What is hepatitis?

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 70 percent in some outbreaks of
HBV and nonexistent in others. In most cases, HDV infection results in subclinical
or mild hepatitis. In about 15 percent of cases, the disease may progress to a
more severe form. HDV may itself be cytopathic (causing pathological changes) for
hepatocytes.

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 health care workers. HCV has been
increasingly recognized as a major health threat, and HCV and HBV together are the
leading cause of liver cancer in the world, accounting for more than 75
percent of cases. HAC 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 low-income countries of
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 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 Centers for Disease Control 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 heterosexuals and homosexual men, 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 Australian Aborigines 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 is unclear; the cancer may result from the chronic
damage to liver tissue associated with long-term infection by HBV.

Cases of HCV continue to climb because of the high numbers of asymptomatic
carriers. According to the World Health Organization (WHO), 130 to 150 million
people worldwide have chronic HCV infection, and 350,000 to 500,000 people die
each year from hepatitis C–related liver diseases. The WHO also reports that more
than 780,000 people die annually due to hepatitis B and estimates that there are
1.4 million cases of hepatitis A each year. According to the WHO, an estimated 57
percent of cases of liver cirrhosis and 78 percent of cases of primary liver
cancer result from hepatitis B or C viral infection.

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