Hepatitis A, D, E & G

Averell H. Sherker, MD, FRCP(C)

At least five viruses, designated by the first five letters of the alphabet, are responsible for the vast majority of cases of acute and chronic virus-associated hepatitis (Table 1). Hepatitis G has recently been described but remains to be proven as an important cause of human liver disease. Additionally, a large number of other viral agents may be responsible for acute inflammatory disease of the liver – most prominently cytomegalovirus, Epstein-Barr virus and herpes simplex virus. A number of these agents are listed in Table 2. Typically, infection with these agents results in clinical manifestations which overshadow the liver involvement. Previous and future issues of Hepatitis Update focus predominantly on clinically relevant topics related to hepatitis B and hepatitis C viruses. In this issue, an overview of the other hepatitis viruses will be presented, highlighting important recent clinically relevant advances.

Hepatitis A Virus

Epidemics of jaundice have been reported since antiquity. During World War II it was clearly established, based on incubation periods and risk factors, that infectious hepatitis and serum hepatitis were distinct entities. The agents presumed to be responsible for these infections were named hepatitis A virus and hepatitis B virus. Hepatitis A virus (HAV) was first identified at the National Institutes of Health in 1973, using electron microscopy performed on the feces of volunteers experimentally infected with infectious hepatitis.

HAV is extremely resistant to degradation by environmental conditions. Infectivity is reduced only 80% after 16 weeks incubation at 4¬įC and only 99% after four weeks at room temperature.

Undoubtedly, this high degree of resistance to unfavourable conditions is an important factor in the maintenance and spread of HAV in populations.

HAV Vaccination

Two highly effective vaccines against hepatitis A have been licensed in Canada (Havrix, SmithKline Beecham; Vaata, MSD). Both result in protective levels of HAV antibody in over 90% of vaccinees within two weeks of administration. Almost all vaccinees have antibodies within one month. Long-term immunity is achieved with a booster dose between six and 12 months after primary vaccination. Half the adult dose of vaccine is used in children and adolescents under the age of 18 years.

Recommendations for HAV Prophylaxis

HAV vaccination is recommended for preexposure prophylaxis in groups at risk including:· Military personnel· Food handlers· Injection drug usersTravellers to endemic regions (essentially anywhere outside of North America, Western Europe and Japan) Frequently affected communities with more than one documented outbreak in the past five years children and staff of daycare centers, their parents, siblings and contacts.Individuals in whom HAV is an occupational risk including healthcare workers, employees of mental health facilities and sewage workersHemophiliacs and others with frequent exposure to blood productsConsumers of high-risk foods (e.g. raw shellfish)Persons at risk from sexual exposure (homosexually-active males and attendees at STD clinics)

It is probably cost-effective to screen potential vaccines over the age of 40 born in endemic regions or with a history of acute hepatitis, for the presence of HAV antibody (total). Vaccination should only be offered to those who are not immune.

When there has been a known or presumed HAV exposure, or an individual is at risk of exposure before protective antibody is likely, hepatitis A vaccine may be administered concomitantly with pooled immunoglobulin. Separate syringes and different sites must be used.

Patients with chronic liver disease – especially chronic hepatitis C – may be at an increased risk for fulminant hepatitis or death with HAV superinfection. It is prudent to offer HAV vaccination to those individuals who are not already immune.

Hepatitis D Virus

Hepatitis D Virus (HDV) or delta virus is a unique incomplete virus that requires hepatitis B virus (HBV) for its replication. The RNA genome is covered by an outer coat of hepatitis B surface antigen. HDV infection occurs worldwide but is endemic in certain regions including the Mediterranean basin, the Balkan peninsula, the former Soviet Union, parts of Africa and the Middle East and the Amazon basin of South America. In these regions, spread is typically intrafamilial and through sexual contact.

In non-endemic regions, such as North America, HDV infection is uncommon in the general population but does occur in intravenous drug users and persons with frequent exposure to blood products (e.g. hemophiliacs) as well as their sexual contacts.

The clinical course of HDV infection depends largely on whether the virus was acquired as a coinfection with hepatitis B or as a superinfection in an individual with a previously established chronic HDV infection. When acquired as a coinfection, HDV typically results in acute self-limited hepatitis although fulminant hepatitis and death are well described. As a superinfection the typical course is one of a rapidly progressive chronic hepatitis.

Prevention of HDV infection is based on HDV vaccination in susceptible individuals. Patients with chronic HDV infection at risk of HDV infection are advised to avoid parenteral and unprotected sexual exposures.

The epidemiology of HAV is that of an enterically transmitted infection. The virus has a worldwide distribution but the prevalence of antibodies to HAV (signifying previous infection and immunity) varies widely between developing and developed countries and between different socioeconomic classes in individual countries. Typically, in developing countries more than 90% of the population is infected with HAV in childhood. Most HAV infections acquired in childhood are subclinical and anicteric, yet antibodies to the virus persist for life and provide immunity to further infection. Adult acquired infections are likely to be symptomatic and over the age of 40 are associated with a case-fatality rate of over 1%.

Paradoxically, with improved sanitation in developing regions, HAV infection is being delayed until adulthood and large symptomatic epidemics are increasingly being described. In 1988, an outbreak of HAV occurred in Shanghai, China with over 310,000 symptomatic cases reported – particularly in young adults between ages 20 and 40.

In North America, preschool daycare centres are important reservoirs for HAV transmission. In one US study, it was estimated that one-third of all reported cases of HAV could be linked to daycare centers. The young children, who are “vectors” of infection, typically remain asymptomatic while their caregivers, parents and older siblings manifest jaundice and symptomatic hepatitis.

Sexual transmission of HAV is well described, particularly among homosexual males. The widespread practice of “safe sex” techniques has led to a paradoxical increase in cases reported in this group, likely related to the handling of soiled condoms.

Spectacular point-source epidemics of HAV have been widely reported in the media, but account for only a very small proportion of cases. Outbreaks have been traced to infected food handlers or other common sources. Some cases of HAV are related to the ingestion of raw shellfish. Bivalve shellfish (mollusks, not crustaceans) concentrate HAV from sewage-polluted water.

A scheme of the clinical and virological events in hepatitis A is presented in Figure 1. The incubation period is 28 days (range 20-45 days). Virus is shed in the feces for the last two weeks of the incubation period and may also be found in the blood. Prodromal symptoms such as fatigue, anorexia and lowgrade fever may be present late in the incubation period. By the time jaundice and elevated liver enzymes occur, antibodies to the virus are detectable in serum and fecal shedding of virus has ceased. IgM anti-HAV antibody is detectable in an acute infection and typically disappears within six months of infection. Neutralizing IgG anti-HAV antibody persists for life and provides immunity from repeat infection.

The single most important predictor of the clinical course of an acute HAV infection is age. As described above, symptomatic infections are uncommon in young children. In adults, 75 to 95% of infections are symptomatic, with jaundice in the majority of cases. Fulminant hepatic failure is rare but increases over the age of 40, and possibly in the context of underlying chronic liver disease (see: HAV Vaccination). In some individuals, HAV causes a biphasic illness with a second bout of jaundice and cholestasis six to 12 weeks after the primary infection. Chronic HAV infection does not occur and liver enzymes are almost always normal within six months of infection.

The course of HAV infection may be modified through the appropriate use of pooled human immunoglobulin. In household contacts, passive prophylaxis with immunoglobulin within two weeks of exposure reduces icteric disease by more than 80% although infection is not necessarily prevented. Immunoglobulin has previously been recommended to temporarily protect against HAV infection in travellers to endemic regions of the world. Long-term immunity can now be afforded by active immunization.

Hepatitis E Virus

Hepatitis E is a self-limited acute form of viral hepatitis that is typically spread by fecally contaminated water. It occurs endemically in developing countries and has been responsible for epidemics involving thousands of cases in regions of Asia, Africa and Central America. Although HEV may be the most common cause of acute viral hepatitis worldwide, it is virtually unheard of in North America. Rare cases have been described in travellers returning from endemic regions.

The clinical hallmark of HEV infection is its extremely high mortality rate when infection occurs in pregnancy, particularly in the third trimester. No HEV vaccine is yet available and it is unlikely that North American-source pooled immunoglobulin would afford protection from infection.

Hepatitis G Virus

Despite the identification of five hepatitis viruses, there remain cases of presumed viral hepatitis which are not attributable to hepatitis A through E. In 1995 and 1996, two independent groups discovered and sequenced an agent with limited homology to hepatitis C virus. these agents were named GBV-C and hepatitis G virus respectively. They have 96% amino acid identity and represent variants of HGV.

It has been demonstrated that HGV infection is common (one to two percent of US blood donors have HGV RNA detectable in their serum) and that the agent is transmitted by transfusion. Chronic HGV infection does not appear to commonly cause important liver disease and does not alter the course of chronic HCV infection. The vast majority of cases of acute non A-E hepatitis have no evidence of HGV infection.

Similarly, HGV has not been proven to cause fulminant hepatitis. In fact, recent studies suggest that the virus may not even replicate in the liver.

Thus, the role of HGV in acute and chronic hepatitis remains to fully defined. At the present time, HGV does not appear to be an important cause of clinical liver disease.

References

1. Purcell RH, Proc Natl Acad Sei USA 1994;91(7):2401-6.
2. Purcell RH. Gastroenterology 1993;104(4):955-63.
3. Miller RH. Semin Liver Dis 1991;11(2):113-20.
4. Levinthal G. Ray M. Gastroenterologist 1996;4(2):107-17.
5. Koff RS. Am J Trop med Hyg 1995;533(6):586-90.
6. Yuan L. Can Fam Physician 1995;41:1199-205.
7. Koff RS, J Infect Dis 1995;171(Suppl 1):S19-23.
8. Werzberger A, Mensch B, Kuter B, et al. N Engl J Med 1992;327(7):453-7.
9. Vento S, Garofano T. Renzini C. et al. N Engl J Med 1998:338(5):286-90.
10. Willner IR, Uhl MD, Howard SC. et al. Ann Intern Med 1998;128(2):111-4.
11. Furesz J. Scheifele DW, Palkonyay L. CMAJ 1995;152(3):343-8.
12. Anonymous. CMAJ 1996;155(3):302-5.
13. Hadziyannis SJ. J Gastroenterol Hepatol 1997;12(4):289-98.
14. Lai MM. annu Rev Biochem 1995;64:259-86.
15. Smedile A, Rizzetto M. Gerin JL. Prof Liver Dis 1994;12:157-75.
16. Mast EE, Purdy MA, Krawczynski K. Baillieres Clin Gastroenterol 1996;10(2):227-42.
17. Mast EE, Krawczynski K. Ann Rev Med 1996;47:257-66.
18. Krawczynski K. hepatology 1993;17(5):932-41.
19. Reyes GR, Purdy MA, Kim JP, et al. Science 1990;247(4948):1335-9.
20. Thomas HC, Pickering J, Karayiannis P.J Viral Hepat 1997;(4 Suppl)1:51-4.
21. Alter MJ, Gallagher m. Morris TT, et al. N Engl J Med 1997;336(11):741-6.
22. Simons JN, Leary TP, Dawson GJ et at. Nat Med 1995;1(6):564-9.

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