitis A vaccine (Havrix) is very effective. It induces protective titres of antibodies in greater than 95%, and 99% of people after the first and second doses, respectively. If time does not permit two doses six months apart, then a single Havrix-1440 (double strength) dose may be given. The first dose of the vaccine probably requires at least three weeks to induce significant antibodies, so those travellers who did not have the foresight to have the first dose administered at least three weeks before departure to a high-endemic area should also have standard gammaglobulin to assure protection. Protective antibody titres to the vaccine last at least three years. At this time the need for booster doses is unclear, but it's likely that, similar to hepatitis B, they will be unnecessary. The vaccine should be administered as an IM injection into the deltoid. Children can be given half-strength (0.5 mL) doses. Although the manufacturer has suggested a very broad range of people to be targeted for vaccination, the National Advisory Committee on Immunization (NACI) only recommends vaccinating: 1) long-term or frequent travellers to endemic regions (which means basically everywhere except Canada, USA, Western Europe, Japan, Australia, and New Zealand). 2) residents of communities with high endemic rates of recurrent outbreaks of hepatitis A, and 3) residents and staff of institutions for the mentally handicapped. Who Should Receive Hepatitis A Vaccination? Long-term or frequent travellers to endemic regions Residents of communities with high endemic rates of hepatitis A Residents and staff of institutions for the mentally handicapped Question: Is there any role for standard gammaglobulin in viral hepatitis prophylaxis? Answer: Basically no. (See the answer above for one last small indication.) Development of highly effective hepatitis A vaccines has obviated the need for gammaglobulin. Note that standard gammaglobulin is useless for immunoprophylaxis against hepatitis B and C. Question: What is universal hepatitis B vaccination? Answer: This refers to vaccination of the entire population, usually at the neonatal or childhood level. The rationale for this is that targeted vaccination of high-risk groups has failed to achieve its aims, because most people in these risk groups are unaware or unwilling to be vaccinated. Moreover, 30% to 40% of hepatitis B virus (HBV) infections occur in people who deny any known risk factor. Question: How is universal HBV vaccination being implemented in Canada? Answer: As of this writing, eleven provinces and territories have opted for elementary schoolchild (grades 4 to 6) vaccination, and only four of the eleven have also targeted neonates. This is despite the recommendations of the Canadian Paediatric Society, NACI, and the American Public Health Service, that the first priority in universal vaccination should be neonates. Recently a consensus statement prepared by the Canadian Association for the Study of Liver (CASL) also endorsed a similar strategy of neonatal universal vaccination, with catch-up programs for school-aged children if funding permits. Why then have provincial health authorities, against the recommendations of their own experts, implemented childhood vaccination schedules? It may be that most provincial health ministries followed the misguided example set by British Columbia, which started by targeting children in grade six. British Columbia was experiencing relatively high rates of acute hepatitis B in teenagers and young adults, especially around the greater Vancouver region, and in this age group, almost all acute HBV is transmitted through sexual contact or intravenous drug use. Accordingly, with schoolchild vaccination, one could observe tangible reduction in acute HBV infections within only a few years, rather than within 15 to 20 years with the neonatal program. However, most health ministries have apparently not distinguished between preventing disease versus preventing mortality. Although acute hepatitis B in teenagers and adults causes some morbidity, it is rarely fatal (approx. 0.3% fatality rate), and the risk of developing chronic carriage of HBV, which is widely quoted as 5% to 10% based on older literature, now seems to have been over-estimated. Recent studies, including an important study that followed up American soldiers 1 acutely infected with HBV during a 1942 epidemic, have found a carrier rate following acute 1-3 HBV of only 0.3% to 0.9% On the other hand, if infection occurs in neonates, it is well known that the chronic carriage rate is greater than 90%, and in early childhood (1 to 6 years), the chronicity rates following acute exposure to HBV are 10% to 80% in an inverse age-dependent manner. Therefore, to prevent chronic HBV carriage, with its attendant sequelae of cirrhosis and hepatocellular carcinoma, one must aim to prevent neonates and infants from being infected by HBV. Although this is partially addressed by universal screening of all pregnancies with hepatitis B immune globulin (HBIG) and vaccination for infants born to HBV-positive mothers, this approach is not completely effective because of high intrafamilial transmission rates. In households where the mother is negative for HBsAg, but at least one child is already infected, there is a 26% transmission rate between 4 siblings. In a static low-endemic population, childhood vaccination will eventually reduce the population pool of chronic HBV carriers, but in Canada the continuing influx of immigrants, the vast majority from high-endemic countries, defeats this strategy. The bottom line is that in immunocompetent individuals, the risk of chronic hepatitis is high before age five, and very low after age ten. Hence it makes sense to give the vaccine at a time when the chance of preventing chronic infection is highest. So, what is the answer to the question regarding the rationale for the current approach to childhood vaccination ? Beats me ! Question: What is the schedule for neonatal protection if the mother is a hepatitis B carrier? Answer: For this patient, hepatitis B vaccine 0.5 mL i.m. is administered within the first 12h after birth, along with HBIG, 1 mL, at the same time (but different injection site). The second dose of vaccine should be given at one week, and the third at one to six months. Without intervention, the replicative HBV carrier (HBeAg-positive) mother has a greater than 80% chance of transmitting the infection to the newborn, while the HBeAg negative mother still has 15% to 20% rates. Because protection is not totally effective even with this immunoprophylaxis, there is still a 5% to 10% transmission rate of HBV. Question: What are the immunoprophylaxis recommendations for household contacts if an individual is found to be positive for HBsAg or develops acute hepatitis B? Answer: All household contacts should be screened for HBsAg and anti-HBs. If the spouse or sexual partner is negative for both, then he or she should be given 5 mL of HBIG and a course of vaccine, if the index case has acute hepatitis B, whereas vaccine alone should suffice for partners of chronic HBsAg carriers. Other household contacts, if serologically negative, require only a course of vaccination. In Canada, almost all public health units will carry out the above or slightly variant programs when notified of a positive HBsAg result. Question: I have a general practice with very little ER work; why should I be vaccinated for HBV? Answer: If your practice involves no work in emergency rooms, hospital wards, institutions for the handicapped and no administration of needles or minor surgery, and you never have hangnails, minor cuts and abrasions on your hands, then it is likely that you would not be susceptible to occupationally-acquired hepatitis B. There are very few practices that fit this description, and all other physicians would benefit from this safe and effective vaccine. Or, put another way, there has been several cases of unvaccinated physicians who died from occupationally-acquired acute hepatitis B; isn't your life worth the $150.00 cost of a course of vaccine? Question: I had a standard course of three deltoid injections of full-dose hepatitis B vaccination, but failed to make protective antibody titres. What does this mean and what should I do now? Answer: Lesser response rates to HBV vaccination are associated with age, increased body mass and smoking. For example, only 60% to 80% of those aged over 60 years make protective antibody titres. No one can reverse aging, but it you are overweight and smoke, losing weight and quitting smoking, followed by revaccination, might be effective. Even in healthy immunocompetent adults, about 5% will not develop protective antibodies after a course of vaccination. Recent work has discovered that the immune response to hepatitis B surface epitopes is genetically determined. For your interest, you probably have HLA haplotypes B8, DR3, SCO1; or B44, DR7, FC31. If a second complete course of vaccinations fails to induce protective titres, you will have to sadly accept that you are not protected against hepatitis B. You can blame your parents for giving you these bad genes. Question: Is a booster dose needed after five or ten years for recipients of hepatitis B vaccination? Answer: No. If you originally demonstrated an adequate antibody response, even though anti-HBs titres may gradually fall below the critical 10 IU/L level, the immune system will mount a sufficiently 5-6 protective anamnestic response if rechallenged with hepatitis B. Question: Is there anything on the horizon for a vaccine against hepatitis C? Answer: No. Effects to develop an effective HCV vaccine have been frustrated by: 1) initial difficulties in actually identifying the virus responsible for hepatitis C (although we knew its molecular structure in 1989, it was not until 1996 that a putative HCV was identified), 2) difficulties in establishing stable cultures of the virus in a cell line, and 3) high mutability of the HCV, which like HIV, mutates at a high rate. Question: What should be done in case of a needle stick injury? Answer: Management will slightly differ depending on whether the recipient (usually a healthcare worker) has previously been vaccinated for HBV. If vaccinated, then the recipient (as a baseline) and the source patient, should be tested for anti-HCV and anti HIV. If not vaccinated, then HBsAg should be added to the tests for the source patient, and both HBsAg and anti-HBs added to the recipient's bloodwork. Since this article is focussed on hepatitis, we will only deal with the HBV and HCV-positive scenarios 1) Source is HBsAg-positive, recipient unvaccinated (and negative for both HBsAg and HBs): give recipient HBIG, 5 mL, i.m., and first dose of hepatitis B vaccine. Complete the standard dosing protocol of vaccine at zero, one, and six months. Without intervention, there is about a 20% chance of the recipient contracting acute hepatitis B, and this figure is a composite of approximately a 50% to 80% chance if the source is HBeAg-positive (replicating, with high viral load), and a 10% to 15% chance if the source is HBeAg-negative. 2) Source is anti-HCV-positive, recipient anti-HCV-negative: test the recipient for ALT at baseline (as soon as possible after needlestick), and HCV-RNA by polymerase chain reaction and ALT at six to eight weeks after exposure. If HCV RNA is negative at this time, the chance of contracting acute hepatitis C is essentially zero. If the HCV-RNA test is not available locally, then the ALT should be repeated at three and six months, and the anti-HCV at six months. If they remain normal or negative at at six months, the likelihood of developing HCV will be nil. If HCV-RNA turns positive at six to eight weeks, this heralds the onset of acute hepatitis C, and these patients should be treated with a- interferon at a dose of three million units s.c. thrice weekly for 24 weeks. In centres where HCV-RNA is not available, the diagnosis of acute HCV can be made using a combination of the ALT and anti-HCV serology, realizing that the development of anti-HCV-positivity, even with third generation enzyme immunoassays, sometimes lags behind the acute hepatitis by a month or more. Therefore, before embarking on interferon therapy with its cost and side effects, I would recommend confirming the diagnosis by HCV-RNA which can be sent out to a lab in a larger centre. Fortunately, acute HCV developing after needle stick injury is uncommon. Several series have indicated that the risk of this occurring is approximately 5% to 10%. Hepatitis B:The Complexities Hepatitis B Virus: A Complex Structure The hepatitis B viron consists of a surface and a core. The core contains a DNA polymerase and the e antigen. The DNA structure is double stranded and circular. There are four major polypeptide reading frames (genes): the S (surface), the C (core), the P (polymerase) and the X (transcriptional transactivating). The S gene consists of three regions, the pre-S1, pre-S2 and encodes the surface proteins (HBsAg). Very rarely a mutation may occur in the S gene and may abort the HBsAg with the result that a person may be HBsAg negative but still have virus present as determined by HBV DNA. The C gene is divided into two regions, the pre-core and the core, and codes for two different proteins, the Core antigen (HBcAg) and the e antigen (HBeAg). A not uncommon mutant is the pre-core mutant, which may stop production of HBeAg, and these persons will be HBsAg positive, HBV DNA positive, but HBeAg negative. A third mutant which appears to have a mutant in the core , the Core antigen (HBcAg) and the e antigen (HBeAg). A not uncommon mutant is the pre-core mutant, which may stop production of HBeAg, and these persons will be HBsAg positive, HBV DNA positive, but HBeAg negative. A third mutant which appears to have a mutant in the core has been described and is referred to as HBV2. These patients are HBsAg positive, but lack HBeAg and HBV DNA, thus also anti-HBc. Another mutant, the YMDD mutant, will be described at a later date. To make it even more complex, the HBsAg particles are antigenically complex and these antigenic determinants have been identified. There is a single common determinant designated a, and four major subdeterminants designated d,y,w and r. Thus, the four major determinants are: adw, adr, ayw and ayr. Multiple Tests are Available Because of the complexity and the antigenic differences of the virus, there are a number of tests available for hepatitis B: Antigens HBsAg = presence of the virus HBcAg = not detected in blood HBeAg = correlates with the viral replication and infectivity Antibodies anti-HBs = antibodies to the surface anti-HBc = antibodies to the core can be either IgM (acute) or IgG (chronic) anti-HBe = antibodies to e and indicates low infectivity and probable recovery Other Markers HBV DNA = indicates virus presence and activity DNA polymerase = determines the presence of HBV DNA HBsAg in liver cells (Orcein stain = Shakata cells) = HBsAg inside hepatocytes Hep B:The Complexities Carrier Rates Vary Greatly Hepatitis B is a serious disease caused by the hepatitis B virus (HBV) that attacks the liver and can be spread to others. HEPATITS B GET VACcINATED You cannot get HBV from: * sneezing or coughing . *Kissing or hugging . *Breast feeding . * food or water . *casual contact (such as an office setting . * sharing eating utensils or drinking glasses . erson d pi ted in these ma t rials a e mode s and us d or illus rative purpose only. How do you now if you have HEPA ITI B? Only blood test can tell or sure. See your doctore to if you have symptoms of hepatitis (extreme tiredness, loss of appetite , joint pain, yellow skin or eyes), or if you think you had direct contact with someone who has hepatitis B. its is very important that all pregnant women get a blood test for hepatitis B early in their pregnancy since a woman who ha s hepatitis B can spread the virus to her baby during birth . Is HEPATITIS B a serious problem? Yes. Each year, thousands of people of all ages get hepatitis B and about 5,000 die of chronic (life-long) liver problems caused by hepatitis B virus (HBV) infection. If you have had other types of hepatitis, such as hepatitis A or hepatitis C, you can still get hepatitis B. HBV is spread by: • having sex with an infected person • direct contact with the blood of an infected person How can you protect yourself from getting infected with HBV? • Get vaccinated! Hepatitis B vaccine is safe, effective, and your best protection. • Practice “safer” sex. If you are having sex, but not with one steady partner, use latex condoms correctly every time you have sex. The efficacy of latex condoms in preventing infection with HBV is unknown, but their proper use may reduce transmission. • Don’t share anything that might have blood on it. o Don’t share drugs, needles, syringes, cookers, cotton, water, or rinse cups. o Don’t share personal care items, such as razors or toothbrushes. • Think about the health risks if you are planning to get a tattoo or body piercing. Make sure the artist or piercer sterilizes needles and equipment, uses disposable gloves, and washes hands properly. • Handle needles and sharps safely. Follow standard precautions if you have a job that exposes you to human blood. If you shoot drugs, get help to stop or get into a treatment program. Get HEPATITIS B vaccine if: • you are under 19 years of age • your sex partner has hepatitis B • you are a man who has sex with men † • you recently had a sexually transmitted disease (e.g., gonorrhea, syphilis) • you have sex with more than one partner • you shoot drugs † • you live with someone who has chronic hepatitis B • you have a job that exposes you to human blood • you are a kidney dialysis patient • you live or travel for more than 6 months in countries where hepatitis B is common † Also get hepatitis A vaccine Is the vaccine safe? Yes. Hepatitis B vaccine is safe and effective. Millions of children and adults have received the vaccine worldwide since 1982. Should you get a blood test after the vaccine series to be sure that you are protected? Most people don’t need to get their blood tested after completing the vaccine series (usually three shots). You should get a blood test 1 to 2 months after you complete the series if: • your sex partner has chronic hepatitis B • your immune system is not working well (e.g., you are on dialysis or you have AIDS) • you have a job that exposes you to human blood Should you ever get a booster shot after the vaccine series? Most people do not need booster shots after getting the vaccine series. After vaccination, babies born to infected mothers should get their blood tested at 9 to 15 months of age to be sure that they are protected. Interpretation of the Hepatitis B Panel Tests HBsAg anti-HBc anti-HBs HBsAg anti-HBc anti-HBs HBsAg anti-HBc anti-HBs HBsAg anti-HBc IgM anti-HBc anti-HBs HBsAg anti-HBc IgM anti-HBc anti-HBs HBsAg anti-HBc anti-HBs Results negative negative negative negative positive positive negative negative positive positive positive positive negative positive positive negative negative negative positive negative Interpretation susceptible immune due to natural infection immune due to hepatitis B vaccination acutely infected chronically infected four interpretations possible Medical Nutrition Therapy in Hepatic Disease by Katherine Phillips Four million Americans have Hepatitis C virus and 2.7 million Americans are chronically infected with Hepatitis C. HCV can lead to cirrhosis and end stage liver disease; however, proper nutrition and the avoidance of alcohol can delay this progression. Hepatitis C virus is currently the leading indication for liver transplantation in the United States. A person with HCV should be educated about a broad array of nutritional aspects, such as vitamin supplementation, ammonia-rich foods, and the hepatotoxic effects of alcohol. When Hepatitis C does advance to cirrhosis, medical nutrition therapy is recommended to help combat the nutritional problems. A doctor should make a referral for the patient to see a Registered Dietitian. The RD can educate the patient on the proper diet modifications that will ease some of the discomforts of cirrhosis. The most common nutritional problems associated with cirrhosis are hypoglycemia, fat malabsorption, steatorrhea, and portal hypertension. A person with cirrhosis should be under the care of a doctor who will monitor their ammonia levels and ascites. The Registered Dietitian will educate the client on eating regularly to maintain blood glucose levels within normal ranges, educate the client about high ammonia foods, educate on the complications associated with alcohol use, and educate the client on eating a high calorie, lowfat diet. The RD can also work with the physician to prescribe a special formula that specifically meets the needs of a hepatic disease patient. Formulas that meet the needs of a patient with Hepatitis C advanced to cirrhosis would be those that contain MCT oils. Bile aids in the absorption of dietary fat, since the scarred liver cannot produce bile easily, MCT oil should be used. The body can absorb medium chain triglycerides without bile. There are many benefits of a person with cirrhosis consulting with a Registered Dietitian. As Hepatitis C cases continue to rise in this country, the role of the RD will become even more important. PROTEIN-CONTROLLED DIET FOR ACUTE AND REFRACTORY HEPATIC ENCEPHALOPATHY Description Adjustment of the amount and type of protein characterizes the Protein-Controlled Diet for Hepatic Encephalopathy. Energy and protein are provided to attempt maintenance of nitrogen balance and support liver regeneration. Indications The diet is used in the treatment of acute and refractory hepatic encephalopathy associated with hepatic disorders, which may include the following:    hepatitis cholestatic liver disease cirrohosis with acute and/or chronic encephalopathy Liver disease causes numerous metabolic problems that can affect all major nutrients and the assessment parameters commonly used to evaluate nutritional status of the patient with hepatic disease. The classic signs of liver disease are anorexia, weight loss, and nausea with marked deficiencies in energy, protein, vitamins, and minerals (1,2). Because of the high risk for malnutrition in persons with hepatic diseases the American Society for Enteral and Parenteral Nutrition (ASPEN) recommends protein restriction be no less than 0.6 to 0.8 g/kg and reserved to those patients during acute or refractory episodes of encephalopathy. Normal protein intake should be resumed of 1 to 1.2 g/kg after the cause of encephalopathy has been identified and treated (3). The widespread practice of protein restriction for all patients with cirrhosis is not justified and often leads to iatrogenic protein malnutrition (3). Although malnutrition does not correlate with the type of liver disease, therapeutic modifications vary according to the type and severity of hepatic insufficiency. Generally, fatty liver requires little to no nutrition intervention, while cirrhosis necessitates major changes in the patient’s food intake. A major goal of medical nutrition therapy in liver disease is to prevent and treat hepatic encephalopathy (1,3). Hepatic disease can profoundly affect the nutritional status of the patient because of its effects on carbohydrate, fat, protein, vitamin, and mineral metabolism. Metabolic disorders of the following are commonly seen in the clinical setting of patients with hepatic insufficiency:  Carbohydrates: Adverse effects can include hypoglycemia or hyperglycemia. Hypoglycemia is most frequently seen in acute hepatitis or fulminant liver disease, probably due to impaired gluconeogenesis (1,3). Hyperglycemia is commonly observed secondary to counteracting catabolic hormones and insulin resistance when superimposed by acute stress and injury (1). Soluble fiber may be beneficial in managing hepatic encephalopathy. Soluble fiber is fermented in the colon by the same mechanism as lactulose, which eliminates ammonia in the form of ammonium ion and bacterial proteins (3). Fats: Malabsorption may occur because of inadequate production of bile salts. This may lead to steatorrhea, which could lead to deficiencies in fat-soluble vitamin and calcium levels. Researchers have found an increase in serum lipids, reflecting lipolysis (1,3). Protein: The effect of hepatic injury on protein metabolism is more dramatic than is carbohydrate or fat metabolism. There is a decrease in synthesis of serum albumin, the transportation of proteins, and the clotting factors (1,3). The ability of the liver to synthesize urea decreases, which results in an accumulation of ammonia and a decrease in serum urea level. This derangement in metabolism elevates the serum aromatic amino acids (AAAs) (phenylalanine, tryptophan, and tyrosine) and methionine and decreases the serum branched-chain amino acids (BCAAs) (valine, isoleucine, and leucine). The only enzymes that metabolize AAAs are located in the hepatocytes. In hepatic insufficiency, there is a decrease in hepatic oxidation of AAAs, leading to an increase in circulation of AAAs in the plasma. In contrast, BCAAs are metabolized primarily by the skeletal muscle. There is an increase in BCAA oxidation in the peripheral tissue during stress, causing a drop in plasma circulation (1).    Vitamins and minerals: Hepatic injury results in decreased absorption, transport, and storage and may alter the metabolism of vitamins and minerals. Cirrhotic livers have been reported to store decreased levels of thiamine; folate; riboflavin; niacin; pantothenic acid; vitamins B 6, B12, and A; zinc; and cobalt (1,4). In chronic liver disease, the hydroxylation of dietary and endogenous vitamin D to the active form (25-hydroxy derivative) is impaired and may lead to a deficiency state with concomitant osteomalacia. Although there are possibilities of vitamin and mineral deficiencies, supplementation should be administered only when a specific nutrient deficiency is identified. Supplementation should be monitored. Vitamin K deficiency may be induced from malabsorption with steatorrhea, dietary deficiency, impaired hepatic storage, and/or decreased production of gut flora due to intake of antibiotics. If vitamin K deficiency occurs, the rate at which prothrombin is converted to thrombin is affected, thus hampering the coagulation process and producing inadequate clotting factors (1). Intravenous or intramuscular vitamin K often is given for 3 days to rule out hypopothrombinemia due to deficiency (4). Nutritional Adequacy Diets containing less than 50 g of protein may be inadequate in thiamin, riboflavin, calcium, niacin, phosphorus, and iron based on the Statement on Nutritional Adequacy in Section IA. Supplementation may be indicated but should be assessed on an individual basis. This diet should be considered a transitional diet. Normal protein intake should be resumed soon after the cause of encephalopathy has been identified and treated. Long-term protein restriction should only be considered in patients with refractory encephalopathy (3). How to Order the Diet The diet order should specify the grams of protein required from food. Base the grams of protein ordered on the patient’s estimated desirable dry weight or adjusted weight. To calculate weight, see Section II (Estimating Energy Needs for Obese Patients, or Weight for Height Calculation – 5’ Rule). If a special formula is requested, the amount should be specified. Specify any restriction such as sodium, fluid, or other nutrients. Planning the Diet The table below outlines the recommended nutrient prescription according to type of hepatic disease (3,5,6). Type of Hepatic Disease Fatty liver/steatosis Nutrient Prescription Abstinence from ethanol Weight reduction, if attributable to obesity Reduced energy and dextrose intake, especially if patient is receiving total parenteral nutrition (PN) Energy: 30 – 35 kcal/kg Protein: 1 – 1.2 g/kg Energy: 30 – 35 kcal/kg Protein: 1 – 1.2 g/kg Energy: 30 – 35 kcal/kg Protein: 1 – 1.2 g/kg (with malnutrition) Liberal diet consistency, normal consistency is encouraged as tolerated Sodium restriction: 2 g/day with diuretics Fluid restriction: use clinical judgment Fat-soluble vitamin supplement up to 100% RDA may be necessary in cholestatic cirrhosis (see steatorrhea) Hepatitis (acute/chronic/alcoholic) Cirrhosis (uncomplicated) Cirrhosis (complicated) Esophageal varices Ascites Hepatic encephalopathy Hepatic coma Steatorrhea >10 g/day Or cholistatic liver disease with weight loss Energy: 35 kcal/kg Protein: 0.6 – 1.2 g/kg. Start at 0.6 g/kg per day and progress to 1 – 1.2 g/kg as tolerated. Do not give products enriched with glutamine. Consider high soluble fiber diet Use tube-feeding Protein: Start at 0.6g/kg per day and progress to 1 – 1.2 g/kg day as tolerated. Do not give products enriched with glutamine. Fat: 40 g/day (long-chain triglycerides) Supplement with medium-chain triglycerides to provide additional energy. Oral supplement with calcium, 1,25 hydroxy-vitamin D, and calcitonin may be required. May require supplementation of fat-soluble vitamins. Meal size and frequency: Some patients require small portions and frequent feedings because ascites limits the capacity for gastric expansion. Studies have shown that the metabolic profile after an overnight fast in patients with cirrhosis is similar to normal individuals undergoing prolonged starvation without any associated stress. Cirrhosis can be considered a disease of accelerated starvation with early recruitment of alternative fuels. A small-scale study showed patients with cirrhosis who received an evening snack to supply energy during sleeping hours were able to maintain a greater positive nitrogen balance than did other patients who were fed less frequently (2). Commercial supplements: Supplementation with enteral formulas is often necessary to increase the patient’s intake. Modular products of carbohydrates and fat can increase energy intake without increasing protein intake. The usefulness of special products containing BCAAs is controversial, and these products generally have a higher cost. The guidelines for nutrition therapy in liver disease developed by the American Society for Enteral and Parenteral Nutrition (ASPEN) restrict the use of BCAA enriched formulas to patients with refractory encephalopathy not responding to medical therapy (7). SAMPLE MENU (50 g of protein) Breakfast Orange Juice (½ c) Oatmeal (½ c) Toast (2 slices) Margarine (2 tsp) Jelly (1 Tbsp) Milk (½ c) Sugar Coffee; Tea Nondairy Creamer Snack Hard Candy (6 pieces) Jelly Beans (1 oz) Noon Garden Green Salad (1 oz) with Dressing (1 Tbsp) Roast Beef Sandwich Roast Beef, Shaved (1 oz) Bread (2 slices) Mayonnaise (2 Tbsp) Sliced Tomato (1 oz) Fresh Fruit Salad (½ c) Fruit Punch Snack Fruit Ice (3 oz) Evening Cranberry Juice Cocktail (½ cup) Oven Fried Chicken (2 oz) Buttered Rice (½ c) Seasoned Green Beans (½ c) Dinner Roll (1) Margarine (2 tsp) Sliced Peaches (½ c) Lemonade Snack Banana (1) Dry Cereal (¾ oz) Milk (½ c) References 1. Wong K, Klein B, Fish J. Nutrition Management of the Adult with Liver Disease. In: Skipper A, ed. Dietitian’s Handbook of Enteral and Parenteral Nutrition. 2nd ed. Gaithersburg, Md: Aspen Publishers; 1998. 2. Levinson M. A practical approach to nutritional support in liver disease. Gastroenterologist. 1995;3:234-240. 3. Teran TC, McCullough AJ. Nutrition In Liver Disease. In: Gottschlich M, ed. The Science and Practice of Nutrition Support A Core Based Curriculum. Dubuque, Ia: Kendall/Hunt Publishing Company; 2001. 4. Hasse JM, Matarese LE. Medical nutrition therapy for liver, biliary system, and exocrine pancreas disorders. In: Mahan K, Escott-Stump E, eds. Krause’s Food, Nutrition and Diet Therapy. 10th ed. Philadelphia, Pa: WB Saunders; 2000:710. 5. Corish C. Nutrition and liver disease. Nutr Rev. 1997;55:17-19. 6. Shronts EP, Fish J. Hepatic failure. In: Merrit RJ, ed. The A.S.P.E.N. Nutrition Support Practice Manual. Silver Spring, Md: Aspen Publishers;1998. 7. ASPEN Board of Directors. Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. J