What are liver disorders?

Quick Answer
As one of the most complex organs in the body, the liver is the target of a wide variety of toxins, infectious agents, and cancers that lead to hepatitis, cirrhosis, abscesses, and liver failure.
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Causes and Symptoms

The liver is the largest internal organ, lying in the upper-right abdominal cavity. Intricately attached to it by a system of ducts on its lower surface is the pear-shaped gallbladder. Unique to the liver is a blood supply that derives from two separate sources: the hepatic artery, carrying freshly oxygenated blood from the heart, and the portal vein, carrying blood rich in the products of digestion from the digestive organs. The liver cells, or hepatocytes, are arranged in thin sheets that are separated by large pores, blood vessels, and ducts. The result is a very soft, spongy organ filled with a large volume of blood.

The liver performs a wide variety of complex and diverse functions, more so than any other organ. Most commonly known is the production of bile, which is formed from the breakdown of red blood cells, cholesterol, and salts, stored in the gallbladder, and used in the small intestine to digest fats. The liver also serves the all-important purpose of detoxification by chemically altering harmful substances such as alcohol, drugs, and ammonia from protein digestion. Additionally, the liver is involved in the formation of such essential materials as blood proteins, blood-clotting factors, and sugar and fat storage compounds.

Because of the liver’s many responsibilities and unique position as an intermediary between the digestive process and the blood (via the portal vein), it easily falls prey to many disease-causing agents. Chemicals, illegal drugs, alcohol, viruses, parasites, hormones, and even medical drugs can damage the liver and have widespread effects on the rest of the body. The liver is also the most frequent target of cancer cells that have spread beyond their primary site. In the United States and other industrialized countries, liver disease is usually related to alcoholism and cancer, while in the developing world, it is often the result of infectious contamination by viruses and parasites.

There are two simplified methods of classifying liver disorders. The first is based on cause: infections (viruses and parasites), injury (alcohol and other toxins), inheritance (inability to perform certain functions), infiltration (iron and copper deposits), and tumors (both benign and malignant). The second method of classification is based on the result, such as hepatitis (inflammation), cirrhosis (permanent injury from alcohol or other toxins), or cancer.

Each of these liver diseases produces a particular set of signs and symptoms depending on the length of time and the specific disruption of structure and function. Pain and swelling rarely occur alone and are usually associated with one or more of the following: nausea and vomiting, jaundice, ascites, blood-clotting defects, and encephalopathy. Indeed, in some cases liver failure ensues, leading to coma and death.

Jaundice, a yellow discoloration of the skin and whites (sclera) of the eyes, is caused by the secretion of bile precursors (bilirubin) from the damaged liver cells directly into the blood rather than into the ducts leading to the gallbladder. Consequently, bilirubin accumulates in the body’s tissues, including the skin and eyes. Ascites, the collection of fluid beneath the liver in the abdomen, is an important sign of liver disease. This fluid comes primarily from the portal vein system, which lies between the liver and the digestive organs. As the liver becomes congested and enlarged in response to injury or infection, blood flow becomes difficult and pressure begins to build, causing liquid to leak from the blood vessels into the abdominal cavity. Easy bruising, excessive bleeding, and other problems with blood clotting are important signs that reflect the failure of the liver to produce essential blood proteins. Neuropsychiatric symptoms such as asterixis (flapping hand tremor) and encephalopathy (a state of mental confusion and disorientation that can quickly progress to coma) are not well understood, but it is likely that they result from an accumulation of toxic substances that would normally be cleared from the blood by the liver. Several other problems, such as the enlargement of male breasts, atrophy of the testicles, and other sexual changes, derive from the inability of the liver to clear the blood of hormones.

Hepatitis, an inflammation of the liver generally caused by viruses, is one of the most common diseases in the world. Hepatitis A, B, and C; Epstein-Barr virus (the causative agent of mononucleosis); and herpes are a few of the organisms that can infect the liver. Hepatitis A, transmitted through contaminated food, water, and shellfish, is usually a self-limited disease that resolves itself. Hepatitis B, transmitted through contact with infected blood and body secretions, is much more serious, with a carrier state, progressive organ damage, cancer, and death as possible sequelae. Hepatitis C is transmitted by intravenous drug use or blood transfusion. Infection most often causes no symptoms initially but leads to chronic infection in about 80 percent of individuals. Chronic infection progresses to cirrhosis in 20 to 30 percent of cases and may lead to liver cancer. Noninfectious causes of hepatitis in susceptible people include such frequently used substances as acetaminophen (Tylenol), halothane (general anesthesia), and oral contraceptives. Nonalcoholic steatohepatitis (NASH) is a disease that causes chronic inflammation and, upon biopsy, resembles alcoholic hepatitis. It is diagnosed in patients with persistent abnormal liver function tests, no evidence of hepatitis B or C, and consumption of less than 40 grams of ethanol per week. NASH is most often found in patients with obesity, type 2 diabetes, and hyperlipidemia.

Cirrhosis is the result of continuous toxic exposure that injures the liver beyond repair. Fibrous scar tissue replaces the normally soft, spongy organ, making it small and firm, with few hepatocytes capable of functioning normally. Chronic alcohol abuse is by far the most frequent factor in the development of cirrhosis. Severe ascites, bleeding disorders, encephalopathy, and sex organ changes often herald imminent liver failure and death from this disease.

In the Western world, liver cancer is most often secondary to malignancies that have spread from other sites. In Asia and Africa, primary tumors of the liver itself are much more common due to high incidences of hepatitis B infection, food toxins, and parasite infestation, among other factors. Chronic injury appears to play the critical role in liver cancer, with the main risk factors established thus far being cirrhosis, hepatitis B and C, and long-term exposure to a variety of chemicals, hormones, and drugs. Benign tumors may occur in young women who use oral contraceptives, but they are relatively infrequent.

Several other hepatic diseases warrant mention. Liver abscesses, or encapsulated areas filled with infectious material, can be caused by bacteria, fungi, or parasites. These organisms enter the bloodstream through ingestion, skin puncture, or even intestinal rupture (as in cases of appendicitis and diverticulitis) and travel to the liver. Two unusual but notable disorders of iron and copper metabolism—hemochromatosis and Wilson’s disease, respectively—have prominent liver involvement. While the disease mechanisms are not well understood, these essential metals are retained in excess and deposited in body tissues in toxic levels, causing damage. Finally, several genetic disorders of bile production run the gamut from mere nuisances to potentially fatal in infancy. Bilirubin metabolism, in which red blood cell waste products are incorporated into bile, is affected or disrupted to varying degrees. Severe jaundice reflects the accumulation of toxic levels of bilirubin in all body tissues, including the brain.

Treatment and Therapy

The diagnosis of a patient with suspected liver disease is an orderly process that begins with a thorough history and physical examination, supported by a number of valuable blood tests and imaging techniques. Liver biopsy, in which a tissue sample is obtained for microscopic analysis, is often a final and definitive procedure if the disorder remains ambiguous. Both the cause and the chronology or state of the disease—that is, whether it is of recent onset or advanced—determine treatment and outcome. While many signs and symptoms are nonspecific, including nausea, vomiting, pain, hepatic enlargement, and jaundice, others such as ascites, encephalopathy, blood-clotting defects, and sex organ changes reflect significant organ damage and an advanced stage of disease.

Careful questioning regarding the recent and past history of a patient can elicit facts that may point to a diagnosis, including exposure to known liver toxins such as alcohol, anesthetics, certain medications, and occupational chemicals; travel to countries with known contaminated water supplies (hepatitis A); blood transfusions, kidney dialysis, sexual promiscuity, or intravenous drug use (hepatitis B and C); unexplained weight loss (cancer); or even a history of gallstones (blocked bile ducts between the liver and gallbladder). Armed with suspicions from the history, the physician performs a physical examination to look for signs that confirm or reject the possibilities. A small and firm liver with ascites, tremor, enlarged male breasts, and small, shrunken testicles all point to an advanced stage of cirrhosis, for example. An enlarged and painful liver, vomiting, jaundice, and fever following recent ingestion of raw shellfish would likely suggest hepatitis A.

Blood tests play a critical role in evaluating liver disease. An elevated bilirubin level would correlate with the severity of jaundice. Blood protein levels (albumin) and blood-clotting factors (prothrombin) may be dangerously low, revealing a near inability of the hepatocytes to synthesize these vital substances. Special chemicals that exist primarily in liver cells (hepatic enzymes and the aminotransferases) may be quite high, indicating that these cells are dying and releasing their contents into the blood. Finally, elevated white blood cell counts and special tests for individual infections (viruses, bacteria, fungi, and parasites) can positively establish the diagnosis.

Depending on the suspected disease, confirmation may be needed from various imaging techniques, chosen specifically for a particular diagnosis. Plain x-rays do little to visualize the liver, although they can reveal air in the abdomen, a consequence of a perforated intestine, appendix, or ulcer. A much more advanced method, the computed tomography (CT) scan, combines computer-generated views of multiple cross-sectional x-rays, providing a highly detailed examination of the liver and thereby establishing a diagnosis in the majority of cases. Two other techniques that have more specific uses are ultrasound, which uses sound-wave transmission, and magnetic resonance imaging (MRI), which uses magnetic fields to create an image. Ultrasound can readily distinguish solid masses from those that are fluid filled (tumors versus abscesses) and can view the bile ducts. MRI is quite helpful in determining blood-flow problems such as portal hypertension.

Finally, if a precise diagnosis remains elusive, a biopsy is performed. A sample of liver tissue is obtained using a large needle inserted through the skin, under the guidance of an ultrasound image. The sample is then viewed microscopically, which should make both the cause and the extent of liver damage readily apparent.

Treatment options for the majority of liver diseases are improving. If drug toxicity is suspected, especially from alcohol, immediate withdrawal of the agent can prevent further damage, as has been shown in cases of cirrhosis. Obstructing gallstones can be surgically removed to relieve pressure in the bile ducts. Combinations of surgery, radiation, and chemotherapy are used in cases of liver cancer, but the prognosis is poor. Little can be done for the inherited diseases of bilirubin metabolism, while some success has been achieved in treating the iron- and copper-storage diseases.

Infections of viral origin have specific treatment regimens. Prevention of hepatitis A and B is possible if pooled serum immunoglobulin is given immediately after exposure. This substance is a concentrated form of antibodies obtained from infected individuals whose diseases have completely resolved; essentially, it is a method of giving passive immunity. Chronic hepatitis B may be effectively treated with several antiviral medications or interferon. Chronic hepatitis C is treated with a combination of an antiviral medication (ribavirin) and interferon. Response rates to therapy range between 50 and 80 percent, depending on the viral load, the genotype of the virus, and compliance with treatment. There are no specific therapies proven effective for treatment of NASH. Treatment is recommended for associated medical conditions, including weight loss, reduction of lipids (cholesterol and triglycerides), and control of diabetes. One area in which effective treatment does exist is in bacterial, fungal, and parasitic infections and abscesses. Appropriate antibiotics and surgical drainage yield dramatic improvement in most cases.

In many cases of liver disease, symptom relief and nutritional support, often carried out in the hospital, are the only options. Pain relief and the administration of intravenous fluid and nutrients to counteract vomiting and dehydration are the first steps. Ascites is relieved through bed rest, salt restriction, diuretics, and paracentesis, a procedure that uses ultrasound to guide a needle into the abdomen and withdraw fluid. Attempts to correct encephalopathy by removing toxins such as ammonia from the blood are generally ineffective, and mental changes, along with other intractable symptoms, often herald complete liver failure and imminent death.

Clearly, preventive measures are the most important factor in liver disease. One effective measure that is widely available is the hepatitis B vaccine, which is recommended during childhood in a three-injection series. Hepatitis A vaccine is available and recommended in children older than one year. Hepatitis A and B vaccines are recommended to any non-immune adult with chronic liver disease.

Perspective and Prospects

Liver transplantation offers approximately four thousand patients per year replacement of the diseased organ with a normal, donated one. The procedure was begun experimentally in the early 1960s, and after decades of low success rates (less than 20 percent), it has finally been accepted as a lifesaving operation, with five-year survival rates approaching 75 percent as of 2012. Technical improvements, especially intraoperative blood circulation and cadaver organ preservation, have been combined with refined patient selection and timing and advances in immunosuppressive therapy that counteract rejection. The result is that liver transplantation has become the method of choice for patients whose liver disease is life-threatening, progressive, and unresponsive to other treatments.

Specific guidelines exist for both children and adults to be considered candidates for the procedure. It is imperative that the person is otherwise healthy and that the heart, lungs, kidneys, and brain are functioning well. Malignancy, human immunodeficiency virus (HIV) infection, incorrectable congenital defects, and continuing drug or alcohol abuse are obvious contraindications. Infants with inherited, inevitably fatal liver disorders are good candidates for transplantation, as are adults with end-stage liver failure, such as from chronic hepatitis. Controversial indications, requiring case-by-case evaluation, include advanced viral hepatitis (as recurrent infection in the donated organ often occurs) and alcohol-induced cirrhosis (because of the likelihood of damage to other organs and the high relapse rate after surgery). Relapse is also very common if the transplantation is done for a primary liver cancer.

Careful donor selection is equally important. The principal source of cadaver organs is victims of head trauma who are declared brain-dead. Organs are accepted from those sixty years of age or younger who have no viral, bacterial, or fungal infections and who were otherwise healthy up to the time of death. In the United States, recipient-donor matches are made through a nationwide organ transplantation registry, with highest priority going to those most critically ill. Only twelve to eighteen hours can elapse between organ retrieval and implantation; beyond that, liver tissue begins to degenerate.

The use of immunosuppressive therapy, drugs that keep the recipient’s immune system in check, has contributed significantly to success and survival. Rejection of the transplanted organ remains one of the most feared postoperative complications, along with hemorrhaging. Because the body recognizes the organ as foreign tissue, the immune system’s white blood cells attack and damage the implanted donor liver. The use of drugs to counteract this process allows the new liver to heal and the body to adapt to the presence of foreign tissue. Despite the use of these potent drugs, which themselves have serious side effects, rejection continues to be a problem. Nevertheless, one-year survival rates are 87 percent, and at five years, 73 percent of transplant patients are alive.

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American Liver Foundation. http://www.liverfoundation.org.

Blumberg, Baruch S. Hepatitis B: The Hunt for a Killer Virus. Princeton, N.J.: Princeton University Press, 2003.

Chopra, Sanjiv. Dr. Sanjiv Chopra's Liver Book: A Comprehensive Guide to Diagnosis, Treatment, and Recovery. New York: Simon & Schuster, 2002.

Feldman, Mark, Lawrence S. Friedman, and Lawrence J. Brandt, eds. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 9th ed. 2 vols. Philadelphia: Saunders/Elsevier, 2010.

Fishman, Mark, et al. Medicine. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2004.

Goldman, Lee, and Dennis Ausiello, eds. Cecil Textbook of Medicine. 23d ed. Philadelphia: Saunders/Elsevier, 2007.

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Yamada, Tadataka, et al., eds. Textbook of Gastroenterology. 5th ed. Hoboken, N.J.: Blackwell, 2009.

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