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Author: Laurence Scott Bailen, M.D.

1. Objectives: Viral Hepatitis

  1. Understand the virology, epidemiology, and clinical syndromes associated with Hepatitis A, B, C, D, and E

  2. Understand that hepatitis A and E do not result in chronic hepatitis or cirrhosis

  3. Be able to describe the blood tests utilized in evaluating patients with viral hepatitis

  4. Understand the meaning of different patterns of hepatitis B serologies.

  5. Understand various treatments available for viral hepatitis

  6. Understand that effective vaccines are available vaccines for hepatitis A and B

2. General

There are several human viruses that can cause hepatitis. Some viruses, such as Epstein-Barr virus, cytomegalovisus, and herpes simplex virus, target multiple organs in the body and although the liver is not the primary target, hepatitis may ensue. Other viruses, which will be the focus of the discussion below, target primarily the liver.

3. Hepatitis A (HAV)

The virus is a 27 nm single-stranded RNA virus of the picornavisus family. It seems to behave with the characteristics of enteric viral infections. It is spread mainly by fecal-oral contamination. It is endemic in the developing regions of the world infecting close to 100% of the population in the first 15 years of life. Such infections are for the most part sub clinical. Its incubation period is short relative to other types of hepatitis: 2-6 weeks. During the late incubation period, the virus may be recovered in stools, and the shedding of the virus reaches its peak at the time of maximum transaminase elevation. Although a viremic phase probably exists in HAV infection, it appears to be of short duration and low level making it difficult to detect the antigen (virus) in the blood.

The diagnosis of hepatitis A is based on the detection of the antibody rather than the antigen in the serum. Antibody to hepatitis A (anti-HAV) becomes detectable in serum at the onset of clinical disease, and its titer rapidly rises. The antibody response is of the IgM and IgG types, but predominantly IgM during an acute infection. The IgM anti-HAV lasts about 4 months and is then replaced by IgG anti-HAV, which persists probably for life.

Hepatitis A is usually a self-limited infection. There is no known carrier state or chronic hepatitis associated with it.

The best animal model for hepatitis A is the marmoset. Tissue culture grown of the virus has met limited success recently opening the horizon to the development of a vaccine. In August 1992, the first large study of a formal inactivated vaccine was reported and it was shown to be highly protective.

4. Hepatitis B (HBV)

The virus is a 42 nm double-stranded DNA particle known as the Dane particle. It has an outer lipoprotein envelope called the Hepatitis B Surface Antigen (HbsAg), previously known as Australia antigen. Inside the surface lipoprotein is another antigen called the Hepatitis B Core Antigen (HBcAg). A third antigen is the “e” antigen (HBeAg), which is believed to be a soluble protein part of the core that is released when the core is disrupted.

The incubation period is 6 weeks – 6 months. It is transmitted via the parenteral route; however, sexual contact is also a common route of spread. HBsAg, which is the main marker of infection, appears in the serum during the latter part of the incubation period and remains positive as long as there is apparent infection. About 90-95% of acute hepatitis B cases recover completely and lose the HBsAg, but 5-10% remain chronic carriers of the virus and the HBsAg remains positive. Chronic carriers of HBsAg may have normal livers, chronic persistent hepatitis, or chronic active hepatitis. Chronic active hepatitis is the most serious of the above and may progress to cirrhosis. It is believed that the hepatitis B virus is not cytotoxic and that the course of the infection is determined by the host’s immune response.

The three antigens associated with HBV infection described above have their counterpart antibodies: antibody to Surface Antigen (anti-HBs), antibody to Core Antigen (anti-HBc) and antibody to “e” antigen (anti-HBe). The appearance and disappearance of these markers is variable and depends on the course of the hepatitis, complete recovery, or the development of the carrier stated. In a patient with acute hepatitis B who is destined to recover completely, the following sequence occurs:

  1. Appearance of HbsAg during late incubation period and its persistence through clinical infection.

  2. Appearance of HBeAg (briefly) and anti-HBc around the time of clinical symptoms.

  3. Appearance of anti-HBe and disappearance of HBeAg.

  4. Disappearance of HBsAg.

  5. Appearance of anti-HBs.

  6. Persistence of anti-HBs and anti-HBc with a decrease in titer, with time.

In a patient who is going to remain a carrier of hepatitis B, the following sequence occurs:

  1. Appearance of HBsAg.

  2. Appearance of HBeAg and anti-HBc.

  3. Persistence of HBsAg, HbeAg and anti-HBc.

  4. No detection of anti-HBe or anti-HBs early in the course of chronic infection, but possible conversion of HBeAg to anti-HBe later in the course.

Although attempts at tissue culture of hepatitis B virus have met even less success than hepatitis A, extraordinary progress has been achieved in the virological and clinical understanding of hepatitis B, which in turn has led to successful production of a vaccine against it. In the largest trial of the vaccine among homosexual men in New York, over 95% of vaccinated subjects developed antibody against the surface antigen (anti-HBs) and the protective efficacy rate was very high. The vaccine used in the study was a highly purified formalin-inactivated preparation of HBsAg particles. Since then recombinant vaccines have become available for commercial use.

Other recent advances include the successful cloning of the hepatitis B virus, and the utilization of DNA in vitro hybridization technology to detect hepatitis B virus DNA (HBV-DNA). The HBV-DNA test will give a more direct and quantitative measure of the number of circulation virions.

These advances in our understanding of and protection against the hepatitis B virus have far reaching consequences beyond the control of the disease. There is now irrefutable evidence incriminating chronic hepatitis B infection as an etiologic agent in primary hepatocellular carcinoma. In one study from the Far East the relative risk of developing a primary hepatocellular carcinoma in chronic carriers of hepatitis B was 390 x compared to controls. HBV-DNA has been detected in an integrated form (covalently linked to host DNA) in the livers of patients with chronic hepatitis B infection and patients with primary hepatocellular carcinoma. The hope is that with greater availability of the vaccine worldwide, and the eradication of hepatitis B would lead to a very significant decrease in the morbidity and mortality from primary hepatocellular carcinoma.

5. Delta Hepatitis (HDV)

The hepatitis D virus, initially called “delta agent” and then “hepatitis delta virus,“ is a defective RNA-containing virus. It is the most unusual among the known hepatitis viruses because it required the hepatitis B virus to survive and replicate. The virion is about 36 nm in diameter and comprises an inner single-stranded RNA core enveloped by an outer coat of hepatitis B surface antigen (HBsAg).

It causes disease in two ways: (1) Co-infection in which case which case there is simultaneous infection of the host with acute HBV and HDV, and (2) Super infection. When co-infection occurs there is a higher incidence of fulminant hepatitis and when super infection occurs, the delta virus can cause acute hepatitis but more often it makes the chronic hepatitis B more severe.

The diagnosis of delta hepatitis is made by the detection of antibody to HDV (anti-HD) in the serum, which appears several days to a few weeks after the onset of illness. There is no commercial test available for detection of the antigen in the serum.

6. Non-A, Non-B Hepatitis

The term non-A, non-B was coined to indicate the presence of a type of hepatitis that was distinct form types A and B, and for which there was no available serological test. Several viruses were identified and serologic tests became available for them.

7. Hepatitis C (HCV)

In 1988, the hepatitis c virus was cloned from nucleic acid that was extracted from the plasma of an infected chimpanzee with a very high infectivity titer. It measures 30-60 nm in diameter and is an approximately 10,000 nucleotide, linear, single stranded RNA virus with properties similar to those of flavaviruses.

In 1990, an immunoassay for the antibody to hepatitis C became commercially available. The earlier available test was neither sensitive nor specific, but second generation tests soon became available and they seem to be more sensitive and specific. The anti-HCV is not a protective antibody; it is a marker of infection, but it does not appear early in the course of the disease (only 60% of patients with hepatitis C have a positive anti-HCV test at 4 months and only 90% are positive at 6 months).

Epidemiologic studies as well as recent serologic testing suggest that this type of hepatitis is responsible for more than 90% of post-transfusion hepatitis in the U.S.A. Hepatitis C is also common in I.V. drug users, hemophiliacs, and hemodialysis patients. Sporadic non-A, non-B hepatitis or hepatitis C can also occur without a recognized parenteral exposure.

Hepatitis C differs from types A and B by the frequency of development of chronic hepatitis (more than 70% of cases particularly in recipients of transfusions). Initially, it was believed that the vast majority of the patients who developed chronic hepatitis had a benign prognosis; however, longer follow-up and better recognition of the entity have now shown that about 20% of these patients develop cirrhosis. To put this in perspective, consider that before the discovery of anti-HCV, about 10% of all patients transfused develop acute non-A, non-B hepatitis, 70% of those develop chronic hepatitis, and 20% of the latter develop cirrhosis, which is an alarming figure. Now that anti-HCV testing of transfused blood has become available, the incidence of post-transfusion hepatitis has declined to less than 1%, and this should decrease the incidence of chronic hepatitis and cirrhosis significantly.

The availability of the anti-HCV has not shed any light on the incubation period of hepatitis C, but epidemiologic studies of post transfusion non-A, non-B hepatitis suggests that the incubation period is variable, usually longer than hepatitis A and shorter than hepatitis B, with a mean of 10.5 weeks. The carrier rate of hepatitis C is believed to be between 0.2-0.5% of the population in the U.S.A.

Another test for the diagnosis of hepatitis C is the measurement of hepatitis C viral RNA (qualitative and quantitative). The latter is being used in many studies to monitor the efficacy of treatment with Interferon.

8. Hepatitis E (HEV)

A different type of non-A, non-B hepatitis was recognized in 1980 when it was initially reported from the Indian subcontinent. This type is similar to hepatitis A in its mode of transmission (fecal-oral) and in the involving of contaminated water. It differs from hepatitis A in one respect: a high incidence of mortality, particularly in pregnant women.

Immune electron microscopy of stools from infected patients has shown the presence of virus-like particles measuring 27-38 nm in diameter.

9. Hepatitis G

Multiple episodes of non-A, non-B hepatitis is humans and chimpanzees suggested the potential presence of another type of blood-borne non-A, non-B hepatitis other than hepatitis C, and this was proven recently with the discovery of hepatitis G. Hepatitis G is an RNA virus that seems to share with hepatitis B and C the means of transmission as well as the presence of a chronic carrier state. The clinical significance of hepatitis G and its natural history are yet to be determined.

Type A Hepatitis

Passive immunization with immune serum globulin (ISG)

Good protection.

Type B Hepatitis

Active immunization with hepatitis B vaccine

Good protection - Passive

Other Hepatitis viruses

No known prophylaxis

10. Table 1. Clinical Features of Viruses Causing Viral Hepatitis

HAV

HBV

HCV

HDV

HEV

HGV

Transmission:

Oral

Percutaneous

Sexual

Perinatal

Yes, common

Rare

No

No

Not likely

Common

Common

Common

Not likely

Common

Yes, uncommon

Yes, ?frequency

No

Common

No

Rare

Yes, common

Unknown

No

Yes, ?frequency

Unknown

Yes

Unknown

Unknown

Incubation Period (Days)

15-49 (average, 25)

60-180

14-160

21-45

15-60

14-35

Clinical Illness

5% pediatric

70-80% adults

5-10%

10%

Higher superinfection

70-80%

Unknown

Jaundice

Adults, 30%

Children, <5%

5-10%

Unknown

Common

Unknown

Fulminant

<1%

Unclear

2-7.5%

<1%, higher in pregnant women

Unclear

Diagnostic Tests:

Acute Infection

Chronic Infection

Immunity

Anti-HAV IgM

N.A. (not available)

Anti-HAV IgG

HBsAg, anti-HBc IgM

HbsAg, anti-HBc IgG

Anti-HBs

HCV RNA (anti-HCV)

Anti-HCV (Elisa) RIBA

N.A.

Anti-HDV IgM

Anti-HDV IgG

N.A.

Anti-HEV IgG (seroconversion)

N.A.

Anti-HEV IgG

HGV RNA

HGV RNA

Unknown

Case-Fatality Rate

0.1-2.7%

1-3%

1-2%

<1% Coinfection

>5% Superinfection

05-.5-4%, 1.5-21% pregnant women

Unknown

Chronic Infection

None

<5%, adults

>90%, infants

80-90%

Superinfection≈80%

Coinfection ≤5%

None

Yes, ?frequency; persistent viremia common

11. Table 2. Hepatitis B Serologic Markers at Different Stages of Infection

Anti-HBs

Anti-HBc IgG

Anti-HBc IgM

HB e Ag

Anti-HBe

Acute hepatitis B

+

-

+ or -

+++

+

-

HBs Ag Carrier

+

-

+++

-

-

+

Chronic hepatitis B

+

-

+++

-

+

-

Recent (<6 months)

Resolved infection

-

++

++

+

-

+

Distant (>6 months)

Resolved inection

-

++

++

-

-

+ or -

HBV vaccinated person

-

++

-

-

-

-