http://bmj.com/cgi/content/full/322/7280/219
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Clinical review
ABC of diseases of liver,
pancreas, and biliary system
Chronic viral hepatitis
S D Ryder
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The main method of spread in areas of high endemicity is
vertical transmission from carrier mother to child, and this may account
for 40-50% of all hepatitis B infections in such areas. Vertical
transmission is highly efficient; more than 95% of children born to
infected mothers become infected and develop chronic viral infection.
In low endemicity countries, the virus is mainly spread by sexual or
blood contact among people at high risk, including intravenous drug
users, patients receiving haemodialysis, homosexual men, and people
living in institutions, especially those with learning disabilities.
These high risk groups are much less likely to develop chronic viral
infection (5-10%). Men are more likely then women to develop chronic
infection, although the reasons for this are unclear.
Up to 300 million people have chronic hepatitis C infection mainly
worldwide. Unlike hepatitis B virus, hepatitis C infection is not
mainly confined to the developing world, with 0.3% to 0.7% of the
United Kingdom population infected. The virus is spread almost
exclusively by blood contact. About 15% of infected patients in
Northern Europe have a history of blood transfusion and about 70%
have used intravenous drugs. Sexual transmission does occur, but is
unusual; less than 5% of long term sexual partners become infected.
Vertical transmission is also unusual.
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Presentation |
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Chronic viral liver disease may be detected as a result of finding abnormal
liver biochemistry during serological testing of asymptomatic
patients in high risk groups or as a result of the complications of
cirrhosis. Patients with chronic viral hepatitis usually have a
sustained increase in alanine transaminase activity. The rise is
lower than in acute infection, usually only two or three times the
upper limit of normal. In hepatitis C infection, the 
-glutamyltransferase activity is also often
raised. The degree of the rise in transaminase activity has little
relevance to the extent of underlying hepatic inflammation. This is
particularly true of hepatitis C infection, when patients often have
normal transaminase activity despite active liver inflammation.
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Hepatitis
B |
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Most patients with chronic hepatitis B infection will be positive for
hepatitis B surface antigen. Hepatitis B surface antigen is on the viral
coat, and its presence in blood implies that the patient is
infected. Measurement of viral DNA in blood has replaced e antigen
as the most sensitive measure of viral activity.
Chronic hepatitis B virus infection can be thought of as occurring in phases
dependent on the degree of immune response to the virus. If a person
is infected when the immune response is "immature," there
is little or no response to the hepatitis B virus. The
concentrations of hepatitis B viral DNA in serum are very high, the
hepatocytes contain abundant viral particles (surface antigen and
core antigen) but little or no ongoing hepatocyte death is seen on
liver biopsy because of the defective immune response. Over some
years the degree of immune recognition usually increases. At this
stage the concentration of viral DNA tends to fall and liver biopsy
shows increasing inflammation in the liver. Two outcomes are then
possible, either the immune response is adequate and the virus is
inactivated and removed from the system or the attempt at removal
results in extensive fibrosis, distortion of the normal liver
architecture, and eventually death from the complications of
cirrhosis.
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Assessment of chronic hepatitis B infection
Patients positive for hepatitis B surface antigen with no evidence
of viral replication, normal liver enzyme activity, and normal
appearance on liver ultrasonography require no further
investigation. Such patients have a low risk of developing symptomatic
liver disease or hepatocellular carcinoma. Reactivation of B virus
replication can occur, and patients should therefore have yearly
serological and liver enzyme tests.
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Patients with abnormal liver biochemistry,
even without detectable hepatitis B viral DNA or an abnormal liver texture on
ultrasonography, should have liver biopsy, as 5% of patients with
only surface antigen carriage at presentation will have cirrhosis.
Detection of cirrhosis is important as patients are at risk of
complications, including variceal bleeding and hepatocellular
carcinoma. Patients with repeatedly normal alanine transaminase
activity and high concentrations of viral DNA are extremely unlikely
to have developed advanced liver disease, and biopsy is not always
required at this stage.
Treatment
Interferon alfa was first shown to be effective for some patients
with hepatitis B infection in the 1980s, and it remains the mainstay
of treatment. The optimal dose and duration of interferon for
hepatitis B is somewhat contentious, but most clinicians use
8-10 million units three times a week for four to six months.
Overall, the probability of response (that is, stopping viral
replication) to interferon therapy is around 40%. Few patients lose
all markers of infection with hepatitis B, and surface antigen
usually remains in the serum. Successful treatment with interferon
produces a sustained improvement in liver histology and reduces the
risk of developing end stage liver disease. The risk of
hepatocellular carcinoma is also probably reduced but is not
abolished in those who remain positive for hepatitis B surface
antigen.
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Factors indicating
likelihood of response to interferon in chronic hepatitis B infection
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Side effects of
treatment with interferon alpha
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In general, about 15% of patients receiving
interferon have no side effects, 15% cannot tolerate treatment, and the
remaining 70% experience side effects but are able to continue
treatment. Depression can be a serious problem, and both suicide and
admissions with acute psychosis are well described. Viral clearance
occurs through induction of immune mediated killing of infected
hepatocytes. Transient hepatitis can therefore occasionally cause
severe decompensation requiring liver transplantation.
Lamivudine is a nucleoside analogue that is a potent
inhibitor of hepatitis B viral DNA replication. It has a good safety profile
and has been widely tested in patients with chronic hepatitis B
virus infection, mainly in the Far East. In long term trials almost
all treated patients showed prompt and sustained inhibition of viral
DNA replication, with about 17% becoming e antigen negative when
treatment was continued for 12 months. There was an associated improvement
of inflammation and a reduction in progression of fibrosis on liver
biopsy. Side effects are generally mild. Combination therapy with
interferon and lamivudine has not been found to have additional
benefit.
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Hepatitis
C |
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Chronic hepatitis C virus infection has a long course, and most patients are
diagnosed in a presymptomatic stage. In the United Kingdom, most
patients are now discovered because of an identifiable risk factor
(intravenous drug use, family history, or blood transfusion) or
because of abnormal liver biochemistry. Screening for hepatitis C
virus infection is based on enzyme linked immonosorbent assays (ELISA)
using recombinant viral antigens and patients' serum. These have
high sensitivity and specificity. The diagnosis is confirmed by
radioimmunoblot and direct detection of viral RNA in peripheral
blood by polymerase chain reaction. Viral RNA is regarded as the
best test to determine infectivity and assess response to treatment.
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Investigations
required in patients positive for antibodies to hepatitis C virus
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Polymerase chain reaction
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Natural course of hepatitis C infection
In order to assess the need for treatment it is important to have a
clear understanding of the natural course of hepatitis C infection
and factors that may predispose to more severe outcome. Our
knowledge is limited because of the relatively recent discovery of
the virus. It is clear, however, that hepatitis C is usually slowly
progressive, with an average time from infection to development of
cirrhosis of around 30 years, albeit with a high level of
variability. The main factors associated with increased risk of
progressive liver disease are age >40 at infection, high alcohol
consumption, and male sex.
Viraemic patients with abnormal alanine transaminase
activity need a liver biopsy to assess the stage of disease (amount of fibrosis)
and degree of necroinflammatory change (Knodell score). Management
is usually based on the degree of liver damage, with patients with
more severe disease being offered treatment. Patients with mild
changes are usually followed up without treatment as their prognosis
is good and future treatment is likely to be more effective than
present regimens.
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Treatment of hepatitis C
Interferon alfa (3 million units three times a week) in
combination with tribavirin (1000 mg a day for patients under
75 kg and 1200 mg for patients 
75 kg) has recently been shown to
be more effective than interferon alone. A large study in Europe
showed no advantage to continuing treatment beyond six months in
patients who had a good chance of response, whereas those with a
poorer outlook needed longer treatment (12 months) to maximise
the chance of clearing their infection. About 30% of patients will
obtain a "cure" (sustained response). The main determinant
of response is viral genotype, with genotypes 1 and 4 having
poor response rates.
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Further reading
Szmuness W. Hepatocellular
carcinoma and the hepatitis B virus: evidence for a causal
association. Prog Med Virol 1978;24:40-8. Stevens CE, Beasley RP, Tsui V,
Lee WC. Vertical transmission of hepatitis B antigen in Taiwan. N
Engl J Med 1975;292:771-4. Knodell RG, Ishak G, Black C,
Chen TS, Craig R, Kaplowitz N, et al. Formulation and application
of numerical scoring system for activity in asymptomatic chronic
active hepatitis. Hepatology 1981;1:431-5. |
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Summary points
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Combination therapy has the same side effects
as interferon monotherapy with the additional risk of haemolytic anaemia.
Patients developing anaemia should have their dose of tribavirin
reduced. All patients should have a full blood count and liver
function tests weekly for the first four weeks of treatment and
monthly thereafter if haemoglobin concentration and white cell count
are stable. Many new treatments are currently entering clinical
trials, including long acting interferons and alternative antiviral
drugs.
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Footnotes |
S D Ryder is consultant hepatologist, Queen's Medical Centre, Nottingham NG7
2UH
The ABC of diseases of liver, pancreas, and biliary system is edited by I J
Beckingham, consultant hepatobiliary and laparoscopic surgeon,
department of surgery, Queen's Medical Centre, Nottingham (Ian.Beckingham@nottingham.ac.uk).
The series will be published as a book later this year.
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This
article has been cited by other articles:
- Kuchimanchi, U., Rooney, G.
(2001). Hepatitis B, lamivudine, and HIV. BMJ 323: 51-51
[Full text]
Rapid Response responses to this article:
Read all Rapid Response
responses
Professional tattooing does carry risk of hepatitis
C
John Battersby, Specialist
Registrar in Public Health Medicine , Suffolk Health Authority
bmj.com, 1 Feb 2001 [Response]
Current evidence does not support screening for
hepatitis C
Faisal F Syed, 4th Year Medical
Student , University of Manchester
bmj.com, 4 Mar 2001 [Response]
Hepatitis B, Lamivudine and HIV
Usha Kuchimanchi and Guy Rooney,
Specialist Registrar and Consultant Physician , Genitourinary Medicine,
Oxford and Genitourinary Medicine, Swindon
bmj.com, 8 Mar 2001 [Response]
Related letters in BMJ:
Hepatitis B, lamivudine, and HIV
Usha Kuchimanchi and Guy Rooney
BMJ 2001 323: 51. [Letter]
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