CLINICAL PHARMACY IN HEPATOLOGY. SYMPTOMS AND SYNDROMES IN DISEASES OF THE HEPATOBILIARY SYSTEM. CLINICAL PHARMACOLOGY OF AGENTS, WHICH ARE USED TO TREAT DISEASES OF HEPATOBILIARY SYSTEM

Hepatitis

 

The liver is the largest organ in the body. It sits in the right-upper abdomen just under the right lung and behind the ribs. It is one of the body’s most versatile organs because it performs so many functions all at the same time. The liver makes proteins, eliminates waste material from the body, produces and metabolizes cholesterol, stores and releases glucose energy, and metabolizes many drugs used in medicine. It produces bile that flows through bile ducts into the intestine to help digest food. This remarkable organ also has the ability to regenerate itself if it is injured or partially removed. The liver receives blood from two different sources — the heart and the intestines. All of this blood flows through the liver and returns to the heart. It is no wonder that the ancient Chinese viewed the liver, not the heart, as the center of the body.

 

Any type of inflammation in the liver is called hepatitis. This inflammation can be caused by many different things: drugs, viruses, bacteria, heredity, fatty tissue, and other causes.

 

The 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.

Are There Other Causes?

• Alcohol — Binge drinking of alcohol can inflict an acute hepatitis injury on the liver.

• Drugs — Certain drugs also can acutely injure the liver in a few people who are hypersensitive or allergic to a particular medicine.

• Autoimmune — There are certain conditions similar to the disease called lupus erythematosus, which can produce injury to the liver. They are known as autoimmune disorders because the body’s own antibody defenses seem to actively damage the liver.

• Hereditary Conditions — There are certain hereditary disorders, such as Wilson’s disease, in which acute damage to the liver can occur.

 

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 right-upper 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 ofteeeds to be hospitalized in the early, acute phase of the illness.

 

Diagnosis

The physician often suspects hepatitis based on the patient’s medical history and physical exam. Certain blood tests, however, are the best indicators of hepatitis, its causes, and its severity. Blood tests are used to follow the course of the infection through to recovery. Additional tests, such as ultrasound (sonography), are performed to study the bile ducts, gallbladder, and liver. Occasionally a liver biopsy may be needed to provide information to the physician.

 

Treatment

No specific treatments are available for acute viral hepatitis. Fortunately, in most cases the body develops antibodies that fight and eventually kill the virus, allowing the liver to recover. For alcohol and drug-induced hepatitis, the patient has to avoid the offending agent. The physician must make an accurate diagnosis, support the patient during the acute phase, and provide advice during recovery. Recovery from viral hepatitis A and B results in protective antibodies so that the patient will not get these infections again and cannot transmit them to anyone else.

 

Chronic Phase

Some people progress to chronic hepatitis. Here, the liver smolders with persistent inflammation. These patients need to be followed closely, usually by a specialist, to address the various problems that can arise from this condition. Effective treatment is available for many types of chronic hepatitis. Because some of these patients are infectious and can transmit the disease, they and their families must be educated about how to protect themselves.

 

Contagion and Spread

In the past, viral hepatitis had a well-deserved reputation for being contagious. Contaminated water and poor sanitation provided easy transmission for these viruses. Today, much is known about how the viruses are transmitted so that prevention is usually possible.

However, infection still can occur through contaminated water or poor sanitation. In addition, during the acute phase, all body secretions — saliva, tears, semen, urine, and especially blood — are infectious. Sexual contact with someone who is infected is known to spread the virus. Also, if a patient is a carrier in the chronic phase, the infection may be spread through sexual contact. Intravenous drug users who share needles are at an extremely high risk of contracting hepatitis, as are people who have multiple sexual partners. Because each hepatitis virus is different, it is always best to discuss this with a physician.

 

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 Associatioow recommends that all infants and children be vaccinated.

 

 

 

Hepatitis B

 

Hepatitis B is caused by the hepatitis B virus (medically abbreviated as 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

In pregnancy, the virus is passed from an infected mother to her child in about 90% of the cases. This usually occurs during delivery. HBV is also carried in breast milk. In about 30% of all cases of hepatitis B, however, it is unknown how the patient contracted the virus. This situation is known as community acquired disease.

HBV is much more contagious than the AIDS virus. For example, it can live outside the body on a dry surface for up to 10 days. Once a person gets the virus, it may take from one to six months for the infection and symptoms to develop. One of three things can then happen — most patients develop acute Hepatitis B and recover completely; a small percentage become HBV carriers; and some develop chronic hepatitis B.

 

Acute Hepatitis B

Many patients with acute hepatitis B have no symptoms, or the symptoms are mild and often mistaken for flu. Their bodies are able to fight the virus off quickly. Some, however, can become quite sick while their bodies are fighting off the virus. 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.

HBV Carriers

HBV carriers recover from the infection completely and feel healthy. They have no ongoing hepatitis or liver damage. However, their blood tests show they still have the virus and have not developed hepatitis B antibodies. Therefore, they can pass on the virus. This is called an HBV carrier. Because carriers do not develop symptoms or feel sick, thousands of people who become carriers of HBV never know it. There may be as many as one million Americans carrying HBV. There is no treatment presently available for this situation. Carriers have a responsibility to practice safe lifestyle habits that will prevent their passing the virus on to others. This especially includes protected sex.

Chronic Hepatitis B

A smaller percentage of patients who cannot fight off the virus will develop chronic hepatitis B. Like HBV carriers, chronic hepatitis B patients are also able to pass on HBV. However, there is a very important difference with chronic hepatitis B. These patients will also have ongoing hepatitis and liver damage. A few may have an increased risk for developing cancer of the liver. Once again, blood tests show that no antibodies have developed.

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 caow 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.

Treatment

In most countries a patient with a positive test result will be referred to a specialist who will carry out further tests to determine the degree to which hepatitis B may be affecting the liver, and what may be the best treatment options. In these tests a small sample of liver tissue may need to be taken (a liver biopsy).

In the majority of patients with active HBV, symptoms will not be severe and treatment will not be required. The patient will be monitored and after a few months the patient’s immune system should fight off the virus, giving the patient natural immunity.

In around 5% of adults, 30-50% of young children (aged 1-4), and 90% of infants, HBV infection will become chronic. The virus is more deadly to the young and those that are infected at birth have a 25% chance of developing a life-threatening liver-related illness.

Antiviral medication is given as treatment to those with chronic symptoms to help prevent further liver damage. These medications may be injected or given in pill form. Examples are Interferon Alpha, Lamivudine and Baraclude. Treatment usually lasts 6 months, during which time the patient will be carefully monitored.

Regardless of whether the infection is producing symptoms or not, the patient will be advised to avoid alcohol, get plenty of rest and maintain a healthy diet.

 

Liver Transplantation

Liver transplantation is a newer and very successful form of therapy for people with a badly damaged liver. In those patients with chronic hepatitis B, the new liver usually becomes infected with the virus, but most transplant medical centers are dealing with this effectively. There are new drugs for chronic hepatitis B now under investigation. However, at the present time the best defense against HBV is prevention.

 

Prevention and Vaccination

There is a safe and effective vaccine to protect or immunize a person against hepatitis B. The vaccine usually offers protection for about 10 years or more. However, it is of no use to those already infected with HBV. Persons who have not been vaccinated and who know they have been exposed to HBV should receive an injection of hepatitis B immune globulin within two weeks of exposure to the virus. This is called a passive immunization. It gives immediate short-term protection for 3-6 months. The Hepatitis B vaccine is active immunization. Active immunization provides long-term (sometimes lifelong) protection. Therefore, people who are at risk of coming in contact with the virus, and especially newborn infants and sexually active teenagers, should be immunized. In the U.S., pediatricians now recommend that all children be actively vaccinated.

There are other 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.

 

Summary

Hepatitis B is a serious disease that may result in long-term complications. While most people recover, some develop chronic hepatitis. Some people become carriers of HBV without knowing it. For this reason, it is important to prevent spread of the disease by vaccination and by lifestyle practices that avoid contact with infected blood and body fluids. For acute infections, no therapy is available or usually necessary. Researchers are continually learning more about hepatitis, and research into new treatments is ongoing. Chronic hepatitis B patients who are monitored frequently and follow the advice of their physicians have every reason to expect a good quality of life.

Hepatitis C

Hepatitis C is caused by a virus (medically abbreviated as HCV). This type of viral hepatitis is different from the others in an important way. All patients with hepatitis A and most with hepatitis B develop an acute infection, recover completely, and develop antibodies that protect them from ever getting the disease again. However, the hepatitis C virus is a “quick-change” artist. Once inside the body, it changes its form to evade discovery and attack by the immune system. Scientists have already identified many forms of HCV, and patients infected with one type are not necessarily safe from other types. Hepatitis C patients do develop antibodies, but they are not curative or protective as in hepatitis A or B. Hepatitis C antibodies may not completely rid the body of the virus. Therefore, most people infected with the HCV virus will develop chronic hepatitis.

Current estimates are that 3.5 million Americans carry the virus that causes hepatitis C, and 150,000 people become infected with HCV each year. This virus is known to be spread through infected blood, blood products, and needles. Prior to the late 1980s, people were most at risk for contracting the disease through blood transfusions. However, a blood test was developed at that time to detect the virus, and the blood supply is now always tested to prevent spread of the disease in this way. Even so, there is a very slight risk for those who must receive blood products on a regular basis, such as hemophiliacs and patients on hemodialysis. Health care workers are also at risk. At this time, the people most at risk for getting hepatitis C are IV drug users who share needles. There are also a larger number of cases among east Asians. In about 40% of all cases of hepatitis C, it is unknown how the patient was infected with the virus. This situation is known as community acquired disease.

 

Symptoms and Diagnosis

Most patients with hepatitis C do not have symptoms. This is especially true early in the disease. If there are symptoms, they are usually mild and flu-like — perhaps nausea and fatigue. It can take from 2 to 26 weeks for the disease to develop once the patient is infected with HCV. Routine blood tests will show an elevation in certain liver enzymes, especially one called the ALT. The physician can then order a specific blood test to determine if the patient has hepatitis C.

 

Chronic Hepatitis C

Hepatitis C is a cause for concern for two reasons. First, most cases become chronic. Second, patients seldom become acutely ill, so it is possible for them to have the disease for some time before it is diagnosed. Late in the disease, fatigue may become increasingly severe. If cirrhosis has developed, other more serious symptoms may occur. However, the elevation in the blood ALT may not correlate with the degree of liver inflammation. In other words, a high ALT may not necessarily mean there is a serious degree of inflammation. Conversely, a low or normal blood ALT level may be present even though there is chronic liver damage. For this reason, a liver biopsy is almost always required to determine how serious the disease may be. Under local anesthesia, a slender needle is inserted into the right lower chest. A small piece of liver tissue is taken out with the needle and examined under a microscope. A biopsy can show if cirrhosis is present and how far it has progressed. It is believed that about 20% of the patients with chronic hepatitis C will develop cirrhosis, and a few of those will go on to develop liver cancer. It may take from 10 to 40 years for serious liver damage to occur.

 

Treatment

 

Both the patient and physician have a role in treating hepatitis C. It is now known that alcohol use, even in socially accepted amounts, makes the liver disease worse. So while the virus is present in the body, it is best to avoid alcohol altogether. Patients should also discuss the use of over-the-counter medicines with the physician. Some drugs such as acetaminophen (Tylenol) that may not be normally toxic can worsen liver damage in HCV. Of course, a healthy diet is always important. The patient will also want to discuss vaccination against hepatitis viruses A and B. If a person with HCV becomes infected with either of these other viruses, the outcome could be quite severe. The patient should be careful to avoid the possibility of getting these other diseases. This means no IV drugs or unprotected sex with a new partner with unknown sexual activity history.

As of 1999, there are two programs available to treat HCV. One is the use of interferon (IFN) by itself. IFN is a synthetic form of a substance the body naturally produces to fight infections and strengthen the immune system. There are some bothersome side effects with the drug, such as fatigue and flu-like symptoms following each injection. Usually, interferon is injected three times a week for at least six months and often for a year. The second treatment is to combine IFN with an oral medication called ribavirin. This is particularly helpful in treating those patients who have not responded to IFN alone. A side effect of ribavirin is a mild anemia or low red cell count in the blood.

HCV Carriers

Certain people infected with HCV have a positive HCV blood test, but a normal liver enzyme test. These individuals are often called HCV carriers, and they can pass the virus on to others. Although they appear not to be seriously ill, there is recent evidence that even these people may have chronic hepatitis. Therefore, each should be evaluated by a liver specialist.

 

Sex and Pregnancy

The risk of transmitting HCV sexually is low compared to hepatitis B and AIDS. In marriages and long-term relationships with monogamous partners, it is often the case that one person is HCV positive and the partner is HCV negative. The current medical recommendation is that in these circumstances, sexual practices need not be changed. However, when people have multiple sex partners or new partners, they should never engage in unprotected sex.

It appears that in pregnancy, HCV is passed on to the fetus less than 5% of the time. It may depend on how high the mother’s blood virus level is during pregnancy. Therefore, hepatitis C infected women should always consult with their physicians before becoming pregnant.

 

Prevention

There is no vaccine currently available to protect against hepatitis C, as there is with hepatitis A and hepatitis B. People can prevent getting hepatitis C by not sharing anything that is likely to hold and transmit blood — razors, manicure tools, toothbrushes, and especially IV drug needles. Practices such as ear piercing and tattooing should be avoided in places where sterile conditions are questionable. Until all circumstances under which HCV can be transmitted have been thoroughly identified, it should be assumed that every person with hepatitis C can pass the virus on to others. Therefore everyone, especially health care workers, should avoid coming in contact with blood and body fluids from infected individuals.

 

Liver Transplantation

Liver transplantation is a newer, successful form of therapy for people with a badly damaged liver. Liver transplants have become more common for people with chronic hepatitis C who develop life-threatening liver damage. However, since these patients continue to carry the virus, they will almost always reinfect their new livers. Nevertheless, with continuing treatment for the chronic infection, liver transplantation offers these patients longer life and improved quality of life.

 

Summary

Hepatitis C is a serious disease that often results in long-term complications. Many patients infected with HCV develop chronic hepatitis C. Some people become carriers of HCV without knowing it. For this reason it is important to prevent spread of the disease by lifestyle practices that avoid contact with infected blood and body fluids. Researchers are continually learning more about hepatitis C, and research into new treatments is ongoing. Chronic hepatitis C patients who are monitored frequently and follow the advice of their physicians have every reason to be hopeful about the future.

 

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.

 

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. 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.

 

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. There may be side effects with prednisone, such as swelling of the face, retention of fluid, and weight gain. Long-term treatment with these drugs may also cause loss of bone. This can lead to osteoporosis, or even severe damage to joints such as the shoulder and knee. Therefore, 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.

 

Liver Transplantation

Liver transplantation is now an accepted form of treatment for chronic, severe liver disease. Advances in surgical techniques and the use of new drugs to suppress rejection have dramatically improved the success rate of transplantation. The outcome for patients with autoimmune hepatitis is excellent. Survival rates for this condition at transplant centers are well over 90 percent, with a good quality of life after recovery.

 

Summary

Autoimmune hepatitis is inflammation of the liver. The inflammation is a result of the immune system developing antibodies against the liver. It is not a contagious disease, but it is a serious chronic disease that can lead to irreversible cirrhosis, and eventually to liver failure. However, the outlook for patients with autoimmune hepatitis is generally very favorable. With early diagnosis, drug treatment to prevent serious liver damage is effective in most patients. For those few patients who do not respond to other treatment, successful liver transplantation is now a standard form of therapy when liver damage is severe.

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.

 

The Causes of Cirrhosis

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.

The 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.

• 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.

 

Diagnosis and Liver Biopsy

The physician can always suspect cirrhosis from the patient’s medical history and physical examination. In addition, certain blood tests and scans or ultrasound (sonography) can provide helpful information. To make a definite diagnosis, however, a liver biopsy (tissue sample) is required. This is performed by anesthetizing the skin of the right-lower chest and inserting a thin, needle into the liver. A core or specimen of tissue is removed and examined under a microscope.

 

The Course of Cirrhosis

When cirrhosis is diagnosed, the patient and physician begin a plan of action designed to preserve the remaining liver cells and correct the complications mentioned above. By following this plan, most patients can lead long, productive lives.

 

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.

 

Treatment

Often, the only required treatment for cirrhosis is removing the offending cause:

• 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 Transplant

Liver transplantation has progressed to the stage where it caow be considered as standard treatment for selected patients.

 

Summary

Cirrhosis of the liver is a common disorder that has many causes. With early diagnosis, much can be done to prevent serious complications. Various treatments are available, depending on the cause of the liver injury and its complications. Ongoing medical research promises major advances in treating cirrhosis in the future.

 

Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC) is a disease of the bile ducts inside the liver. It progresses slowly, so patients may lead active, productive lives for many years. In PBC, the bile ducts in the liver become inflamed. The inflammation is chronic (constant over a long period of time), and causes scaring that eventually blocks and destroys the bile ducts.

This condition interferes with the proper drainage of bile, so the bile backs up into the liver and into the bloodstream, causing various symptoms. Eventually the liver itself becomes badly damaged and scarred. This is known as cirrhosis.

 

Cause

The exact cause of PBC is unknown. Scientists believe there could be more than one contributing factor. While it does not have the traits of an inherited disease, it does appear more often in some families. People with PBC sometimes have a history of allergies or autoimmune disturbances — that is when the body’s immune system recognizes a part of the body as foreign and injures or goes to war against it. Rheumatoid arthritis and lupus are examples of autoimmune disorders.

 

Symptoms

PBC occurs in both men and women, but women get the disease 10 times more often than men. It usually begins between the ages of 30 and 60. Early in the disease, many patients have no symptoms. The only findings may be abnormal blood laboratory results. For example, a high level of the liver enzyme called alkaline phosphatase may be found in the blood. Itching and fatigue are common symptoms later in the disease. Itching is caused by bile entering the bloodstream.

As PBC progresses, other symptoms occur. There may be jaundice (yellowing of skin and eyes from excess bile in the blood), cholesterol deposits in the skin, fluid accumulation or edema, and darkening of the skin. Other immune related problems may also be present. For example, the tear and salivary glands may not function properly, causing dry eyes and mouth. Arthritis and thyroid problems may be present, and osteoporosis can develop in later stages. The bones become soft and fragile, leading to increased risk of fractures. The development of cirrhosis is the end result of PBC.

 

Diagnosis

PBC diagnosis is based on several pieces of information. Itching and fatigue alert the physician that bile ducts may be damaged. As previously mentioned, high levels of certain liver enzymes in the blood are important clues. Probably the most important laboratory test is one for mitochondrial antibodies. Mitochondria are the energy sources within cells. For unknown reasons a protein antibody develops against them in 95 percent of PBC cases. The physician must look at the whole picture to make the diagnosis of PBC.

Often the physician x-rays the bile ducts to rule out other causes of obstruction. This x-ray, called an ERCP, is performed under light sedation. A lighted, flexible endoscope is inserted through the mouth, stomach, and then into the small intestine. A thin tube is placed through the scope into the bile ducts, and dye is injected to highlight the bile ducts on the x- ray.

As the disease progresses, a liver biopsy is needed to determine how much damage has occurred. Under local anesthesia, a slender needle is inserted through the right lower chest to extract a small piece of liver for microscopic analysis.

 

Treatment

Because PBC advances slowly, patients often have no symptoms for many years. Initial treatment for PBC is aimed at reducing symptoms when they occur. Itching can be controlled by drugs such as Questran. Bile is usually reabsorbed into the bloodstream from the large intestine, and goes back to the liver to be reused. Questran binds up bile in the intestine, allowing it to be eliminated with the stool instead. This helps to reduce the build-up of bile in the body.

The diet should be well-balanced. At least 1,200 mg of calcium per day is needed to prevent osteoporosis. Also, if blood levels of vitamin D are below normal, the physician may prescribe a supplement. Vitamin D helps the body absorb calcium from the intestine. If thyroid function is low, it too can be treated with medication. Diuretics (fluid pills) and reducing salt intake can help reduce edema or swelling.

Some drugs seem to improve liver function blood tests. Some research studies suggest these drugs reduce damage to the liver. Actigall changes the make-up of bile in the liver and seems to reduce liver damage. Colchicine is an older drug that may reduce scar formation in the liver. Another drug that shows promise is methotrexate (trade name Rheumatrex). It suppresses the immune response in the body. When PBC progresses to a point where too much liver damage has occurred, liver transplantation must be considered.

 

Liver Transplantation

Liver transplantation is now an accepted form of treatment for chronic, severe liver disease. Advances in surgical techniques and the use of new drugs to suppress rejection have improved the success rate of transplantation. The outcome for PBC patients is excellent. Because of the disease’s slow progress, it is possible to plan elective transplant surgery. Survival rates at transplant centers are well over 90 percent, with a good quality of life after recovery.

Summary

Primary biliary cirrhosis is a slow, progressive disease. Once diagnosed, treatment is directed at managing symptoms and slowing down liver damage. A great deal of research is underway aimed at discovering the cause, preventing damage to the bile ducts and liver, improving symptoms, and prolonging life. Transplantation is now a standard form of treatment for advanced disease. By working closely with the physician, there is good reason to expect a favorable long-term outlook.

GALL  BLADDER AND BILLIARY SYSTEM

Prevalence of gallstones

Gallstones may be present at any age but are unusual before the third decade. The prevalence of gallstones is strongly influenced both by age and sex. There is a progressive increase in the presence of gallstones with age but the prevalence is two to three times higher in women than in men, although this difference is less marked in the sixth and seventh decade. At this age the prevalence ranges between 25% and 30%. The increase in life expectancy is reflected in an increased burden of symptomatic gallstone disease.

There are considerable racial differences, gallstones being more common in Scandinavia, South America and Native North Americans but less common in Asian and African groups.

Types of gallstones

Two principal types of gallstone disease occur. In the western world 80% of gallstones contain cholesterol. The second, less frequent, type of gallstone is ‘pigment stones’, being predominantly composed of calcium bilirubinate or polymerlike complexes with calcium, copper and some cholesterol.

Risk factors for cholesterol gallstones

Increasing age

Sex (F > M)

Family history

Multiparity

Obesity ± metabolic syndrome

Rapid weight loss

Diet (e.g. high in animal fat/low in fibre)

Drugs (e.g. contraceptive pill)

Ileal disease or resection

Diabetes mellitus

Acromegaly treated with octreotide

Liver cirrhosis

Clinical presentation of gallstones

 

The majority of gallstones are asymptomatic and remain so during a person’s lifetime. Gallstones are increasingly detected as an incidental finding at the time of either abdominal radiography or ultrasound scanning. Over a 10- to 15-year period approximately 20% of these stones will be the cause of symptoms with 10% having severe complications.

Once gallstones have become symptomatic there is a strong trend towards recurrent complications, often of increasing severity. Gallstones do not cause dyspepsia, fat intolerance, flatulence or other vague upper abdominal symptoms. The chances of a fair, fat, female of 40 having gallstones are the same as in the general population.

Biliary or gallstone colic

Biliary colic is the term used for the pain associated with the temporary obstruction of the cystic or common bile duct by a stone usually migrating from the gall bladder. Despite the term ‘colic’, the pain of stone-induced ductular obstruction is severe but constant and has a crescendo characteristic. Many sufferers can relate the symptoms to over-indulgence with food, particularly when this has a high fat content. The most common time of day for such an episode is in the midevening and lasting until the early hours of the morning.

The initial site of pain is usually in the epigastrium but there may be a right upper quadrant component. Radiation may occur over the right shoulder and right subscapular region.

Nausea and vomiting frequently accompany the more severe attacks. The cessation of the attack may be spontaneous after a number of hours or terminated by the administration of opiate analgesia. More protracted pain, particularly when associated with fevers and rigors, suggests secondary complications such as cholecystitis, cholangitis or gallstonerelated pancreatitis

Acute cholecystitis

The initial event in acute cholecystitis is obstruction to gall bladder emptying. In 95% of cases a gall bladder stone can be identified as the cause. Such obstruction results in an increase of gall bladder glandular secretion leading to progressivedistension which in turn may compromise the vascular supply to the gall bladder.

There is also an inflammatory response secondary to retained bile within the gall bladder. Infection is a secondary phenomenon following the vascular and inflammatory events described above.

The initial clinical features of an episode of cholecystitis are similar to those of biliary colic described above. However, over a number of hours there is progression with severe localized right upper quadrant abdominal pain corresponding to parietal peritoneal involvement in the inflammatory process.

The pain is associated with tenderness and muscle guarding or rigidity. Occasionally the gall bladder can become distended by pus (an empyema) and rarely an acute gangrenous cholecystitis develops which can perforate, with generalized peritonitis.

Investigations

Biliary colic as a consequence of a stone in the neck of the gall bladder or cystic duct is unlikely to be associated with significant abnormality of laboratory tests. Acute cholecystitis is usually associated with a moderate leucocytosis and raised inflammatory markers (e.g. C reactive protein).

■ The serum bilirubin, alkaline phosphatase and  aminotransferase levels may be marginally elevated in the presence of cholecystitis alone, even in the absence bilirubin and alkaline phosphatase is in keeping with bile duct obstruction.

■ An abdominal ultrasound scan is the single most useful investigation for the diagnosis of gallstone-related disease. Look for:

(a) gallstones within the gall bladder, particularly when these are obstructing the gall bladder neck or cystic duct

(b) focal tenderness over the underlying gall bladder

(c) thickening of the gall bladder wall. This may also be seen with hypoalbuminaemia, portal hypertension and acute viral hepatitis. Gallstones are a common finding in an ageing population, and in the absence of specific symptoms great care should be taken when determining whether the gallstones are responsible for the symptoms.

■ Biliary scintigraphy using technetium derivatives of iminodiacetate. These isotopes are taken up by hepatocytes and excreted into bile. They delineate the extrahepatic biliary tree. The absence of cystic duct and gall bladder filling provides evidence towards acute cholecystitis although the findings must be closely correlated with the presenting symptoms.

MANAGEMENT

Cholecystectomy

Cholecystectomy is the treatment of choice for virtually all patients with symptomatic gall bladder stones. In patients admitted with specific gallstone-related complications (see below) cholecystectomy should be carried out during the period of that admission to prevent the risk of recurrence.

For those presenting with pain alone an elective procedure can be planned but the waiting time should be minimized to avoid the high risk of recurrent symptoms (approximately 30% over 4 months) and the need for hospital admission. Cholecystectomy should not be performed in the absence of typical symptoms just because stones are found on investigation. There is an ongoing debate as to whether prophylactic cholecystectomy is justified in young patients found to have small stones. Such patients have a long period over which they may develop symptomatic disease and small stones are an independent risk factor for the potentially serious complication of gallstone pancreatitis. Each case should be discussed on an individual risk benefit basis. The laparotomy approach to cholecystectomy has now been largely replaced by the laparoscopic technique. Postoperative pain is minimized with only a short period of ileus and the early ability to mobilize the patient. Laparoscopic cholecystectomy can be safely carried out on a day-care basis in otherwise fit patients (although in most cases an overnight stay remains the norm). This has considerable cost benefits over open cholecystectomy, which is now reserved for a small proportion of patients with contraindications such as extensive previous upper abdominal surgery, ongoing bile duct obstruction or portal hypertension.

In approximately 5% of cases a laparoscopic cholecystectomy is converted to an open operation because of technical difficulties, in particular adhesions in the right upper quadrant or difficulty in identifying the biliary anatomy.

Acute cholecystitis. The initial management is conservative, consisting of nil by mouth, intravenous fluids, opiate analgesia and intravenous antibiotics (dictated by local policy with options including extended spectrum cephalosporins, fluoroquinolones or piperacillin/tazobactam). Cholecystectomy is usually delayed for a few days to allow the symptoms to settle but can then be carried out quite safely in the majority of cases.

When the clinical situation fails to respond to this conservative management, particularly if there is increasing pain and fever, an empyema or gangrene of the gall bladder may have occurred. Urgent ultrasound is performed and urgent surgery will be required if these complications have developed.

Specific complications of cholecystectomy include a biliary leak either from the cystic duct or from the gall bladder bed. Injury to the bile duct itself occurs in up to 0.5% of laparoscopic operations and may have serious long-term sequelae in the form of biliary sepsis and secondary biliary liver injury. There is an overall mortality of 0.2%.

Stone dissolution and shock wave lithotripsy

These non-surgical techniques for the management of gall bladder stones are infrequently used but may still have a role in a few highly selected patients who may not be fit for laparoscopic cholecystectomy.

Dissolution. Pure or near-pure cholesterol stones can be solubilized by increasing the bile salt content of bile. Chenodeoxycholic acid and ursodeoxycholic acid were used but now laparoscopic surgery has made this treatment redundant.

In any event, its efficacy was limited and the recurrence rate of gallstones was high. These limitations have restricted the application of this approach. Further benefit may be attained by the addition of an HMG-CoA reductase inhibitor (e.g. simvastatin) to a regimen of ursodeoxycholic acid. This will then combine reduced cholesterol content of bile as well an enhanced bile salt concentration but uses are still limited.

Extracorporeal shock wave lithotripsy. A shock wave can be directed either radiologically or by ultrasound on to gall bladder stones. This technique was highly successful but in only a restricted patient population.

The post-cholecystectomy syndrome

This refers to right upper quadrant pain, often biliary in type, which occurs a few months after the cholecystectomy but may be delayed for a number of years. The patients often comment that the pain is identical to that for which the original operation was carried out. In many cases this syndrome is related to functional large bowel disease with colonic spasm at the hepatic flexure (hepatic flexure syndrome). In a small proportion of patients the pain is a result of a retained common bile duct stone. In a further minority of patients, hypertension of the sphincter of Oddi is a potential cause.

This is most likely in patients with abnormal liver biochemistry and dilatation of the common bile duct (on ultrasound) during episodes of pain (and in the absence of a documented retained stone). The diagnosis is confirmed by pressure measurements of the sphincter of Oddi, and the condition can be successfully managed by endoscopic sphincterotomy.

Bile Acid Therapy for Gallstones

Ursodiol (ursodeoxycholic acid) is a naturally occurring bile acid that makes up less than 5% of the circulating bile salt pool in humans and a much higher percentage in bears. After oral administration, it is absorbed, conjugated in the liver with glycine or taurine, and excreted in the bile. Conjugated ursodiol undergoes extensive enterohepatic recirculation. The serum half-life is approximately 100 hours. With long-term daily administration, ursodiol constitutes 30–50% of the circulating bile acid pool. A small amount of unabsorbed conjugated or unconjugated ursodiol passes into the colon, where it is either excreted or undergoes dehydroxylation by colonic bacteria to lithocholic acid, a substance with potential hepatic toxicity.

Pharmacodynamics

The solubility of cholesterol in bile is determined by the relative proportions of bile acids, lecithin, and cholesterol. Although prolonged ursodiol therapy expands the bile acid pool, this does not appear to be the principal mechanism of action for dissolution of gallstones. Ursodiol decreases the cholesterol content of bile by reducing hepatic cholesterol secretion. Ursodiol also appears to stabilize hepatocyte canalicular membranes, possibly through a reduction in the concentration of other endogenous bile acids or through inhibition of immune-mediated hepatocyte destruction.

Clinical Use

Ursodiol is used for dissolution of small cholesterol gallstones in patients with symptomatic gallbladder disease who refuse cholecystectomy or who are poor surgical candidates. At a dosage of 10 mg/kg/d for 12–24 months, dissolution occurs in up to 50% of patients with small (< 5–10 mm) noncalcified gallstones. It is also effective for the prevention of gallstones in obese patients undergoing rapid weight loss therapy. Several trials demonstrate that ursodiol 13–15 mg/kg/d is helpful for patients with early-stage primary biliary cirrhosis, reducing liver function abnormalities and improving liver histology.

Adverse Effects

Ursodiol is practically free of serious adverse effects. Bile salt-induced diarrhea is uncommon. Unlike its predecessor, chenodeoxycholate, ursodiol has not been associated with hepatotoxicity.

COMPLICATIONS OF GALLSTONES

■ Acute cholecystitis and acute cholangitis have been discussed.

■ Gallstone-related pancreatitis.

■ Gallstones can occasionally erode through the wall of the gall bladder into the intestine giving rise to a biliary enteric fistula. Passage of a gallstone through into the small bowel can give rise to an ileus or true obstruction.

■ There is little evidence that gallstones are associated with an increased risk of adenocarcinoma of the gall bladder.

 

Non-calculous cholecystitis

Almost 10% of gall bladders removed for biliary symptoms are shown to have chronic inflammation within the wall but an absence of gallstones. Such cases are described as noncalculous cholecystitis. In many instances the gall bladder inflammation is minor and of doubtful significance. In a minority of cases non-calculous cholecystitis is characterized by severe inflammation frequently associated with gall bladder perforation. This condition is characteristically found in an elderly and critically ill group of patients. Chemical inflammation of the gall bladder may also occur from reflux of pancreatic enzymes back into the biliary tree, usually through the common channel at the ampulla of Vater. Bacterial infection of the gall bladder has occasionally been recognized as a cause of chronic inflammation.

The decision to carry out cholecystectomy in the absence of defined gall bladder stones should be guided by the specific features of the history and whether there is evidence of a diseased gall bladder wall on ultrasound scanning.

Cholesterolosis of the gall bladder

In cholesterolosis, cholesterol and other lipids are deposited in macrophages within the lamina propria of the gall bladder. These may be diffusely situated, giving a granular appearance to the gall bladder wall, or on occasions more discrete, giving a polypoid appearance. Cholesterolosis of the gall bladder may coexist with gallstones but occurs independently. Some degree of cholesterolosis may be found in up to 25% of autopsies in an elderly population. It is doubtful whether this is a cause of symptoms.

Adenomyomatosis of the gall bladder

Adenomyomatosis is a gall bladder abnormality characterized by hyperplasia of the mucosa, thickening of the muscle wall and multiple intramural diverticula (the so-called ‘Rokitansky–Aschoff sinuses’). The condition is usually detected as an incidental finding during investigation for possible gall bladder disease. It has been suggested that this condition is secondary to increased intraluminal gall bladder pressure but this is not proven.

Gallstones may frequently coexist but there is no evidence to support a direct relationship. It is unlikely that adenomyomatosis alone is a cause of biliary symptoms.

Chronic cholecystitis

There are no symptoms or signs that can conclusively be shown to be due to chronic cholecystitis. Symptoms attributed to this condition are vague, such as indigestion, upper abdominal discomfort or distension. There is no doubt that gall bladders studied histologically can show signs of chronic inflammation, and occasionally a small, shrunken gall bladder is found either radiologically or on ultrasound examination. However, these findings can be seen in asymptomatic people and therefore this clinical diagnosis should not be made. Most patients with chronic right hypochondrial pain suffer from functional bowel disease.

 

THE PANCREAS

Assessment of exocrine function

The assessment of pancreatic exocrine function is used in the investigation of patients with possible chronic pancreatic disease. Clinically evident fat malabsorption does not occur until there has been an 85–90% reduction in pancreatic lipase and is therefore a very late manifestation of pancreatic disease.

Direct tests of pancreatic function

These tests rely upon the analysis of a duodenal aspirate following pancreatic stimulation. The original test involved the oral administration of a specified meal. Pancreatic stimulation is now achieved by intravenous secretin and cholecystokinin.

The aspirate is assessed for pancreatic enzymes and bicarbonate production. The procedure is time-consuming and requires a meticulous technique. There is a good correlation with moderate to severe pancreatic function loss, but not for mild damage. These tests are not widely available. The measurement of peak bicarbonate secretion following secretin stimulation has recently been described using an endoscopic technique for aspirate collection. This method offers similar levels of predictive accuracy as seen with the secretin–cholecystokinin stimulation test but does require a 30 minute endoscopic intubation.

Non-invasive indirect tests of pancreatic function

Faecal tests

■ Faecal fat estimation.

■ Faecal chymotrypsin. The test is not useful until severe impairment of pancreatic function is present.

■ Faecal elastase. This pancreatic specific enzyme is not degraded in the intestine and has high concentrations within the faeces. Diminished levels may be detected in moderate as well as severe pancreatic insufficiency. This has replaced the faecal chymotrypsin test.

Oral pancreatic function tests

■ PABA test. Oral N-benzoyl-l-tyrosyl-p-aminobenzoic acid is hydrolysed by chymotrypsin to release paminobenzoic acid (PABA), which is then absorbed, conjugated and excreted in the urine where it can be measured. The test is time-consuming but is specific for pancreatic insufficiency, with a 65–80% sensitivity.

■ Fluorescein dilaurate test. Oral fluorescein dilaurate is digested by pancreatic esterase to release the fluorescein which is then absorbed and excreted in the urine. This test is relatively inexpensive and commercially available as the ‘Pancreolauryl test’. This is highly sensitive and specific in severe pancreatic insufficiency but has only a 50% sensitivity in mild to moderate disease.

Clinical application of pancreatic function tests

Whilst the invasive duodenal aspiration tests represent the most sensitive and specific means of assessing pancreatic function, these are very rarely used outside specialized centres. The Pancreolauryl and PABA tests are non-invasive  and are widely available but are only highly sensitive in the detection of severe pancreatic insufficiency. The faecal elastase test (in a commercially available form) provides similar sensitivity and specificity and is the test of choice as a screening tool for pancreatic insufficiency, but again detection of mild disease is problematic.

Pancreatic imaging Imaging has a pivotal role in the investigation and management of pancreatic disease, which covers the spectrum of acute, chronic and malignant conditions.

■ A plain abdominal radiograph may show the calcification associated with chronic pancreatitis, particularly when alcohol is the aetiology.

■ Ultrasound of the pancreas is a useful screening investigation for inflammation and neoplasia. Views may be limited by overlying bowel gas.

■

Spiral CT

scan with contrast enhancement and following a specific pancreatic protocol remains the gold standard imaging technique for the investigation of pancreatic disease.

■ MRI scanning represents an alternative to CT. Magnetic resonance cholangiopancreatography (MRCP) gives clear definition of the pancreatic duct as well as the biliary tree. Gallstones (including microcalculi) may also be identified in the biliary tree using MRI/MRCP.

■ Endoscopic ultrasound is very useful for identifying distal common bile duct stones which may be the aetiology of an episode of acute pancreatitis. Endoscopic ultrasound can identify the early changes of chronic pancreatitis before these are evident on other imaging methods. There is also an increasing role for this technique to stage the operability of pancreatic adenocarcinoma, particularly with respect to vascular invasion. Endoscopic ultrasound is now considered the imaging technique of choice for investigating cystic lesions of the pancreas. The technique allows fine-needle aspiration and histological sampling as well as the therapeutic option of cyst drainage. Endoscopic ultrasound is a sensitive means of detecting small pancreatic tumours, particularly those of neuroendocrine origin.

■ Endoscopic retrograde cholangiopancreatography (ERCP) was considered the gold standard for diagnosing pancreatic disease. However, with the advent of MRCP and endoscopic ultrasound, ERCP is restricted to therapeutic intervention.

Pancreatitis

Classification

Pancreatitis is divided into acute and chronic. By definition acute pancreatitis is a process that occurs on the background of a previously normal pancreas and can return to normal after resolution of the episode. In chronic pancreatitis there is continuing inflammation with irreversible structural changes.

In practice the differentiation between acute and chronic pancreatitis may be extremely difficult. Any of the causes of acute pancreatitis if untreated may result in recurrent episodes classified as acute relapsing pancreatitis. In other cases the recurrent episodes of recurrent pancreatitis may represent exacerbations of an underlying chronic process.

Acute pancreatitis

In the western world, gallstones and alcohol account for the vast majority of episodes. Alcohol also causes chronic pancreatitis (see below). The severity of the pancreatitis may range from mild and self-limiting to extremely severe with extensive pancreatic and peripancreatic necrosis as well as haemorrhage. In the most severe form of pancreatitis the mortality rises to between 40% and 50%.

Pathogenesis

Mechanisms by which pancreatic necrosis occurs remain speculative. Any theory must take into account how a very diverse group of aetiological factors can produce the same end point. There is some suggestion that the final common pathway is a marked elevation of intracellular calcium which in turn leads to activation of intracellular proteases. It is these activated enzymes which are responsible for cellular necrosis.

In the case of gallstone-related pancreatitis it is believed that stones occlude the pancreatic drainage at the level of the ampulla leading to pancreatic ductular hypertension.

Such ductular hypertension has been shown in animal models to increase cytosolic free ionized calcium. There is also evidence that alcohol interferes with calcium homeostasis in pancreatic acinar cells.

Clinical features

Acute pancreatitis is a differential diagnosis in any patient with upper abdominal pain. The pain usually begins in the epigastrium accompanied by nausea and vomiting. As inflammation spreads throughout the peritoneal cavity the pain becomes more intense. Involvement of the retroperitoneum frequently leads to back pain.

The patient may give a history of previous similar episodes or be known to have gallstones. An attack may follow an alcoholic binge. However, in many cases there are no obvious aetiological factors. Physical examination at the time of presentation may show little more than a patient in pain with some upper abdominal tenderness but no systemic abnormalities. In more severe disease the patient may have a tachycardia, hypotension and be oliguric. Abdominal examination may show widespread tenderness with guarding as well as reduced or absent bowel sounds. Specific clinical signs that support a diagnosis of severe necrotizing pancreatitis include periumbilical (Cullen’s sign) and flank bruising (Grey Turner’s sign). In patients with a gallstone aetiology the clinical picture may also include the features of jaundice or cholangitis.

Diagnosis

Blood tests

■ Serum amylase is an extremely sensitive test if it is 3 times the upper limit of normal when measured within 24 hours of the onset of pain. A number of other conditions may occasionally cause a very elevated amylase. Amylase levels gradually fall back towards normal over the next 3–5 days. With a late presentation the serum amylase level may give a false-negative result.

■ Urinary amylase levels may be diagnostic as these remain elevated over a longer period of time.

■ Serum lipase levels are also raised in acute pancreatitis and these remain elevated for a longer period of time than those of amylase. However, overall, the accuracy of serum lipase is not significantly greater than amylase and it is technically more difficult to measure.

■ C reactive protein level is useful in assessing disease severity and prognosis.

■ Other baseline investigations include a full blood count, urea and electrolytes, blood glucose, liver biochemistry, plasma calcium and arterial blood gases. These are documented at presentation and then repeated at 24 and 48 hours and provide a basis for assessing the severity of an attack.

Radiology

■ An erect chest X-ray is mandatory to exclude gastroduodenal perforation, which also raises the serum amylase. A supine abdominal film may show gallstones or pancreatic calcification.

■ An abdominal ultrasound scan is used as a screening test to identify a possible biliary (gallstone) cause of pancreatitis. Gallstones are difficult to detect in the distal common bile duct but dilated intrahepatic ducts may be present in the presence of bile duct obstruction. Stones within the gall bladder are not sufficient to justify a diagnosis of gallstone-related pancreatitis. The ultrasound may also demonstrate pancreatic swelling and necrosis as well as peripancreatic fluid collections if present. In severe pancreatitis the pancreas may be difficult to visualize because of gas-filled loops of bowel.

■ Contrast-enhanced spiral CT scanning is essential in all but the most mild attacks of pancreatitis It should be performed after 72 hours to assess the extent of pancreatic necrosis. CT provides very valuable prognostic information. Later, repeated CT scans can detect other complications including fluid collections, abscess formation and pseudocyst development.

■ MRI (MRCP) assesses the degree of pancreatic damage and identifies gallstones within the biliary tree. MRI is particularly useful to differentiate between fluid and solid inflammatory masses.

■ ERCP is used as a treatment measure to remove bile duct stones in the presence of gallstone-related pancreatitis.

Assessment of disease severity

The majority of cases of acute pancreatitis are mild but approximately 25% run a more complicated course which may result in haemodynamic instability and multiple organ failure. The early prediction of such a severe attack allows appropriate monitoring and intensive care to be in place.

Early clinical assessment has been shown to have poor sensitivity for predicting a severe attack. Similarly, individual laboratory tests have very limited value. Elevations of CRP of 200 mg/L in the first 4 days have an 80% predictive value of a severe attack. Multiple factors are also used to develop scoring systems. The Ranson and Glasgow scoring systems are based on such parameters and have been shown to have an 80% sensitivity for predicting a severe attack, although only after 48 hours following presentation.

The acute physiology and chronic health evaluation (APACHE) score has been extensively adopted as a means of assessing the severity of a wide spectrum of illness.

The APACHE scoring system is based on common physiological and laboratory values and adjusted for age as well as the presence or absence of a number of other chronic health problems. This scoring system appears to have a high sensitivity as early as 24 hours after onset of symptoms. There is evidence that obesity predicts the outcome from an episode of pancreatitis as the excessive adipose tissue is a substrate for activated enzyme activity.

This will in turn generate an extensive inflammatory reaction. Even modest obesity (body mass index (BMI) between 25 and 30) has an adverse effect. This is incorporated as an adverse factor in the APACHE score for acute pancreatitis, and other variables have also been added.

Treatment

The initial management of acute pancreatitis is similar, whatever the cause. A multiple factor scoring system (ideally APACHE II with a modification for obesity) should be used at the end of the first 24 hours after presentation to allow identification of the 25% of patients with a predicted severe attack. This should be repeated at 48 hours to identify a further subgroup who appear to be moving into the severe category. These patients should then be managed on a highdependency or intensive care unit. Even patients outside the severe category may require considerable supportive care. Early fluid losses in acute pancreatitis may be large, requiring well-maintained intravenous access as well as a central line and urinary catheter to monitor circulating volume and renal function.

■ Nasogastric suction prevents abdominal distension and vomitus and hence the risk of aspiration pneumonia.

■ Baseline arterial blood gases determine the need for continuous oxygen administration.

■ Prophylactic antibiotics. Broad-spectrum antibiotics, e.g. cefuroxime, or aztreonam, along with an agent active against Gram-positive cocci, reduce the risk of infective complications and are given from the outset.

■ Analgesia requirements. Pethidine and tramadol are the drugs of choice for immediate post-presentation pain control. Unless there is prompt resolution of pain, a patient-controlled system of administration is indicated to provide continuous and adequate pain relief. Fentanyl has been used widely for this application. There is a theoretical risk that morphine and diamorphine might exacerbate pancreatic ductular hypertension by causing sphincter of Oddi contraction and they are best avoided in acute pancreatitis.

■ Feeding. In patients with a severe episode there is little likelihood of oral nutrition for a number of weeks. Total parenteral nutrition has been associated with a high risk of infection and has been replaced by enteral nutrition. In the absence of gastroparesis most patients will tolerate nasogastric administration of feed without exacerbation of pain. In those with gastroparesis or poorly tolerated nasogastric feeding (exacerbation of pain or precipitation of nausea and vomitus), postpyloric feeding should be instituted by the endoscopic placement of a nasojejunal tube.

■ Anticoagulation with a low molecular weight heparin for DVT prophylaxis. In a small proportion of patients, multiorgan failure will develop in the first few days after presentation, reflecting the extent of pancreatic necrosis. Such patients will require positive-pressure ventilation and often renal support. The mortality in this group is extremely high (in excess of 80%).

Gallstone-related pancreatitis

In patients with gallstone-related pancreatitis and associated bile duct obstruction (particularly when complicated by cholangitis), endoscopic intervention with sphincterotomy and stone extraction is the treatment of choice. In the absence of bile duct obstruction, sphincterotomy and stone extraction is only of proven benefit when the episode of pancreatitis is predicted as severe. In less severe cases of gallstone-related pancreatitis the presence of residual bile duct stones can be assessed by MRCP or endoscopic ultrasound after recovery from the episode of pancreatitis (usually a 6 week period is allowed) and, if present, removed at the time of ERCP. To prevent a recurrent episode of pancreatitis cholecystectomy should be carried out at a similar time interval.

Late complications of acute pancreatitis

Within the first 7 days the morbidity and mortality of acute pancreatitis reflect the systemic inflammatory response, which in turn results in multiple organ failure. After this initial period the prognosis thereafter is most closely related to the extent of pancreatic necrosis. This can be most accurately assessed by contrast-enhanced CT, which should be carried out in all patients with severe disease after the first week. Extensive necrosis (greater than 50% of the pancreas) is associated with high risk of further complicated disease, frequently requiring surgical intervention.

It is infection of the necrotic pancreas which is of most concern and which may rapidly lead to overwhelming sepsis. Prophylactic antibiotics have been used to prevent this but do not reliably do so. If there is evidence of incipient infection, monitored by a rising neutrophil count and CRP level, an aspirate of the necrotic pancreas is taken under ultrasound control and cultured. The vast majority of patients with a positive culture should be considered for surgical resection of the necrotic pancreas. In the most severe cases multiple operations are required to fully resect the areas of necrosis.

Peripancreatic fluid collections are common in the early stages of acute pancreatitis; the vast majority will resolve spontaneously. Some fluid collections will be surrounded by granulation tissue producing the so-called ‘pseudocyst’. These by definition are not fully formed until 6 weeks after the onset of the illness. The smaller pseudocysts (less than 6 cm in diameter) frequently resolve on their own but others may persist in the long term, giving rise to potential complications such as infection, intraperitoneal bleeding and gastric outlet obstruction. Larger pseudocysts persisting for longer than 6 weeks are usually actively managed by endoscopic drainage under endoscopic ultrasound guidance. Surgical drainage may be indicated in cases in which the cyst anatomy is not compatible with endoscopic drainage.

Long-term outcome

The vast majority of patients with a mild to moderate episode of acute pancreatitis will make a full recovery with no longterm sequelae. Recurrent episodes of pancreatitis may occur, particularly if there has been any long-term pancreatic ductular damage. Patients with more severe acute pancreatitis may become pancreatic insufficient both with respect to exocrine (malabsorption) and endocrine function (diabetes).

 

Chronic pancreatitis

Aetiology

In developed countries by far the most common cause of chronic pancreatitis is alcohol, accounting for 60–80% of cases.

Tropical chronic pancreatitis is commonly found in children and young adults. The aetiology is unknown but there is some evidence of a genetic susceptibility with increased prevalence of mutations of the trypsin inhibitor gene SPINK-1. There is a strong likelihood of an interaction between genetic susceptibility and environmental triggers.

Hereditary chronic pancreatitis is an autosomal dominant condition with variable penetrance. The gene mutations have been mapped to a cluster of trypsinogen genes situated on the long arm of chromosome 7.

Autoimmune chronic pancreatitis also occurs. This is seen predominantly in middle-aged men and associated with raised titres of anti-nuclear factor and particularly raised levels of IgG4. As well as pancreatic-related complications these patients often have other autoimmune phenomena such as a cholangiopathy, Sjцgren’s syndrome and renal disease.

Cystic fibrosis. Almost all patients have established chronic pancreatitis, usually from birth. Cystic fibrosis gene mutations have also been identified in patients with chronic pancreatitis but in whom there were no other manifestations of cystic fibrosis.

Obstruction of the pancreatic duct because of either a benign or malignant process may result in chronic pancreatitis. Congenital abnormalities of the pancreatic duct, in particular pancreas divisum, have been implicated.

Pathogenesis

A possible common pathway for pancreatic damage is the inappropriate activation of enzymes within the pancreas. This has been well demonstrated in the case of hereditary pancreatitis where genetic abnormalities of cationic trypsinogen and its inhibitory proteins have led to unopposed trypsin activity within the pancreas itself.

Chronic alcohol intake is also believed to increase the level of trypsinogen relative to its inhibitor. Human trypsinogen has a propensity to autoactivate, and any relative impairment or deficiency of inhibitor proteins will lead to unopposed enzyme activity and possible pancreatic damage. It is believed that the intrapancreatic enzyme activity leads to the precipitation of proteins within the duct lumen in the form of plugs. These then form a nidus for calcification but are also the cause of ductal obstruction leading to ductal hypertension and further pancreatic damage. Cytokine activation and oxygen stress are thought to play a role in perpetuating this process.

Clinical features

Pain is the most common presentation of chronic pancreatitis. It is usually epigastric and often radiates through into the back. The pattern of pain may be episodic, with short periods of severe pain, or chronic unremitting. Exacerbations of the pain may follow further alcohol excess although this is not a uniform relationship. During periods of abdominal pain anorexia is common and weight loss may be severe. This is particularly so in those patients with chronic unremitting symptoms. Exocrine and endocrine insufficiency may develop at any time, and occasionally malabsorption or diabetes is the presenting feature in the absence of abdominal pain. Jaundice secondary to obstruction of the common bile duct during its course through the fibrosed head of pancreas may also occur and may be a presenting feature in a small proportion of patients.

Investigations

The extent to which investigations are required is dependent upon the clinical setting. In a patient with known alcohol abuse and typical pain, few confirmatory tests are required.

■ Serum amylase and lipase levels are rarely significantly elevated in established chronic pancreatitis.

■ Faecal elastase level will be abnormal in the majority of patients with moderate to severe pancreatic disease.

■ PABA and Pancreolauryl tests.

■ Transabdominal ultrasound scan is used for initial assessment.

■ Contrast-enhanced spiral CT scan provides a more detailed assessment. In the presence of pancreatic calcification and a dilated pancreatic duct the diagnosis of chronic pancreatitis can be easily established. This may be much more difficult when these features are not present and in particular with an atypical presentation such as with steatorrhoea alone.

■ MRI with MRCP is increasingly utilized to define more subtle abnormalities of the pancreatic duct which may be seen ion-dilated chronic pancreatitis.

■ Endoscopic ultrasound is used in a small proportion of patients in whom the diagnosis is not confirmed with the above imaging or specifically for assessing complications of chronic pancreatitis including pseudocyst formation.

■ Diagnostic ERCP has been replaced by MRCP.

Treatment

In patients with alcohol-related chronic pancreatitis longterm abstinence is likely to be of benefit although this has been difficult to prove.

Abdominal pain. For short-term flare-ups of pain a combination of a non-steroidal anti-inflammatory drug and an opiate (tramadol) is usually sufficient for symptomatic relief. In patients with chronic unremitting pain this may be inadequate and also risks opiate addiction. Tricyclic antidepressants (e.g. amitriptyline) are used for chronic pain and reduce the need for opiates. Antioxidants are not of proven benefit. Coeliac axis nerve block may produce good pain relief but is unreliable in its extent and duration of action. In the majority of patients some spontaneous improvement in pain control occurs with time. After a 6- to 10-year period some 60% of patients will become pain-free. For patients with recurrent severe or debilitating chronic pain, both endoscopic and surgical intervention has been used but with limited success. The endoscopic approach has centred upon improving duct drainage by removing intraductal stones and repeated stenting to maintain duct patency. Extracorporeal shock wave lithotripsy has been used to fragment stones within the head of pancreas. Surgical intervention usually involves a duct drainage procedure combined with partial resection of the diseased head of pancreas. There is recent evidence suggesting improved symptom control following surgical intervention as compared to the endoscopic approach. However, it is reasonable to attempt endoscopic therapy as a first measure.

Steatorrhoea. The steatorrhoea associated with pancreatic insufficiency may be high, with up to 30 mmol of fat lost per 24 hours. This will usually improve with pancreatic enzymes supplements. Current preparations are presented in the form of microspheres which reduce the problems of acid degradation in the stomach. An acid suppressor (H2-receptor antagonist or proton pump inhibitor) is also given. Despite this, a proportion of patients continue to malabsorb, usually reflecting the inadequate mixing of the pancreatic supplements with the food as well as the low pH in the duodenum secondary to inadequate pancreatic bicarbonate production. There is no justification to reduce fat intake below the recommended levels of a normal diet as this may contribute to malnutrition seen in patients with chronic pancreatitis.

Diabetes associated with pancreatic endocrine failure may be difficult to control, with a rapid progression from oral hypoglycaemic agents to an insulin requirement.