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CLINICAL PHARMACY IN HEPATOLOGY THE LIVER The liver is the largest organ in the body. It is found high in the right upper abdomen, behind the ribs. It is a very complex organ and has many functions. They include: Storing energy in the form of sugar (glucose) Storing vitamins, iron, and other minerals Making proteins, including blood clotting factors, to keep the body healthy and help it grow Processing worn out red blood cells Making bile which is needed for food digestion Metabolizing or breaking down many medications and alcohol Killing germs that enter the body through the intestine The liver shoulders a heavy work load for the body, and almost never complains. It even has a remarkable power to regenerate itself. Still, it should not be taken for granted. The liver is subject to illnesses that can lead to permanent damage. One example is autoimmune hepatitis, a condition in which the body fights against its own liver. Hepatitis When cells in the body are injured by such things as chemicals or infection, the area that is wounded becomes inflamed. Hepatitis is inflammation of the liver, which in turn causes damage to individual liver cells. It is most often caused by viral infection. However, it can also be caused by alcohol, certain drugs, chemicals or poisons, or other diseases. Hepatitis may be either acute or chronic. In acute hepatitis, the inflammation develops quickly and lasts only a short period of time. The patient usually recovers completely, but it can take up to several months. Occasionally, a person fails to recover fully, and the hepatitis becomes chronic. In other words, it continues at a smoldering pace. Chronic hepatitis can develop over a number of years without the patient ever having acute hepatitis or even feeling sick. As the liver repairs itself, fibrous tissue develops, much like a scar forms after a cut or injury to the skin heals. Advanced scarring of the liver is called cirrhosis. Over time, cirrhosis irreversibly damages the liver, eventually ending in liver failure. Types of Viral Hepatitis Type A -- Previously known as infectious hepatitis, it can be contracted through contaminated water or food. During the acute infection, the patient's blood and body fluids are also infectious. Although some patients become acutely and desperately sick from this infection, most people tolerate it well and fully recover. No chronic infection occurs with this virus. Type B -- Previously known as serum hepatitis. Patients are sicker initially with this very unpleasant virus and take longer to recover, some-times several months. Furthermore, about 10 percent of patients progress into a state of chronic smoldering infection in the liver. A person can be infected by a contaminated needle or through sexual contact. Homosexual men, intravenous drug users, or persons who have sexual contact with these people are at an especially high risk for contracting this disease. Type C -- This virus infection was previously known as non-A non-B hepatitis. In the past, it was transmitted mostly by blood transfusion. There are now good blood tests to check for this virus before blood is given. Most cases now occur in people who use contaminated needles for drug use. However, many cases are "community acquired," meaning the physicians really don't know how they occur. It is difficult, but not impossible, to transmit this virus by unprotected sexual intercourse. Many people who acquire this infection go on to a chronic phase. Other Viruses -- There are now types recognized -- D, E, and G viruses -that can cause hepatitis. Infectious mono virus, CMV virus, and several other viruses are also capable of infecting the liver. Viral Hepatitis. Symptoms As with other illnesses, symptoms of hepatitis can be severe, mild, or not present at all. It depends on how badly the liver is damaged. With mild viral hepatitis, slight fatigue may be the only symptom. When hepatitis is severe, the patient loses the taste for food and cigarettes, develops a heaviness in the rightupper abdomen and, especially with acute B hepatitis, may have diarrhea and arthritis. The liver and even the spleen can enlarge. jaundice then develops. The eyes and skin turn yellow, the urine dark, and the stool a putty-white color. Jaundice results when the yellow bile pigment, which normally flows through the bile ducts to the intestine, backs up and spills into the blood. Acute hepatitis can last from two weeks to several months. The patient often needs to be hospitalized in the early, acute phase of the illness. Hepatitis B is caused by the hepatitis B virus (HBV). Current estimates are that over 250,000 people in the United States contract HBV each year. It is often spread through sexual contact, accounting for about 50% of the reported cases. It is also spread through contact with blood or body fluids from a person carrying HBV. Some groups have a higher risk of becoming infected with HBV. These include: Intravenous drug users Health care workers, funeral workers, police People in an HBV infected person's household People with multiple heterosexual or, especially, homosexual partners Residents of nursing homes Hemophiliac and hemodialysis patients Prisoners and prison workers Travelers to underdeveloped countries Certain ethnic groups such as Asians, Hispanics, American Indians, Alaskan Natives, or people from developing countries The following are symptoms of acute hepatitis B: Loss of appetite, nausea, vomiting, fever Aching muscles and sometimes joint pain Tenderness in the right upper abdomen Jaundice (yellowing of skin and eyes) Tea-colored urine; putty-like or white stool Diagnosis of the disease is made by a blood test. It is called the hepatitis B surface antigen test (HBsAg). No specific treatment is available or usually necessary for acute hepatitis infection. The physician may recommend supportive measures to help the patient maintain strength and avoid taxing the liver while the body's natural defenses are fighting the virus. Acute hepatitis B patients recover completely within six months and develop antibodies that give them a life-long immunity. Some patients who become infected, however, do not recover completely. Up to 10% of adults with Hepatitis B and up to 50% of infected children under five years of age are not able to completely fight off the virus within six months. This occurs because their bodies are unable to develop antibodies against hepatitis B. Most of these patients become HBV carriers. Vaccination Passive (short-acting) and active (permanent and long-lasting) vaccines now are available against hepatitis A and B. People who travel to underdeveloped countries are encouraged to receive these vaccinations. The following high-risk groups should also receive active immunization: health care workers, especially those who handle body fluids such as blood; people who have multiple sex partners; intravenous drug users; and prostitutes. The American Pediatric Association now recommends that all infants and children be vaccinated. Prevention There are precautions people should take to protect themselves against hepatitis B. Since the virus is most often spread through sexual contact, it is most important to avoid unprotected sex with those who have or are likely to have the infection. Precautions must be taken to avoid coming in contact with blood or body fluids from an infected individual. For those living in households with infected patients, surfaces which may hold the virus should be cleaned with one part household bleach to 10 parts water. Items such as razors, toothbrushes, IV needles or pierced earrings should never be shared. People should also avoid such practices as tattooing and ear piercing in places where sterile conditions are questionable. Women who are pregnant should be tested for HBV and follow their physicians' advice to protect their unborn children. Chronic hepatitis B (a smaller percentage of patients who cannot fight off the virus will develop chronic hepatitis B) Patients with chronic hepatitis B should avoid alcohol because it can cause additional liver damage. Some medicines and drug combinations may cause liver injury, so patients should review all medications they are taking with their physicians. Patients should never take over-the-counter drugs without the physician's approval. Chronic hepatitis B can now be treated with interferon (trade name: Intron A). Some patients, however, are not good candidates for interferon therapy. A liver disease specialist is often required to determine if the patient should be placed on this therapy. Interferon has been shown to reduce inflammation and liver damage in about 30% of treated patients. A few go on to apparent complete recovery. In some, however, the disease returns when therapy is stopped, and treatment may have to be restarted. There are bothersome side effects with the drug, and treatment must be evaluated with the physician on an individual basis. Autoimmune Hepatitis The immune system consists of different types of white blood cells that help to fight infections. Some of these cells produce antibodies. Antibodies act as warriors. They defend the body by destroying bacteria, viruses and other foreign materials. There are different kinds of antibodies, each fighting against a specific foreign substance. Thus, the immune system protects the body against outside invasion by germs. But sometimes, the immune system mistakenly recognizes the body's own organs as foreign. It can develop antibodies against these organs. This can cause various illnesses, such as rheumatoid arthritis and lupus. These illnesses are called autoimmune disorders because the body is literally fighting against itself. When the immune system attacks the liver in this way, it is called autoimmune hepatitis. Autoimmune hepatitis is not caused by a virus or bacteria, so it is not a contagious disease. Exactly what triggers the immune system against the liver is unknown. The inflammation is usually chronic, and without treatment it can cause serious injury to the liver. Autoimmune Hepatitis (cont’d) Symptoms and Diagnosis Autoimmune hepatitis occurs mainly in adolescent or young adult women (about 70% of the time). However, there have also been cases of older women and men developing the disease. Early symptoms are the same as those for most types of hepatitis: fatigue, abdominal discomfort, and aching joints. These early symptoms are sometimes mild and mistaken for other illnesses, such as the flu. So, it is wise for people with these symptoms to consult a physician. When autoimmune hepatitis progresses to severe cirrhosis, there may be jaundice (yellow coloring to the skin and eyes), marked swelling of the abdomen from fluid inside the abdomen, intestinal bleeding, or mental confusion. The physician often suspects autoimmune hepatitis from the patient's medical history. For example, patients with other autoimmune diseases -- thyroiditis, ulcerative colitis, diabetes mellitus, vitiligo (a patchy loss of pigment in the skin), Sjogren's syndrome (a condition causing dry eyes and mouth) -- are more likely to have autoimmune hepatitis. Autoimmune Hepatitis (cont’d) Symptoms and Diagnosis A definite diagnosis of autoimmune hepatitis is obtained with blood testing. Two antibodies that may develop in the blood are the ANA (antinuclear antibody) and the SMA (smooth muscle antibody). Also, a certain type of blood protein called gamma globulin is frequently elevated. A liver biopsy is always needed to determine how much inflammation and scarring has developed. This exam is performed under local anesthesia. A slender needle is inserted through the right lower chest to extract a small piece of liver tissue. The tissue is then examined under a microscope. This information allows the physician to tailor the treatment to each individual patient. Autoimmune Hepatitis (cont’d) Treatment The treatment of autoimmune hepatitis is aimed at curbing the autoimmune response, and therefore the damage to liver cells. It is most effective when begun at an early stage of the disease. In most cases, the initial treatment is with a cortisone drug, usually prednisone (trade names: Deltasone, Orasone). Sometimes a second drug, such as Imuran, may be added. The medication is taken daily, usually for at least a year. The physician may attempt to taper and stop treatment if the patient is doing well. However, a relapse often occurs, and the medication then must be restarted and taken indefinitely. The physician uses the lowest dosage possible to decrease symptoms, improve liver tests, and slow liver damage. Unfortunately, a few patients do not respond well to treatment, especially if the disease is diagnosed late and cirrhosis is well advanced. When the patient no longer responds to treatment with medication and liver damage is severe, a liver transplant is considered. Cirrhosis Many types of chronic injury to the liver can result in scar tissue. This scarring distorts the normal structure and regrowth of liver cells. The flow of blood through the liver from the intestine is blocked and the work done by the liver, such as processing drugs or producing proteins, is hindered. Cirrhosis can be caused by many things, some known and others unknown: Alcohol -- Using alcohol in excess is the most common cause of cirrhosis in the United States. Chronic Viral Hepatitis -- Type B and Type C hepatitis, and perhaps other viruses, can infect and damage the liver over a prolonged time and eventually cause cirrhosis. Chronic Bile Duct Blockage -- This condition can occur at birth (biliary atresia) or develop later in life (primary biliary cirrhosis). The cause of the latter remains unknown. When the bile ducts outside the liver become narrowed and blocked, the condition is called primary sclerosing cholangitis. This condition is often associated with chronic ulceration of the colon (colitis). Abnormal Storage of Copper (Wilson's Disease) or Iron (Hemochromatosis) -These metals are present in all body cells. When abnormal amounts of them accumulate in the liver, scarring and cirrhosis may develop. Drugs and Toxins -- Prolonged exposure to certain chemicals or drugs can scar the liver. Autoimmune Hepatitis -- This chronic inflammation occurs when the body's protective antibodies fail to recognize the liver as its own tissue. The antibodies injure the liver cells as though they were a foreign protein or bacteria. Cystic Fibrosis and Alpha l-antitrypsin Deficiency -- These disorders are inherited. Cirrhosis. Signs and Symptoms Cirrhosis takes years to develop. During this time, there are usually no symptoms, although fatigue, weakness and decreased appetite may occur and worsen with time. When cirrhosis is fully developed, a number of signs may be present: Fluid retention in the legs and abdomen -The liver produces a protein, called albumin, that holds fluid in blood vessels. When the blood level of albumen falls, fluid seeps out of the tissues into the legs and abdomen, causing edema (fluid accumulation) and swelling. Jaundice -The liver produces bile that normally flows into the intestine.With advanced cirrhosis, bile can back up into the blood, causing the skin and eyes to turn yellow and the urine to darken. Intense Itching -Certain types of cirrhosis, such as chronic bile duct blockage, can produce troublesome itching. Cirrhosis. Signs and Symptoms Gallstones -Cirrhosis causes the abnormal metabolism of bile pigment. Because of this, gallstones develop twice as often in cirrhosis patients as in those without the disorder. Coagulation Defects -The liver makes certain proteins that help clot blood. When these proteins are deficient, excessive or prolonged bleeding happens. Mental Function Change -The liver processes toxins from the intestine. When these substances escape into the bloodstream, as occurs in severe cases of cirrhosis, a variety of changes in mental function can develop. Esophageal Vein Bleeding -In advanced cirrhosis, intestinal blood bypasses the liver and flows up and around the esophagus (the food tube) to the heart. The veins in the esophagus dilate (widen) and may rupture, causing slow or massive intestinal bleeding. Cirrhosis. Prevention Perhaps 90 percent of cirrhosis is caused by excessive alcohol consumption or hepatitis viruses. Of course, alcohol can be avoided. Alcohol consumption should always be limited to no more than 1 or 2 drinks per day. And type B hepatitis now has an effective vaccine against it. Vaccination against B hepatitis virus is safe and inexpensive. It should be taken especially by certain high-risk groups: all health care professionals, persons traveling to third world countries, homosexuals, intravenous drug users, and prostitutes. Cirrhosis. Treatment The alcoholic patient must permanently stop consuming alcohol. When iron is being retained in the body, chronic removal of blood by vein eliminates large amounts of iron. Cortisone medicine helps treat autoimmune hepatitis and cirrhosis. Restricting salt and using fluid pills (diuretics ) reduce edema and abdominal swelling. Toxins and injurious drugs must be avoided. Decreasing dietary protein and using certain laxatives generally can prevent changes in mental function. Bleeding veins in the esophagus can be injected with sclerosing (clotting) agents or closed with small rubber bands. Occasionally, surgery is necessary to prevent recurrent massive bleeding. Ursodiol (Actigall) and other drugs have been helpful in treating primary biliary cirrhosis and primary sclerosing cholangitis. Liver transplantation has progressed to the stage where it can now be considered as standard treatment for selected patients. Chronic pancreatitis There is no cure for chronic pancreatitis. Once the pancreas is damaged, then it is not able to return to normal function and there is always the potential for further attacks. Treatment is, therefore, directed towards preventing attacks, controlling the pain and treating the complications. Preventing symptoms worsening Patients with chronic pancreatitis should avoid alcohol altogether. If the pancreatitis is due to excess alcohol consumption, then this is essential. If it is due to other causes, then it seems sensible to avoid a substance which is capable of damaging the pancreas. If an underlying cause has been identified then this should be treated. Disorders of calcium metabolism and of fat metabolism will be treated appropriately. Your doctor may recommend removal of the gall bladder if pancreatitis is thought to be caused by gall stones. Chronic pancreatitis Preventing attacks The long-standing principle has been to try and rest the pancreas. This involves giving pancreatic supplements such as Creon (which contain pancreatic enzymes in high concentration) together with drugs which reduce acid secretion by the stomach. Patients should also follow a low-fat diet. These measures reduce the presence of fat in the duodenum, reduce acid in the duodenum and reduce the need for pancreatic enzyme secretion. These measures are very successful in about a third of patients, moderately successful in a third and unhelpful in a third. Some eminent specialists have supported the use of antioxidants in the treatment of chronic pancreatitis. These antioxidants include selenium and vitamin C. Chronic pancreatitis Control of pain This is a very important aspect of the treatment of chronic pancreatitis. Pancreatic pain varies in severity from mild (controllable with simple analgesics such as paracetamol (eg Panadol)) to severe (requiring morphine-like drugs for control). In addition to the preventive measures listed above, the basic principle is to use the drug lowest down the analgesic ladder which controls the pain. Since the pain is often worse at night and since both body and mind are at their lowest ebb in the early hours of the morning, the lowest rung of the analgesic ladder may be pethidine or morphine (eg MST continus tablets). Since the pain is chronic and severe, there is a fine line between adequate analgesia and addiction.