Hepatitis B

March 15, 2009

There are three antigen-antibody systems related to hepatitis B Hepatitis B surface Hepatitis B surface antigen is a spherical particle about 22 nm in size. This is extra core material was not incorporated during the assembly of the virus during its replication within the liver. The actual virus is 42-nm donut shape particle called the Dane particle. It contains a core surface antigen, core antigen, e antigen, DNA polymerase, and DNA. Then 3 antigen antibodies systems related to hepatitis B are surface antigens, core antigen, and e antigen. The Corresponding antibodies are surface antibody, core antibody, and e-antibody.

hepatitis B, microbiology

In a typical patient with acute hepatitis B, less than 1% get full hepatitis B. 95 to 98% go into complete recovery. Only about 2% that go on are chronically infected. Remember for hepatitis A it is zero and for hepatitis C, it is an astounding 70 to 80% that go on to become chronically infected. In B it is about 2 to 5 %. These patients develop chronic hepatitis cirrhosis that can eventuate later into primary hepatocellular carcinoma. In every part of the world where hepatitis B is endemic, 20 to 30% of patients with chronic hepatitis B, do not have underlying cirrhosis. In contrast, that is very rare with hepatitis C. I have yet to see a patient with hepatitis C with a hepatoma who did not have underlying cirrhosis. This is important for screening ramifications. I do not screen for hepatoma in a patient with hepatitis C, unless they have cirrhosis. I will screen for hepatoma in a patient with hepatitis B if they are from a part of the world where hepatitis B is endemic, vertical transmission from the mother, family history of hepatoma, and, even in the absence of cirrhosis and abnormal liver function tests, those individuals should be screened. The most important determinant of who is going to become chronically infected after getting acute hepatitis B is age of acquisition of acute hepatitis B. If you get it as an adult it is only 2%. If you
get it as a newborn it is 90%. If you get it as a young child, it is about 50 to 70%. Hence, the importance of screening all pregnant women for chronic hepatitis B infection and the universal vaccination. The catch up program is important, and we are in the midst of it right now in adolescence in our
country who didn’t get vaccinated years ago, but who are now becoming sexually active, using drugs, and are in situations in which they are at risk of getting chronic hepatitis B infections. Global vaccination is the answer to this problem.

What are the epidemiologic features of hepatitis B? There is a high
prevalence around the world. There is a large human carrier reservoir where
about 350 million worldwide, which is mind boggling 5% of the entire human
population are chronically infected with hepatitis B virus. There are various
modes of transmissions. In 1941 there was a yellow fever vaccine given to
army recruits in our country and one lot was contaminated with hepatitis B. It
led to about 49,000 cases of hepatitis B infection.

What should we do when we see somebody with chronic hepatitis B? When
you see somebody with chronic hepatitis B I’d like you to address the
following 5 questions with them. What is their stage of liver disease? Are
these healthy asymptomatic chronic carriers? Do they have chronic hepatitis?
Do they have cirrhosis? If they have cirrhosis, do they have varices? Should
we put them on prophylactic beta-blocker therapy to prevent the first variceal
bleed? It is made on the basis of biochemistry testing and if necessary on
liver biopsy. 2) Are they candidates for interferon treatment? They have to
fulfill certain criteria. They have to be replicative. They have to be e antigen
positive. They have to have abnormal liver function tests. They have to have
an elevated ALT. We don’t treat people who have normal ALT and AST.

The chronic carriers don’t respond to interferon. There should be no
contraindications to treatment. They shouldn’t have decompensated liver
disease. They shouldn’t be cirrhotics with ascites. They shouldn’t be
depressed. They should have cytopenia, low bleed count, low white count.
What is the candidacy for interferon treatment? What is the risk of liver
cancer? If this is a patient from a part of the world where hepatitis B is
endemic and there is a strong family history of hepatoma then that is a high
risk. If this is a person who was born and bred in the United States and they
antigen (HBsAg); hepatitis B core antigen (HBcAg) and e antigen (HBeAg); and
their corresponding antibodies

Hepatitis B surface antigen (HBsAg): A unique feature of HBV infection is that
concentrations of viral antigen and viral particles in the blood may reach 500μg/mL
and 5-10 trillion particles/mL respectively. HBsAg exceeds Dane particles by a
factor of 103 to 106 in the circulation. Blood that is positive for HBsAg connotes one
of three possibilities: 1) the subject is incubating HBV infection: 2) active HBV
infection is present: 3) a chronic carrier state is in existence

Anti-HBs is a neutralizing body detected in secretions and excretions. Its
appearance together with that of core antibody (Anti-HBc) signals recovery from
hepatitis B and the development of subsequent immunity. Anti-HBs is the only
antibody that appears in persons who have been administered the vaccine which
consists of purified hepatitis B surface antigen. Among hospital personnel, prior to
vaccination, the antibody is most prevalent in surgeons, pediatricians, and
pathologists, and those with close contact with blood products and tissues.
Hepatitis B core antigen (HBcAg): The second antigen-antibody system is hepatitis
B core antigen (HBcAg) and core antibody (anti-HBc) HBcAg is present in the
nucleus of infected hepatocytes. Testing for core antigen is not a routine aid for
diagnosing HBV infection. In contrast in patients with acute hepatitis B, core
antibody can be detected in serum before ant-HBs, which generally appears about
four months after the acute illness. High titer IgM, anti-HBc is the only serological
marker present during the so-called gap or “window” period, which refers to a
period of time when the patient has acute infection, but tests for HBsAg and anti-
HBs are negative.

Hepatitis B e antigen (HBeAg): There is the e antigen and e antibody (anti-HBe)
system. Hepatitis B e antigen appears early, transiently, and universally in the
serum of patients with acute HBV infection. Therefore, the mere presence of this
antigen does not correlate with severity or with chronicity. However, persistence of
this antigen for greater than 12 weeks suggests a high likelihood of the development
of a chronic carrier state. In addition, in chronic carriers, e antigen positively
correlates with infectivity (both horizontal and vertical transmission).
Horizontal transmission refers to contamination through accidental contact such as
splashing of mucous membranes or needle sticks. Vertical transmission which has
been the major mode of transmission in many parts of the world, refers to
transmission from mother to newborn, and may occur either when the mother is an
asymptomatic carrier or when she has the misfortune of developing acute hepatitis
B virus infection during pregnancy. In the later instance, the risk of transmitting
HBV to the newborn is greatest if the infection develops during the third trimester
of within two months of delivery.

The incubation period is 50-180 days. HBsAg generally disappears by 20 weeks.
During the “window” period, which may last four weeks or longer, the only
serological marker of hepatitis B is anti-HBc. It is present in high titer and is of the
IgM class. HbeAg often disappears and anti-HBe appears during recovery.
It is estimated that there are 300 million chronic carriers of HBsAg. This is 5% of
the entire world population. In past studies, serological markers of hepatitis B were
present in 70% of gay men and 25% of patients with Down’s syndrome,
lepromatous leprosy, polyarteritis nodosa, and chronic renal failure receiving
dialysis as well a needle-using drug addicts, were chronic carriers of HBsAg.
Modes of transmission are varied and range from tattoos and acupunctures to sports
such as orienteering, which is common in Scandinavia. The prevalence of HBsAg is
happen to get hepatitis B as an adult and there is no other family member,
they are healthy, they are asymptomatic, they have normal liver function tests,
then hepatoma is very unlikely. I have yet to see a hepatoma in such a
patient. I don’t even screen them for hepatoma. What is their serologic
status? If appropriate the ones who need to should get the vaccine. If
somebody has chronic hepatitis B and drinks moderate amounts of alcohol
they are more likely to get hepatoma and more likely to get it a decade earlier
then their colleagues with the same disease who don’t drink alcohol. The
indications for treatment are biochemical evidence of ongoing hepatitis,
elevated ALT, serologic evidence of viral replication, e antigen should be
positive, they should have compensated liver disease, which means they can
be cirrhotics, decent albumins, no ascites, and no encephalopathy. Those
patients you can treat with interferon. If they have decompensated liver
disease and you treat with interferon, interferon can induce a flare and that
flare can be fatal in a patient with decompensated liver disease. You’ve got to
exclude other causes of liver dysfunction. If the patient has chronic hepatitis
B and abnormal LFTs, it doesn’t mean that it is necessarily chronic hepatitis
B as a cause of the abnormal liver profile. That patient could have
hemochromatosis, taking niacin, or could have many other reasons for having
chronic liver disease, so we need to do a biopsy and a work-up before you say
this is chronic hepatitis B infection.

The patients most likely to respond to interferon are those with high
pretreatment serum ALT, low serum HBDNA, active hepatitis, recent
acquisition, negative for delta, and negative for HIV. If they have had chronic
hepatitis B for 5 or 10 years, they are more likely to respond then if they have
had it for 30 or 40 years. They should be negative for delta and HIV. If the
biopsy shows active hepatitis then they are more likely to respond. The
higher the pre-treatment ALT value, the better the response. The single most
important determinant predictor is the pre-treatment ALT. The higher the pretreatment
ALT is the better the response is. If the ALT is less than 2 times the
upper limit of normal the response is 3%. If it is 2 to 3 times the upper limit of
normal it is 33%. If it is more than 3 times the upper limit of normal it is 66%.
In the laboratory the high normal value is 40. If the pre-treatment ALT is
150-200, then that is good and they have about a two-thirds chance of
responding to interferon. If the ALT value is 60, it is not worth treating with
interferon. It is expensive. It has side effects and it is not likely to work.
Then if they have a flare, which is defined as a doubling of the pre-treatment
ALT, exceeding 200 international units, then they are more likely to respond.
What we really need to do at that point is to continue the interferon to
congratulate the patient and to monitor them carefully, but tell them they are
likely to respond. They actually have a better chance of responding than if
they have no flare.

What does interferon result in? It results in durable loss of HBV and e
antigen, durable loss of surface antigen, sustained normalization of ALT, and
a documented decrease in liver inflammation, so virochemical, virologic, and
histologic response are all achieved in chronic hepatitis B with interferon
treatment. Contraindications are decompensated liver disease, significant
neuropsychiatric disease, and depression. We do treat patients with mild
depression. You can put them on anti-depressants and you need to follow
them carefully with a psychiatrist. If they have an underlying autoimmune
disorder like rheumatoid arthritis, psoriasis, ITP, Crohns, lupus, you have to
be concerned because interferon has a proclivity to produce autoantibodies
and you can exacerbate the underlying disease. One has to be very cautious.

It is not an absolute contraindication, but I forewarn those patients that if they
develop symptoms related to their underlying autoimmune disease, then we
often will stop the medication.
Lamivudine or 3TC is being investigated actively in the treatment of chronic
hepatitis B, and it appears to be very promising. It inhibits DNA synthesis by
terminating the provirus DNA chain. Lamivudine doesn’t appear to cause
lactic acidosis, hepatic failure, renal failure, or pancreatitis. There are some
mild constitutional symptoms and mild laboratory abnormalities. I’m using
this drug in conjunction with interferon or without interferon if interferon is
highest in parts of southeast Asia and sub-Saharan Africa.

About 1% of patients seeking medical attention will have fulminant hepatitis, while
90-95% recover completely. Two to five percent of patients with acute hepatitis B
will become chronic carriers, a state defined as the persistence of hepatitis B
surface antigenemia for longer than 6 months. Some carriers develop chronic
hepatitis or cirrhosis and a significant number succumb to primary hepatocellular
carcinoma. The latter is especially true if the infection was acquired during early
childhood or infancy.

Carcinoma
There is a strong association between chronic hepatitis B virus infection and
primary hepatocellular carcinoma The worldwide prevalence of primary
hepatocellular carcinoma is similar to that for the prevalence of hepatitis B surface
antigenemia.

Infection as attested to by the presence of anti-HBs, anti-HBc, or both of these
antibodies. Therefore, the presence of the chronic carrier state of hepatitis B
infection confers an extremely high risk for the development of primary
hepatocellular carcinoma On a worldwide basis, primary hepatocellular carcinoma
is the most common malignant visceral neoplasm.

The hepatitis B vaccine holds great promise in eradicating of significantly curtailing
HBV infection on a worldwide basis has been hailed as the first “anti-cancer
vaccine”. Synthetic yeast-derived vaccines have been licensed for use.
Interferon at a dose of 5 million units daily for four to six months results in loss of
hepatitis B virus DNA and hepatitis B e antigen in 30-50% of patients.

Aminotransferase levels normalize in 40% of patients. Hepatitis B surface antigen
is lost initially in approximately 15%. Most patients who seroconvert from e
antigen to e antibody will also likely become negative for HBsAg with the passage
of time.

Interferon-related adverse effects are common and include fever, flu-like illness,
irritability, depression, malaise, and alopecia. Careful monitoring of the
hematological indices (WBC count, platelet count) is necessary, and patients with
low platelet counts (less than 50,000 - 75,000) are not suitable candidates.
However, the majority of patients are able to tolerate treatment and discontinuation
of the drug because of intolerable side-effects is necessary in less than 5% of
treated patients. Remissions in chronic hepatitis B induced by alfa interferon are
durable in most patients, and remissions are followed by loss of HBsAg and
evidence of residual viral infection.

Lamivudine, a nucleoside antagonist appears to be a promising agent against
hepatitis B virus in initial pilot studies.