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Indian Journal of Medical Sciences
Medknow Publications on behalf of Indian Journal of Medical Sciences Trust
ISSN: 0019-5359 EISSN: 1998-3654
Vol. 57, Num. 8, 2003, pp. 363-368
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Indian Journal of Medical Sciences, Volume 57, Number 8, August 2003, pp.
363-368
Practitioners Section
VIRAL HEPATITIS (Part - I)
D D Banker
Correspondence: D. D. Banker, Consultant Pathologist, Mumbai, India.
Accepted Date: 01-07-2003
Code Number: ms03015
HISTORICAL
During the first half of 20th century viral etiology of hepatitis was established.
Viral hepatitis causes a set of typical clinical biochemical and histological
changes with or without icterus resulting from hepatic cell damage. It may
be acute or chronic. It is a global disease of major public health importance.
At a current estimate more than 300 million people worldwide suffer from viral
hepatitis. Nearly 300 deaths per year attributed to fulminant acute disease
and some 15,000 persons succumb each year to chronic liver disease. The acute
form causes considerable morbidity and mortality and the chronic sequelae may
play a havoc resulting in liver cirrhosis and hepatocellular carcinoma (HCC).
Viral hepatitisis thus a major public health problem in all parts of the world.
The disease has an enormous impact on health and national economy of many countries
including India.1-3
At least five etiological agents alphabetically named A, B, C, D and E have
definitely been recognized while putative agents F and G have also been described.
Candidate virus F is no longer accepted as hepatotrophic. However it has been
associated with some sporadic and parenteral acute cases and may give rise
to fulminant hepatitis with liver failure requiring transplantation.4,6 Hepatitis
G virus (HGV) is widely distributed among people who have received multiple
transfusions and among IV drug abusers.
It is also found in association with HBV and HCV.5-8 Recently
TTV (Transfusion Transmitted Virus) and SEN virus have been incriminated with
some
cases of viral hepatitis.9-13 Other viruses causing hepatitis
are those of yellow fever, infectious mononucleosis, cytomegalovirus, parvovirus
B 19, herpes simplex and rubella, the last two particularly in the newborn.5,13,14 These
are not considered to be `hepatitis viruses' because the infection is not
confined only to liver. Infectious mononucleosis also called glandular fever
is due
to Epstein-Barr virus, a member of herpes group. It is characterized by acute
fever, sore throat, generalized lymphadenopathy splenomegaly and sometimes
hepatitis. Epstein Barr (EB) virus causes rise in liver enzymes in almost
all cases of acute infection, but it is uncommon for the liver injury to
be sufficiently
severe to cause jaundice. When jaundice does occur in EB virus infection
it may be prolonged with a large cholestatic element. Diagnosis can be made
by
typical symptoms and specific serologic tests. Cytomegalovirus infection
may also cause acute hepatitis. This is uncommon, rarely severe and runs
a chronic
course only in immuno-compromised patients. 5,14
Epidemic infective jaundice has been a major problem for centuries, particularly
in military campaigns. It was long thought to be due to catarrhal inflammation
of bile ducts. Its viral origin had been suspected in the 1930s but was not
proved until during and after the Second World War by studies in human volunteers.
The previous catarrhal jaundice was then named viral hepatitis A (HA). By then
a second category of infective hepatitis was identified, particularly following
serum administration and also in diabetic and venereal clinics. Initially termed
homologous serum jaundice in 1943, it later became known as viral hepatitis
B (HB). The causal role of inadequately sterilized syringes was first appreciated
by British Scientist F. O. MacCallum in the same year. The next big forward
step was the discovery in 1965 by Blumberg in USA of the so-called Australia
Antigen, now known as hepatitis B surface antigen (HBsAg). It was a pure basic
scientific study leading on to findings of major practical and clinical importance.
An antigen found in the blood of an Australian aborigine being investigated
for leukemia was found to be linked with hepatitis B but not with hepatitis
A. this discovery was followed by electron-microscopic identification of viral
particles in the blood of hepatitis patients by Bayer in 1968 in USA. At that
time a third clinical category of non A- non B hepatitis was formed which included
those cases where no cause could be detected. Research continued into epidemiological
background of viral hepatitis and in successful transmission of virus into
chimpangees. Vaccines against hepatitis B and later against hepatitis A were
developed. Viruses C, D and E were identified which reduced the number of hepatitis
cases of unknown etiology to only about 10 percent. Candidate viruses which
are being investigated for this are F, G, SEN viruses and TTV, as stated earlier.
CLINICAL FEATURES
Acute viral hepatitis is a systemic infection that predominantly affects liver.
In most cases the virus does not damage hepatocytes, liver damage and subsequent
clinical symptoms are generally due to host's response to infection. The clinical
features of infection with various hepatitis viruses are similar and laboratory
investigations are required to identify the responsible virus. From
asymptomatic and subclinical infection, the symptoms may present anicteric
form of disease, acute illness with jaundice, severe prolonged jaundice, subacute
or chronic hepatitis and acute fulminant hepatitis. Besides chronic hepatitis,
the sequelae include liver cirrhosis and primary hepatocellular carcinoma (HCC),
particularly with hepatitis B, C, and D viruses.5,14,15
The chief serological manifestation in acute hepatitis is elevated level of
the enzyme alanine aminotransferasse (ALT or formerly called SGTP). Sometimes
the ALT activity may be 100 times normal. For specific diagnosis other serological
markers are needed, as described below for each virus.
Acute hepatitis is defined as one in which clinical and biochemical abnormalities
are present for up to 6 months. The viral infection produces severe inflammation
of liver and in acute stage, symptoms include anorexia, nausea, vomiting, tremendous
weakness and fatique, abdominal pain, mild fever, jaundice, dark urine and
clay coloured stools. Signs include yellow discolouration of sclera, enlarged
tender liver and often splenomegaly. Hepatitis A and E viruses are cleared
from the body within 6 months, while B, C, and D may persist longer, leading
to chronic hepatitis, liver cirrhosis and HCC. In the last 50 years liver biopsies
and better epidemiological and virological methods have helped to establish
the different types of liver diseases. Types A, B, and D can already be prevented
by use of vaccines. Development of vaccines against types C and E will greatly
improve preventive measures against these infections.5,7,16
PATHOLOGICAL FEATURES OF ACUTE VIRAL HEPATITIS
Acute injury to liver shows similar morphology whatever may be the etiology.
There is two-fold
mechanism involved in causing damage
i) The virus may have direct cytopathogenic effect on liver parenchyma,
ii) Immunological attack on liver cells by cytotoxic T cells. Hepatomegaly
is due to swelling of liver cells, portal tract expansion and infiltration
by inflammatory cells. The three basic histological features are : hepatocellular
injury, inflammatory cell infiltrate chiefly by mononuclear cells and hepatocyte
regeneration. In mild cases there may only be focal necrosis of liver cells
while in severe cases there may be widespread destruction of liver cells. Hepatocyte
regeneration occurs early in infection and hyperplasia and hypertrophy are
seen in surviving cells. The liver quickly recovers from the acute injury.5,14,15
HEPATITIS A (HA)
This infection is present worldwide and is inversely proportional to the levels
of environmental sanitation and personal hygiene. In developing countries like
India where sanitation and hygiene are unsatisfactory specially among those
belonging to lower socioeconomic group, nearly 100 per cent of the population
is infected as shown by presence of antibodies in early life and manifest infection
in adults is rare. In developed countries e.g. USA only about 40% of population
have antibodies and are thus susceptible to HAV infection.5,14
CLINICAL FEATURES
HAV is classified under the genus Hepatovirus within the picornaviridae family.
HAV produces liver cell damage by direct cytopathic effect. Many infections
are silent especially in young children. Usually the course is mild. The incubation
period is 14 to 42 days. HAV first multiplies in intestines and then enters
liver where it causes necrosis.
Viremia precedes clinical symptoms and during this incubation period feces
and blood are potentially infectious. If jaundice is severe it may be accompanied
by itching. Mortality in young adults is upto 1% but it increases with age.
Death is due to fulminant hepatic necrosis. The important features of HA
are :
i) Chronic hepatitis is rare
ii) Infection with HAV confers lifelong immunity. 5,14,15
The HA infection formerly called infectious hepatitis is benign. Many children
have a mild or subclinical infection without jaundice. The mortality rate in
children is less than 0.1 percent, the disease is self-limited and does not
become chronic. In developed countries the disease with jaundice may occur
in young adults who lack immunity and who are not careful about food and water,
when they travel to endemic areas. Only one serotype of HAV is known. HA viremia
is relatively brief with maximal infectivity occurring prior to clinical symptoms.
Severity of HA varies with age of the patient. Fulminant (i.e. sudden explosive)
hepatitis is rare and also age dependent, occurring more frequently in older
patients. The incidence also varies, being 0.1% in USA and about 4.0% in France.
Mild to moderate tenderness over an enlarged liver can usually be detected.
In about 80% of cases the duration of jaundice is less than two weeks. In the
majority of adults the infection is cleared within 6 months. Relapse and prolonged
cholestasis are rare. Normally HA is an acute infection and is not prolonged.
However in rare cases superimposition of HAV infection on cirrhosis has bean
observed.5,14,15
SEROLOGY
Serum alanine aminotransferase (ALT or SGPT) and asparate aminotransferase
(AST or SGOT) rise rapidly during the prodromal period, whereas
serum bilirubin levels reach their peak later and decline less rapidly than
aminotransferases. Specific immunoglobulin M (IgM) antibodies appear during
the acute phase and are present in high liter by the time jaundice appears.
These decline after 6 months. During recovery IgG antibodies to HAV develop
and persist indefinitely. The presence of anti-HAV IgG antibodies confers immunity
to reinfection.5,14,15
TREATMENT
This is mainly symptomatic and the disease is usually self-limiting. During
acute phase bed-rest is advisable. Diet should be light and nourishing. Oily
and spicy food should be avoided. Plenty of glucose should be given by mouth
or glucose-saline infusion to support the diseased liver. In severe cases ribavirin,
an oral antiviral agent has been found beneficial in developing countries in
a dose of 400 mg. three times a day.15
EPIDEMIOLOGY
HA is spread principally by feco-oral route due to contaminated food or water
or from person to person. HAV survives for long periods in water and wet environment.
Important factors in transmission of HAV infection are personal sanitation
e.g. handwashing after visiting toilet, availability of clean drinking water
and proper sewage disposal. Hence prevalence is high among developing countries,
where 80% of the people have evidence of infection by the age of 20 years and
100% by the age of 50, compared to about 40% in developed countries. Large
quantities of virus are excreted in feces for several days, before and after
the onset of jaundice, but after one week of clinical illness the patient's
stools may be considered non-infectious. Both endemic and epidemic forms occur;
some of the latter have been traced to ingestion of infected shellfish. HA
can be acquired by swimming in contaminated water. HA is the third most important
foreign travel-associated infection after diarrhea and malaria. There is no
evidence of vertical transmission from mother to child. Parenteral transmission
of HAV may occur but it is rare due to the short period of viremia during the
initial period of illness.5,14
Outbreaks have occurred in day care centres. Nosocomial infections have been
reported in nurseries as well as among adults in institutions. Post transfusion
HA has developed in neonatal intensive care unit. HA may relapse and develop
prolonged intrahepatic cholestasis. Superinfection on hepatic cirrhosis may
also occur.17,18
Several outbreaks have occurred due to consumption of raw oysters or improperly
cooked clams obtained from sewage polluted waters. Sudden, large epidemics
of HA usually result from fecal contamination of a single source such as drinking
water, food or milk. The largest ever recorded outbreak of HAV infection occurred
in Shanghai in 1988 involving 2,90,000 people and was traced to consumption
of raw clams. Outbreaks by person to person spread commonly occur among families,
institutions and troops. Very rarely HAV may be transmitted by the use of contaminated
syringes, needles, clotting factor concentrates or blood transfusion because
there is a short period of viremia in infected persons. However, transplacental
transmission is not common in infected persons.14
PREVENTION
From consideration of epidemiology it is obvious that prevention of HA is
primarily through sanitation. Clean water for drinking and cooking is essential.
Waste disposal must be separate from water supply. Hand washing, boiling of
water, thorough cooking of food and peeling of vegetables and fruits should
be practiced HAV is
inactivated by chlorination, ultraviolet radiation and boiling of water for
20 minutes. Stable and uncooked food should be avoided. Salad should be properly
washed in running water before consumption. Segregation or isolation of patient
from family member is not imperative, but soiled clothing & should be boiled
and washed separately.14,19
ACTIVE IMMUNIZATION
HAV was propagated in cell culture in 1979 and molecular cloning of the genome
was carried out in 1983. This enabled development of various types of vaccines
in different countries. A single dose of inactivated vaccine generates protective
antibodies that last for several years. A booster dose given between 6 and
12 months after the first dose extends the duration of protection by a decade
or more. The two inactivated vaccines approved for use in the USA have been
well tolerated. The most common adverse reaction reported is mild transient
soreness at the site of injection. Immunization with inactivated HA vaccine
is a safe and effective method for susceptible children, adults and travellers
to endemic areas.20 HA vaccine can be successfully combined with
HB vaccine, specially for infant's.21 Live attennated oral vaccine
is also developed of which two doses are to be taken two weeks apart.
INDICATIONS FOR HA VACCINES
These are Children, institutionalized adults, travellers to endemic areas,
prison inmates, asylums, military personnel certain ethnic groups with high
rates of HA such as Native Americans, Native Alaskans, persons engaging in
high risk sexual activity, IV drug users and those with occupational exposure
like laboratory and health personnel. Future widespread immunization of children
would reduce overall prevalence and
ultimately help eradication of the disease, though at present this is not required
in countries like India.22
PASSIVE IMMUNIZATION
Human immunoglobulin (Ig) prepared from large pools of normal adult plasma
gives useful passive protection when administered within two weeks before or
after exposure to HAV. The protection lasts for about 4 months, and could be
used by travellers to endemic areas if active immunization is not possible.
Ig may be given concomitantly with inactivated vaccine in persons requiring
both immediate and long term protection, with care taken to use different limbs
for injection to minimise interference by passive antibodies. In such patients
a vaccine booster dose may be required sooner than usual.
DIAGNOSIS
Acute infection is diagnosed by positive anti-HAV IgM in serum taken during
the early illness. Antibody titres reach a peak within a few weeks of onset
of symptoms and then rapidly decline in 6 to 12 months. Third generation radio-immunoassay
(RIA) and enzyme-linked lmmunoassay (ELISA) are most commonly used. Established
immunity to HAV or prior infection is determined by the presence of total antibodies
(IgM + IgG) to HAV.
PEDIATRIC INFECTIONS OF HA
These account for more than one third of the recognized cases of HA. Children
generally experience subclinical infection or a milder clinical course than
adults and clinical manifestations may often go unnoticed. Once HA, infection
sets in, treatment is similar to that described for adults, namely adequate
bed rest, hydration and nutritional support.
PREGNANCY
During pregnancy also HA infection is self-limiting and does not carry a different
prognosis than that in non-pregnant patients. No teratogenic effects of acute
HAV infection during pregnancy have been noted. Transmission to the neonate
from an infected mother can occur by the usual feco-oral route during delivery
and the postpartum period. Intrauterine transmission is, however, extremely
rare. HA vaccine should be used during pregnancy only when clearly indicated.
Newborn infants of HAV infected mothers whose symptoms first manifested between
2 weeks before and 9 weeks after delivery should receive specific HA immunoglobulin.
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Copyright 2003 - Indian Journal of Medical Sciences.
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