Hepatitis and hepatitis viruses

Hepatitis is inflammation of the liver, a potentially life-threatening disease most frequently caused by viral infections but which may also result from liver damage caused by toxic substances such as alcohol and certain drugs. Hepatitis viruses identified to date occur in six major types: hepatitis A HAV), hepatitis B (HBV), hepatitis C (HCV), hepatitis D (HDV), and hepatitis E (HEV) and hepatitis G (HGV). All types are potentially serious and, because clinical symptoms are similar, positive identification of the infecting strain is possible only through serologic testing (analyzing the clear, fluid portion of the blood). Symptoms may include a generalized feeling of listlessness and fatigue, perhaps including mental depression, nausea, vomiting, lack of appetite, dark urine and pale feces, jaundice (yellowing of the skin), pain in the upper right portion of the abdomen (where the liver is located), and enlargement of both the liver and the spleen. Severe cases of some types of hepatitis can lead to scarring and fibrosis of the liver (cirrhosis), and even to cancer of the liver.

Epidemics of liver disease were recorded as long ago as Hippocrates' time and, despite major advances in diagnosis and prevention methods over the past two decades, viral hepatitis remains one of the most serious global health problems facing humans today.

The incidence and spread of HAV is directly related to poor personal and social hygiene and is a serious problem not only in developing countries where sanitation and water purification standards are poor, but also in developed, industrialized nations, including the United States, where it accounts for 30% of all incidences of clinical hepatitis. Except in one to four percent of cases where sudden liver failure may result in death, chronic liver disease and serious liver damage very rarely develop, and "chronic carrier state," in which infected people with no visible symptoms harbor the virus and transfer the disease to non-infected individuals, never occurs. Also, reinfection seldom develops in recovered HAV patients because the body eventually develops antibodies, cells which provide a natural immunity to the specific virus attacking the host. Although HAV is self-limiting (after time, ends as a result of its own progress), there is as yet no effective treatment once it is contracted.

Apart from the symptoms described above, HAV commonly produces a medium-grade fever, diarrhea, headaches, and muscle pain. The primary route of HAV transmission is fecal-oral through ingestion of water contaminated with raw sewage, raw or undercooked shell-fish grown in contaminated water, food contaminated by infected food handlers, and close physical contact with an infected person. Heterosexual and homosexual activities with multiple partners, travel from countries with low incidences to countries with high rates of infected population, and, less frequently, blood transfusions and intravenous drug use also spread infection.

During the infectious stage, large numbers of viruses are eliminated with the stool. Although HAV infection occurs in all age groups, high rates of disease transmission occur in day-care centers and nursery schools where children are not yet toilet trained or able to wash their hands thoroughly after defecating. The disease may then be transmitted to day-care workers and carried home to parents and siblings. In areas of the world where living quarters are extremely crowded and many people live in unhygienic conditions, large outbreaks of HAV threaten people of all ages. Because during the viruses'incubation period—from 14 to 49 days—no symptoms are observable, and because symptoms seldom develop in young children, particularly those under the age of two, the disease is often unknowingly but readily transmitted before infected people can be isolated.

A vaccine against HAV is available. It appears to provide good protection, if the first immunization has been received at least four weeks prior to exposure. For adults, two immunizations about 6 months apart are recommended; for children, three immunizations are necessary (two a month apart, and the third six months later). High-risk groups who should receive HAV vaccine include child care workers, military personnel, Alaskan natives, frequent travelers to HAV endemic areas, laboratory technicians where HAV is handled, people who work with primates. The immunization lasts for 20 years.

If someone who is unimmunized is exposed to HAV, or if a traveler cannot wait four weeks prior to departure for an HAV endemic area, then immune globulin may be utilized to avoid infection. Immune globulin is a naturally occurring substance harvested from the plasma in human blood, then injected into an individual exposed to the HAV. Immune globulin prevents disease development in 80–90% of cases in clinical trials. It also seems to be effective in reducing the number of cases normally expected after outbreaks in schools and other institutions. As yet, the most effective control mechanisms are public education regarding the importance of improved personal hygiene, which in many instances is as simple as washing hands thoroughly after using the toilet and before handing food, and concerted worldwide efforts to purify water supplies (including rivers and oceans) and improve sanitation methods.

Acute HBV is currently the greatest cause of viral hepatitis throughout the world. World Health Organization figures released in 1992 indicate that as many as 350 million people worldwide carry the highly infectious HBV. Because of its severity and often lengthy duration, 40% of those carriers—possibly as many as two million per year—will eventually die from resultant liver cancer or cirrhosis. HBV-related liver cancer deaths are second only to tobacco-related deaths worldwide. Infected children who survive into adulthood may suffer for years from the damage caused to the liver. In the United States alone, as many as 300,000 people become infected with HBV every year, medical costs amount to more than $1 million per day, and the death rate over the last 15 or so years has more than doubled in the United States and Canada.

If serology (blood) tests detect the presence of HBV six months or more from time of initial diagnosis, the virus is then termed "chronic." Chronic persistent hepatitis may develop following a severe episode of acute HBV. Within a year or two, however, this type usually runs its course and the patient recovers without serious liver damage. Chronic active hepatitis also may follow a severe attack of acute HBV infection, or it may simply develop almost unnoticed. Unlike persistent hepatitis, the chronic active type usually continues until fatal liver damage occurs. In long-term studies of 17 patients with chronic active hepatitis, 70% developed cirrhosis of the liver within two to five years.

Symptoms are similar to those manifested by HAV and may include weight loss, muscle aches, headaches, flu-like symptoms, mild temperature elevation, and constipation or diarrhea. By the time jaundice appears, the patient may feel somewhat better overall but the urine becomes dark, stools light or yellowish, the liver and possibly the spleen enlarged and painful, and fluid may accumulate around the abdominal area. Early in the disease's life, however, symptoms may be very slight or even virtually nonexistent, particularly in children, facilitating infection of others before isolation is implemented.

The incubation period for HBV varies widely—anywhere from four weeks to six months. Primary routes of transmission are blood or blood product transfusion; body fluids such as semen, blood, and saliva (including a bite by an infected human) organ and/or tissue transplants; contaminated needles and syringes in hospitals or clinical settings; contaminated needles or syringes in illegal intravenous drug use; and vertical transmission—from mother to baby during pregnancy, birth, or after birth through breast milk. Even though they may not develop symptoms of the disease during childhood, and will remain healthy, almost all infected newborns become chronic carriers, capable of spreading the disease. Many of these infected yet apparently healthy children, particularly the males, will develop cirrhosis and liver cancer in adulthood. Where the incidence of the disease is relatively low, the primary mode of transmission appears to be sexual and strongly related to multiple sex partners, particularly in homosexual men. In locations where disease prevalence is high, the most common form of transmission is from mother to infant.

Controlling HBV infection is an overwhelming task. In spite of the development of safe and effective vaccines capable of preventing HBV in uninfected individuals, and regardless of programs designed to vaccinate adults in high-risk categories such as male homosexuals, prostitutes, intravenous drug users, health-care workers, and families of people known to be carriers, the disease still remains relatively unchecked, particularly in developing countries.

Although effective vaccines have been available since the mid-1980s, the cost of mass immunization world-wide, and particularly in developing countries, was initially prohibitive, while immunizing high-risk adult populations did little to halt the spread of infection. Authorities now believe the most effective disease control method will be immunization of all babies within the first weeks following birth. Concerted efforts of researchers and health authorities worldwide, including the foundation in 1986 of an International Task Force for Hepatitis B Immunization are investigating various avenues for providing cost-effective, mass vaccination programs. These include incorporating HBV vaccination into the existing Expanded Program of Immunization controlled by the World Health Organization. Methods of cost containment, storing the vaccine, and distribution to midwives in remote villages (60% of the world's births occur at home), have been designed and are continually being refined to ultimately attain the goal of universal infant immunization. This will not only drastically decrease the number of babies infected through vertical transmission (which constitutes 40% of all HBV transmission in Asia), preventing them from becoming adult carriers, it also provides immunity throughout adulthood.

Finding an effective treatment for those infected with HBV presents a major challenge to researchers—a challenge equal to that posed by any other disease which still remains unconquered. And HBV may present yet another challenge: mutant forms of the virus seem to be developing in resistance to the current vaccines, thus finding a way to survive, replicate and continue its devastating course. Necessary measures in disease control include: education programs aimed at health care workers to prevent accidental HBV transfer—from an infected patient to an uninfected patient, or to themselves; strict controls over testing of blood, blood products, organs, and tissue prior to transfusion or transplantation; and the "passive" immunization with immunoglobulin containing HBV antibodies as soon as possible after exposure to the active virus. Treatment with Interferon and new drug, Lamivudine, have shown positive results in managing HBV.

Relatively recently discovered hepatitis viruses, often called non-A, non-B hepatitis, exist in more than 100 million carriers worldwide, with 175,000 new cases developing each year in the U.S. and Europe.

Not until 1990 were serology tests available to identify the hepatitis C virus (HCV). Research since then has determined that HCV is distributed globally and, like HBV, is implicated in both acute and chronic hepatitis, as well as liver cancer and cirrhosis. Eighty-five percent of all transfusion-related hepatitis is caused by HCV, and mother-baby and sexual transmission are also thought to spread the disease. Symptoms are similar but usually less severe than HBV; however, it results in higher rates of chronic infection and liver disease.

Control and prevention of HCV is a serious problem. First, infected people may show no overt symptoms and the likelihood that infection will become chronic means that many unsuspecting carriers will transmit the disease. Second, HCV infection does not appear to stimulate the development of antibodies, which not only means infected people often become reinfected, it creates a major challenge in the development of an effective vaccine. Third, HCV exists in the same general high-risk populations as does HBV. Combined, these factors make reducing the spread of infection extremely difficult. On a positive note, the development of accurate blood screening for HCV has almost completely eliminated transfusion-related spread of hepatitis in developed countries. Immunoglobulin injections do not protect people who have been exposed to HCV; the search is on for an adequate immunization, although this effort is hampered by characteristics of HCV, which include rapid mutation of the virus. Treatment with interferon remains the most effective measure in managing the long term effects of HCV.

Undiscovered until 1980, Hepatitis E virus (HEV) is thought to transmit in a similar fashion to HAV. HEV is most prevalent in India, Asia, Africa, and Central America. Contaminated water supplies, conditions that predispose to poor hygiene (as in developing countries), and travel to developing countries all contribute to the spread of HEV. Symptoms are similar to other hepatitis viruses and, like HAV, it is usually self-limiting, does not develop into the chronic stage, and seldom causes fatal liver damage. It does seem, however, that a higher percentage of pregnant women (from 10–20%) die from HEV than from HAV.

Research into the virus was slow because of the limited amounts which could be isolated and collected from both naturally infected humans and experimentally infected primates. Recently, successful genetic cloning (artificial duplication of genes) is greatly enhancing research efforts. Surprisingly, research found that antibodies exist in between one to five percent of people who have never been infected with hepatitis. Until an effective vaccine is developed, sanitation remains the most important factor in preventing the spread of HEV.

Because it is a "defective" virus requiring "coinfection" with HBV in order to live and reproduce, HDV alone poses no threat in the spread of viral hepatitis. It also poses no threat to people vaccinated against HBV. However, when this extremely infectious and potent virus is contracted by unsuspecting carriers of HBV, rapidly developing chronic and even fatal hepatitis often follows. The coexistent requirements of HDV as yet remain unclear. Research into development of an effective vaccine is ongoing, and genetic cloning may aid in this effort.

Little is currently known about a relatively recently discovered hepatitis virus, G. HGV appears to be passed through contaminated blood, as is HCV. In fact, many infections with HVG occur in people already infected with HCV. HGV, however, does not seem to change the disease course in people infected with both HCV and HGV. In cases of isolated HGV infection, little liver injury is noted, and there does not appear to be a risk of chronic liver injury. Much more information must be sought about this particular hepatitis virus, and its risks.

See also Epidemics, viral; Interferon actions; Public health, current issues; Viruses and responses to viral infection