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Published: September 2008Print Record of Viewing
Hepatitis A and hepatitis E are relatively uncommon in the United States. The viruses share similar transmission routes and have similar clinical presentation.
Dr. Joseph Yao discusses appropriate selection of laboratory tests for diagnosis of these viral hepatitides.
Presenter: Joseph Yao MD, from the Division of Clinical Microbiology at Mayo Clinic
Welcome to Mayo Medical Laboratories’ Hot Topics. These presentations provide short discussion of current topics and may be helpful to you in your practice.
Our presenter for this program is Dr. Joseph Yao, from the Division of Clinical Microbiology at Mayo Clinic. Dr. Yao will be discussing the epidemiology of Hepatitis A and Hepatitis E and the appropriate laboratory testing for these viruses.
Let’s begin by looking at the patient case of a health care worker presenting for a post-employment health evaluation. The patient is a 35 year-old, foreign-born, healthy woman. She is interested in knowing her immunity status to Hepatitis A.
What laboratory test can be used to determine if this she has had Hepatitis A in the past or is immune to this viral hepatitis?
This is a geographic distribution of Hepatitis A virus infection in the world. Those countries or regions shown in red are those with high prevalence of Hepatitis A infection whereas those with yellow or white are those with low or very low prevalence of infection. So you can see then in North America, the population is relatively low in prevalence for Hepatitis A.
Most cases of Hepatitis A are sporadic, however there are outbreaks known to occur in North America, and these are usually food borne outbreaks. The most common transmission occurs through contaminated food or water sources, but there can also be person-to-person transmission through fecal-oral routes.
The source of the infection comes also from persons excreting Hepatitis A particles in their stool. They are infectious from 2-3 weeks before the onset of jaundice, up to about a week after jaundice appears in the infected individuals. Fortunately, there is no carrier state, and thus there is no chronic Hepatitis A as a sequelae.
This is the typical serologic course of Hepatitis A infection. Within 1-2 weeks after exposure to this virus, the virus will appear in the stool as well as in the blood. The viremic phase is very short, usually 4 weeks or less. At the end of the viremic phase, the liver enzymes, ALT for example, usually rise, which corresponds to the appearance of clinical illness. It is also at this time that Hepatitis A-specific IgM antibodies appear in the blood. This is followed by the appearance of Hepatitis A IgG antibodies; however, in the clinical laboratories we are not able to determine Hepatitis A-specific IgG antibodies only. We are able to determine Hepatitis A IgM and Hepatitis A total antibodies, which measures both IgG and IgM together in the result.
Hepatitis A diagnosis depends on a strong clinical suspicion in those individuals with clinical findings suggestive of viral hepatitis belong with epidemiologic exposures to potential sources of contaminated food or water. The diagnosis can then be confirmed by laboratory testing and specifically serologic tests for Hepatitis A specific IgM is sufficient to determine the presence of acute Hepatitis A. Hepatitis A-specific total antibodies will be present for those with acute infection, but it is more useful for determining a past infection or immunity to Hepatitis A vaccines.
The current laboratory methods for Hepatitis A serologic marker testing are listed here. There are enzyme immunoassays EIA, such as DiaSorin the manual assay or and their automated ETI-MAX instrumentation. The microparticle EIA such as the Abbott AxSYM or IMx method, or the chemiluminescence immunoassays such as those with the Ortho Vitros ECi/ECiQ, Siemens ADVIA Centaur, Siemens Immulite 2000, as well as the Abbott Architect system.
Back to our patient study, using tests available at Mayo Medical Laboratory, there are two options for testing this individual’s immune status to Hepatitis A vaccination. One can order either the Hepatitis A total antibodies test or the Hepatitis A total antibodies with reflex to IgM antibodies test.
In this individual, the provider requested the Hepatitis A total antibodies only and the results came back positive.
Now, with the positive Hepatitis A total antibodies, there are actually two possibilities. It could be acute Hepatitis A, or past Hepatitis A infection or vaccine immunity. Without knowing the Hepatitis A IgM antibody status, it may be difficult to distinguish between the first two conditions listed on this table. However, in individuals who have no signs or symptoms of viral hepatitis at the time of testing, it is most likely that this represents either past infection or vaccine immunity.
In this non-symptomatic healthcare worker, the presence of Hepatitis A total antibodies most likely indicates either past infection or vaccine immunity. Note that those who have never been infected or vaccinated or who have never been exposed, the Hepatitis A total antibodies would be negative.
In our individual of this case, she did not have a history of Hepatitis A vaccinations in the past, so the presence of the total Hepatitis A antibody reflects past infection. Based on the history that she is foreign-born and potentially comes from a Hepatitis A endemic area, she probably acquired this infection in the remote past and has lifelong immunity based on this past infection.
In healthy individuals without a history of Hepatitis A vaccination, presence of the Hepatitis A total antibody indicates most likely Hepatitis A IgG antibodies and this is a reflection on past Hepatitis A infections. For those with a history of Hepatitis A vaccination, this result could be due to past infection or vaccine immunity since we do not routinely test for past infection prior to vaccination.
Let’s review the current epidemiology of acute Hepatitis A in the United States. In the last 20 years, you can see that the incidence of acute Hepatitis A has decreased remarkably from about 12-14 cases per 100,000 people in population to 2 or fewer cases per 100,000 people in population in the last 10 years. This observation is due in part to improved sanitation and water treatment as well as immunization recommendation from the advisory committee on immunization practice at the CDC. The Hepatitis A vaccine is now a routine vaccination for children.
We also see that in the last 15 years, the incidence of acute Hepatitis A is highest at the adolescent and early young adult age group, indicated by the dotted lines and long dash lines. In all age groups that have been surveyed and monitored closely, the incidence has decreased at the same rates for all five age groups indicated here in the last 10 years.
Among those who do acquire acute Hepatitis A, we can see from these graphs that the three major risk factors for acquisition of this virus are"
Other reported cases includes injection drug use, day care employees, and men who have sex with men, but these cases are half or less compared to the other three known risk groups.
The incidence of Hepatitis A has also decreased among the various races and ethnic groups over the last 15 years. You can see that a remarkable drop is most evident among the American Indian and Alaskan Natives population and also decreased in the Hispanic ethnic group as well.
Next I’m going to discuss Hepatitis E as it is very similar in transmission modes and presentation to acute Hepatitis A. You can see from this geographic distribution of Hepatitis A that the cases are mainly found in the developing countries near the tropical and sub-tropical areas of the world. Outbreaks of Hepatitis E account for more than 25% of the sporadic non-A, non-B, and non-C acute hepatitis in these regions.
Hepatitis E is transmitted in the same way as Hepatitis A – through contaminated water or food and from person-to-person, though the person-to-person is quite rare through fecal-to-oral transmission. As indicated in the previous geographical distribution slide, the transmission is mainly in developing countries and acquired in travelers to developing countries. Hepatitis E is rarely found endemic in developed countries. There are also no carrier state sequelae similar to the situation in Hepatitis A.
This is the typical serologic course of Hepatitis A infection. You can see that within three weeks of exposure to this viral infection it appears in the stool of the infected individuals and symptoms of viral hepatitis appear at the time when ALT and Hepatitis A IgM appear in the blood and then similarly with the decline of symptoms and Hepatitis A IgM, Hepatitis A-specific IgG appears in the serum.
Diagnosis of Hepatitis E is again confirmed by serologic testing. As you can see from this table, acute Hepatitis A is confirmed by the presence of Hepatitis A-specific IgM antibody whereas past infection is defined by the presence of Hepatitis A-specific IgG antibody. However, a note of caution is needed here because in populations with low prevalence of Hepatitis A infection, such as North America, Hepatitis A IgM results are frequently falsely-positive due to the low positive predictive value of this test in such low-prevalence populations.
In summary, Hepatitis A diagnosis requires a high index of suspicion in patients with epidemiologic exposure history. Hepatitis A IgM positive results must be correlated carefully with clinical findings and epidemiologic exposure history because of the frequency of false-positive results.
The presence of Hepatitis A-specific total antibodies in individuals who are non-symptomatic usually represent past infection or vaccination with the Hepatitis A vaccine.
For Hepatitis E, again the diagnosis requires a high index of suspicion for those individuals with a travel history to developing countries.
Finally, one must be aware of false-positives of IgM results for Hepatitis A and so such results must be correlated with clinical findings and epidemiologic exposures.
I wish to disclose that I receive research grants currently and in the past from Roche Diagnostics, Siemens Healthcare Diagnostics, and Third Wave Technologies. I have also served on the advisory board for Roche Diagnostics and Siemens Healthcare Diagnostics.