Hepatitis

ANATOMY OR SYSTEM AFFECTED: Liver

DEFINITION: An inflammatory condition of the liver, characterized by discomfort, jaundice, and enlargement of the organ; bacterial, viral, or immunological in origin; may also result from use of alcohol and other drugs

CAUSES: Bacterial or viral infection; immunological disorder; liver damage from alcohol, drug overdose, or poison

SYMPTOMS: Jaundice, liver enlargement, bloating, discomfort, fatigue, low-grade fever, nausea and vomiting, loss of appetite, weight loss, dark urine or pale stools

DURATION: Ranges from short-term to chronic

TREATMENTS: Antibiotics, hospitalization

Causes and Symptoms

Hepatitis, an inflammation of the liver, may result from any of a variety of causes but commonly follows bacterial or viral infection. Hepatitis may be associated with an autoimmune phenomenon in which the body produces antibodies against liver tissue. Liver inflammation may also be an aftereffect of the use of alcohol or various hepatotoxic chemicals, either through the taking of illegal drugs or as a side effect of prescription pharmacological agents. Among the pharmaceuticals that can cause liver damage are antibiotics such as isoniazid and sulfa drugs, the painkiller acetaminophen, tetracyclines, and anabolic steroids.

Symptoms associated with hepatitis are a reflection of the function of the liver. The liver is arguably the most complex organ in the body. More than five hundred different functions have been associated with the organ, including the production of bile for emulsification of fats and the secretion of glucose, proteins, or vitamins for use elsewhere in the body. The liver plays a major role in the detoxification of the blood, removing alcohol, nicotine, and other potentially poisonous substances. The Kupffer cells in the liver function in the removal of infectious agents or foreign material from the blood. More than 10 percent of the blood supply in the body is found within the liver at any time.

Among the functions of the liver is the removal of hemoglobin in the blood, which is released as a result of the lysis (disintegration) of red blood cells. A breakdown product of hemoglobin is the yellowish compound bilirubin. It is the buildup of bilirubin in blood that results in the appearance of jaundice in cases of inadequate liver function, such as during hepatitis.

Although hepatitis may develop from a variety of causes, it most commonly results from infection of the liver. Nearly any infectious agent may potentially damage the liver, but generally these involve one of several types of viruses, bacteria, parasites, fungi, or amoebas. Liver disease may also be significantly exacerbated by alcohol abuse, as is seen in patients with cirrhosis. Regardless of the specific cause, symptoms of liver disease remain similar in most cases. The liver is often enlarged and tender to physical examination. The person may feel tired and run a low-grade fever. It is not unusual for the person to feel nauseous and lose weight. Jaundice is common in most patients; the concentrations of the enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) may rise. Levels of these enzymes, however, are not necessarily indications of the severity of liver disease; in any event, their levels often fall over the course of the disease.

Three particular viruses have been associated with most forms of viral hepatitis (hepatitis viruses A, B, and C), while a fourth (type D) appears as a passenger during some cases of hepatitis B. Several additional viruses, designated hepatitis E (HEV) through hepatitis G (HGV), have also been linked to forms of the disease. Hepatitis A results from infection with the hepatitis A virus (HAV), a virus classified in the same group as the poliovirus and rhinoviruses (cold viruses). The disease is transmitted through a fecal-to-oral method and is self-limited (running a definite and limited course). Often the disease is subclinical (undetectable), particularly as seen in children. Replication of the virus occurs in hepatocytes (liver cells); the virus then passes into the intestine and is eliminated with the feces. A long incubation period following ingestion may occur, sometimes as long as one month, and during the incubation period, the person is capable of transmitting the disease. In otherwise healthy individuals, recovery is complete and occurs over several weeks. Anti-HAV antibodies are present in the blood of about 30 to 40 percent of the general population, reflecting the widespread nature of the disease.

Hepatitis B (HBV), formerly called serum hepatitis, is a potentially much more severe form of the disease. The disease in young children is frequently asymptomatic, with the appearance of symptoms in older individuals being more common. In general, however, the most frequent result of primary infection with HBV is a mild or subclinical course of infection. The disease is most commonly seen in patients aged fifteen to thirty-five years, in part reflecting its method of transmission (through blood or body fluids).

Persistent infection with HBV, occurring in approximately 1 to 3 percent of patients, can be associated with either an asymptomatic carrier state or chronic hepatitis. The chronic state may be severe, with progression to cirrhosis and cellular degeneration or inflammation. In fact, it is the immune response to the presence of HBV that may contribute to liver degeneration. HBV infection results in the expression of viral antigens, which stimulate an immune response on the surface of liver cells. Among the inflammatory cells present at the sites of infection are a large proportion of lymphocytes. These include cytotoxic T cells, which are lymphocytes associated with the killing of virally infected cells. Because immunologically impaired individuals infected with HBV often suffer a mild form of the disease, the possibility exists that it is the immune response itself that contributes to the ensuing liver damage.

Hepatitis B transmission occurs through blood or bodily fluids, including semen and vaginal secretions. Because HBV is also found in saliva, the disease may be transmitted among family members through nonsexual contact. Maternal-neonatal transmission may occasionally occur while the fetus is in the uterus but more likely during the labor or birth process. There is, however, no evidence for transmission through food or water or by an airborne means.

Clinical features of HBV infections are similar to those associated with other forms of hepatitis. In the asymptomatic form of type B disease, AST or ALT levels may be elevated, but jaundice is absent. Adults with symptomatic hepatitis B may suffer jaundice (referred to as icteric hepatitis), or they may not (nonicteric hepatitis). There is generally a mild fever, fatigue, and weakness.

Accompanying an indeterminant number of HBV infections is a second virus, designated the hepatitis D virus (HDV). HDV is a defective virus and is capable of replication only in the presence of HBV. Not surprisingly, its geographic distribution and mode of transmission are similar to those of HBV. The prevalence of HDV has been found to be as high as 60 percent in some outbreaks of HBV and nonexistent in others. In most cases, HDV infection results in subclinical or mild hepatitis. In fewer than 5 percent of cases, the disease may progress to a chronic form. HDV may itself be cytopathic (causing pathological changes) for hepatocytes. In 70 to 90 percent of co-infections with chronic HBV, HDV increases disease severity and speeds cirrhosis development.

Based on the exclusion of other types of etiologic agents, including HAV, HBV, Epstein-Barr virus, and cytomegalovirus, non-A, non-B (NANB) hepatitis was considered a clinical entity. During the late 1980s, NANB hepatitis was determined to be caused by a newly isolated infectious agent, designated hepatitis C virus (HCV). The study of HCV was hampered by the inability to grow the virus in cell culture. Ironically, the virus was cloned and characterized before it was even physically observed, allowing for the development of a screening assay used for the detection of contaminated serum. Before screening procedures were put into place in 1992, HCV infection was the major complication of blood transfusions or transfusions of blood products. Infection now occurs primarily through sexual intercourse, the sharing of intravenous needles, and accidental needle punctures among healthcare workers. HCV has been increasingly recognized as a major health threat. HCV and HBV are among the leading causes of liver cancer in the world. HAV creates serious liver damage and is the leading cause of liver transplants. It is all the more dangerous because patients are often asymptomatic and learn of the infection when their blood is screened for other reasons. As a result, many people are unknowing carriers of the virus.

Outbreaks of an enterically transmitted NANB hepatitis (NANB hepatitis transmitted through the intestines), designated hepatitis E, have also been found in some parts of the world. Although hepatitis E was first documented in 1955, it was not until the late 1980s that it was determined to be a unique form of the disease. Transmission occurs through eating or drinking contaminated food or water, though there is evidence that household contact with infected persons may also transmit the disease. Hepatitis E is most common in East and South Asia, with sporadic outbreaks elsewhere. The few cases found in the United States have involved travelers to these areas.

Acute hepatitis is less commonly associated with infection by other viruses. These include the herpes family of viruses, such as herpes simplex, cytomegalovirus, and Epstein-Barr virus. Because the prevalence of these viruses is quite high, immunosuppressed or immunodeficient patients may be at particular risk.

Certain forms of hepatitis are associated with an autoimmune response. In these cases, the cause is not an infectious agent but rather a form of rejection by the body of its own liver tissue. Autoimmune hepatitis is suspected in individuals in which the disease persists for at least six months with no evidence of exposure to an infectious agent or hepatotoxin. In nearly one-third of these individuals, other immunological diseases such as lupus or arthritis may be present. The clinical manifestations of autoimmune hepatitis are similar to those of other forms of the disease. Most patients exhibit jaundice, a mild fever, weakness, and weight loss. The liver is often enlarged and tender. Unlike other forms of hepatitis, found equally in men and women, autoimmune hepatitis is most commonly found in women. Prognosis of the disease is unclear, as an unknown percentage of cases are subclinical. Severe forms have a high fatality rate.

Treatment and Therapy

Treatment for the various forms of viral hepatitis is, for the most part, symptomatic and supportive. Hospitalization may be required in severe cases, but, in general, any restriction of activity is left up to the patient. Recovery often involves a long convalescence. As long as a healthy diet and adequate hydration is maintained, no special dietary requirements exist, but a high-calorie diet is often preferable. Drugs or chemicals that are potentially damaging to the liver, including alcohol and certain antibiotics or painkillers, should be avoided.

Hepatitis induced by other forms of infectious agents such as bacteria or fungi may be treated using an appropriate course of antibiotic therapy. In cases of drug-induced disease, avoidance of the chemical is a key to recovery. Bacterial infections of the liver are often associated with patients who are malnourished, such as the elderly or alcoholics, or who may be immunosuppressed. These problems must also be addressed during the course of treatment.

Prevention of the disease is preferable, however, and because the means of viral spread has been well established in most cases, appropriate measures can often be taken. For the most part, the viruses associated with hepatitis have little in common with one another aside from their predilection for hepatocytes. Thus, preventing their spread involves different strategies.

HAV is almost always spread through a fecal-oral means of transmission. Often the source is an infected person involved in the preparation of uncooked foods. Common sense dictates that the person should wash after every use of a toilet, but this is often not the case. Not surprisingly, children attending day-care centers frequently become infected. Contaminated groundwater is also a potential source of outbreak in areas in which proper sewage treatment does not take place. Less commonly, HAV is spread directly from person to person through sexual contact. A method called immunoprophylaxis can prevent the development of symptoms in individuals exposed to hepatitis A by utilizing a form of passive immunity. Developed during World War II, the procedure involves the pooling of serum from immune individuals. In most cases, inoculation is effective in prevention of the disease. Management of HAV includes avoidance of alcohol and acetaminophen, rest, and adequate nutrition and hydration. Oral corticosteroids may also be used.

In 1994, SmithKline Beecham Pharmaceuticals developed and received approval from the US Food and Drug Administration (FDA) for the first vaccine shown to be safe and effective in preventing HAV infection. Manufactured under the trade name Havrix, the vaccine consists of a formalin-inactivated strain of HAV to be administered in three doses to children. In 1996, a similar vaccine was developed by Merck to be sold under the trade name Vagta. In 2001, a combined hepatitis A and hepatitis B vaccine was developed and approved in the United States for use in individuals eighteen and older. It is given in three doses over a period of six months. In 2002, the US Centers for Disease Control and Prevention (CDC) recommended that any individuals at risk for hepatitis A infection or those at risk for becoming seriously ill if infected should receive immunization against the virus.

The transmission of HBV generally involves passage via contaminated blood or body secretions. Before blood screening was standard procedure, blood transfusions were the most common means of spreading the disease—hence the designation “serum hepatitis.” Since the 1980s, however, the most common means of documented spread has been through either sexual contact or through the sharing of contaminated hypodermic needles. Semen, vaginal secretions, and saliva from infected individuals all contain the active virus, and limiting exchange of these fluids is key to prevention of transmission. Even so, the means of infection in nearly one-third of symptomatic cases remains unknown.

In 2002, the CDC recommended that certain groups of individuals who are at high risk for exposure to HBV be vaccinated against the virus: children (newborn to eighteen years old), intravenous drug users, sexually active individuals, healthcare workers, and those in contact with hepatitis B-infected individuals. It was also recommended that those who would become seriously ill if they contracted the virus be vaccinated: newborns, individuals with hemophilia, those with any chronic liver disease, and those waiting for a liver transplant.

HBV medications do not eradicate the virus and have limited long-term efficacy; however, medications for the treatment of HBV include interferons such as peginterferon alfa-2a and interferon alfa-2a and nucleoside or nucleotide analogs such as entecavir and tenofovir.

Because the hepatitis D virus is defective in replication and requires the presence of HBV, no specific measures of prevention are necessary. Immunization against HBV is sufficient to prevent the spread of HDV.

HCV is treated with antiviral agents, such as sofosbuvir, ribavirin, and peginterferon-alfa. Abstinence from smoking and alcohol is recommended, as well as vaccination against hepatitis A and B. Patients with active HCV infection should receive education to help reduce progression of liver disease and to prevent transmission of HCV.

Hepatitis E is also transmitted through a fecal-oral route. Drinking water contaminated by sewage has been the most common source of transmission. Because no active means of prevention has been developed, prevention of exposure requires that the individual avoid any food or water potentially contaminated with sewage. This is particularly true in areas of the world in which hepatitis E is found. Though the precaution may seem obvious, the safety of the water, as well as any object washed in the water, is not always readily apparent.

Autoimmune hepatitis results from an aberrant immune system rather than from an infectious agent. Pretreatment with vaccination against hepatitis A and B is recommended. Treatment generally involves the use of immunosuppressive drugs to limit the immune response. Corticosteroids such as prednisone, often taken in combination with azathioprine, have proven effective in the therapy of many patients. Treatment generally is carried out over a long period of time, at least a year, and relapses are common. Often, the patient requires lifetime therapy. The immunosuppressive activity of the therapy may also leave the patient more susceptible to infection. Adjunctive therapies for bone disease due to immunosuppression include vitamin D, calcium, and bisphosphonates. In some cases, liver transplantation has proven effective, at least in the short term. Because the liver rejection was caused by an autoimmune response in the first place, the transplant may also be subject to the same phenomenon.

Perspective and Prospects

Inflammation of the liver resulting in hepatitis can develop from a variety of mechanisms. Most often, these mechanisms are associated with either a chemical injury or infection by a microbiological agent.

Infections of the liver generally involve one of several viral agents. The association of liver disease, or at least jaundice, with an infectious agent was suspected as early as the fifth century BCE when Hippocrates described a syndrome that was undoubtedly viral hepatitis. The disease was also described in the Babylonian Talmud about eight hundred years later. Epidemics of the disease, which most likely involved outbreaks of hepatitis A, have been reported since the Middle Ages. The spread of this disease through personal contact was confirmed in the 1930s.

Hepatitis B was described as a clinical entity by A. Lurman in 1855. Lurman observed that 15 percent of shipyard workers in Bremen, Germany, who received a smallpox vaccine containing human lymph developed jaundice within the following six months. In the early years of the twentieth century, jaundice frequently developed among patients who received vaccines prepared from convalescent serums or who underwent procedures such as venipuncture using instruments that had not been properly sterilized. By 1926, the blood-borne nature of the disease had been confirmed. In 1942, more than twenty-eight thousand American soldiers developed jaundice after being vaccinated against yellow fever with a vaccine prepared from pooled human serums. By then it had become obvious that at least two forms of infectious agents were associated with viral hepatitis.

The isolation of HBV occurred as a result of studies initiated by Baruch Blumberg in 1963. Blumberg was actually attempting to correlate the development of diseases such as cancer with particular patterns of proteins found in the serum of individuals. His approach was to collect blood from persons in various parts of the world and then analyze their serum proteins. Blumberg found an antigen, a protein, in the blood of Indigenous Australians that reacted with antibodies in the blood of an American with hemophilia. Blumberg called the protein the Australia (Au) antigen. It later became apparent that the Au antigen could be isolated from the blood of patients with serum hepatitis. By 1970, it was established that what Blumberg had referred to as the Au antigen was in fact the HBV particle.

HBV is associated with more than simply viral hepatitis. Chronic hepatitis associated with HBV can often develop into hepatocellular carcinoma, or cancer of the liver. The precise reason remained unclear; the cancer may result from the chronic damage to liver tissue associated with long-term infection by HBV.

Cases of HCV continued to climb because of the high numbers of asymptomatic carriers. According to the World Health Organization (WHO), in 2022 58 million people worldwide had chronic HCV infection, and 290,000 people died from hepatitis C–related liver diseases in 2019. The WHO also reported that in 2019 296 million people were infected with chronic hepatitis B and some 820,000 died of the disease. In 2022, concerns grew in the medical field when there were reports of a large number of children in areas throughout the world being diagnosed with probable cases of severe acute hepatitis of unknown origin. The outbreak was initially detected in the United Kingdom in January of that year, and by July, the WHO was reporting that thirty-five countries had experienced over one thousand total probable cases. The consequences of the outbreak were serious; twenty-two children died and forty-six needed a liver transplant. Scientists focused on identifying a cause of the outbreak, largely in children five years old and younger, with UK researchers presenting findings in July indicating potential connections to the COVID-19 pandemic's disruption to children's exposure and immunity to various viruses. While the cause of the outbreak was still being investigated in 2024, health orricials believed that because of COVID-19 lockdowns, children were exposed to multiple viruses for the first time, as a wave of adenovirus preceded the pediatric hepatitis in some cases.

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