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Journal of Clinical Microbiology, January 1999, p. 235-237, Vol. 37, No. 1
0095-1137/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Viral Superinfection in Previously Unrecognized
Chronic Carriers of Hepatitis B Virus with Superimposed Acute Fulminant
versus Nonfulminant Hepatitis
Chia-Ming
Chu,*
Chau-Ting
Yeh, and
Yun-Fan
Liaw
Liver Research Unit, Chang Gung Memorial
Hospital, Chang Gung University, Taipei, Taiwan
Received 20 May 1998/Returned for modification 3 August
1998/Accepted 13 October 1998
 |
ABSTRACT |
The role of viral superinfection in hepatitis B surface antigen
carriers with superimposed fulminant (n = 60) versus
nonfulminant (n = 90) acute hepatitis was studied. The
frequency of hepatitis A virus (HAV) (0 versus 2.2%), HCV (18.3 versus
21.1%), HDV (15.0 versus 7.8%), and HEV (1.7 versus 4.4%) infection
showed no significant difference, while simultaneous HCV and HDV
infection was significantly more prevalent in the former (8.3 versus
0%). Only 3.6% of fulminant cases and 3.3% of nonfulminant controls
were HGV RNA positive.
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TEXT |
It has long been recognized that a
substantial proportion of hepatitis B surface antigen (HBsAg)-positive
patients with fulminant hepatitis in previous studies were negative for
immunoglobulin M (IgM) antibody hepatitis B core antigen (IgM anti-HBc)
(1, 3, 19, 21, 26, 28). These findings suggested that many HBsAg-positive patients with fulminant hepatitis were indeed previously unrecognized HBsAg carriers with acute exacerbation of chronic hepatitis B virus (HBV) infection or viral superinfection (2, 4,
10), though the possibility of acute HBV infection with poor IgM
anti-HBc response due to mutation of HBV core gene cannot be completely
excluded. Earlier studies revealed that 60 to 80% of HBsAg carriers
with fulminant hepatitis had serological evidence of HDV infection
(9, 26). Since the availability of HCV testing, serological
evidence of HCV infection also has been detected frequently in these
cases in several small reported series of studies (3, 7,
30). With the advent of serological and virological
identification techniques, it is time to revisit the prevalence and
significance of the hepatotropic virus as well as the newly discovered
HGV superinfection in HBsAg carriers with superimposed fulminant versus nonfulminant acute hepatitis.
Patients.
Sixty consecutive HBsAg-positive but IgM
anti-HBc-negative patients, as assayed by radioimmunoassay
(Abbott Laboratories), referred for fulminant hepatitis to our
hospital in a 6-year period from 1990 to 1995, were studied.
Forty-five were men and 15 were women; ages were 18 to 78 years (median
age, 40 years). All received only supportive medical treatment, and 43 patients (88.3%) died shortly after hospitalization. The controls
consisted of 90 age and sex-matched HBsAg-positive but IgM
anti-HBc-negative patients with icteric nonfulminant acute hepatitis
who were admitted to our hospital during the same period. Sixty-seven
were men and 23 were women; ages were 18 to 84 years (median age, 40 years). All study patients and controls were previously healthy
subjects without preexisting liver disease. They were first recognized as chronic HBsAg carriers while presenting these episodes of acute hepatitis. The onset and the likely mode of transmission of HBV infection in these cases were unknown, but chronic HBV infection in
Taiwan is usually acquired perinatally or in early childhood (27). All patients denied homosexual activity or intravenous drug abuse. Drugs and alcohol were excluded as likely etiologic agents.
Serological tests.
Serodiagnosis of acute non-B hepatotropic
virus infection in HBsAg carriers was done by using commercial kits.
The serological tests, assay name, and diagnostic criteria for acute
HAV, HCV, HDV, and HEV superinfection are summarized in Table
1. Among patients who had no evidence of
HAV, HCV, HDV, and HEV superinfection, acute reactivation of the
underlying chronic HBV infection was suspected if serum HBV DNA was
positive by spot hybridization (5), though the presence of
HBV DNA in itself was not diagnostic of this event, and patients were
presumed to have acute hepatitis of unidentified cause if serum HBV DNA
was negative by spot hybridization, but the possibility of acute
reactivation of chronic HBV infection with early clearance of viremia
could not be completely excluded (15). The presence of serum
HGV RNA, as detected by PCR with specific primers
(5'-GAGATTCCTTTTTATGGGCATGG-3' and
5'-CACCAGGTCTCCGTCTTTGAT-3') which were designed in
accordance with the published consensus NS3 region of HGV
(13), in the study cases and controls was then correlated
with the established etiology of acute hepatitis.
Results and discussion.
The results of serological tests for
acute fulminant versus nonfulminant hepatitis superimposed upon chronic
HBsAg carriers are listed in Table 2.
Serological evidence of acute HAV, HCV, HDV, or HEV superinfection was
demonstrated in 27 (45%) of 60 HBsAg carriers with fulminant hepatitis
and in 35.6% (32 of 90) of those with nonfulminant hepatitis
(P > 0.2). Among patients who had no evidence of
hepatotropic virus superinfection, the frequency of HBV DNA positivity
by dot spot hybridization showed no significant difference between
patients with fulminant hepatitis and those with nonfulminant
hepatitis. All but one IgM anti-HDV-positive patient were also positive
for IgG anti-HDV in titers of less than 1:100, suggesting acute rather
than chronic HDV infection (11). Only a few patients with
serum HCV RNA were anti-HCV positive by second-generation enzyme
immunoassay (Table 2), and all had signal cutoff ratios of less than
2.0. These findings might be compatible with acute HCV infection.
However, the possibility of interference of concurrent chronic HBV
infection with anti-HCV response cannot be excluded, as observed in
patients with concurrent chronic HBV and HCV infection (18).
View this table:
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TABLE 2.
Results of serological tests for acute fulminant versus
nonfulminant hepatitis superimposed upon chronic HBsAg carriers
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|
Only a few cases of acute hepatitis in this study could be attributed
to acute HAV superinfection. This finding is in keeping
with the
previous observations that acute hepatitis A is extremely
rare in
adults in Taiwan (
2), as more than 95% of the adults
in the
general population have ever been infected with HAV (
31).
On
the other hand, although Taiwan is not an area of endemicity
for HEV,
sporadic cases of acute hepatitis E not associated with
travel to areas
of endemicity have been reported elsewhere (
14).
Regarding
the possible transmission routes for HCV and HDV, all
patients in this
study denied a history of blood transfusion,
tattooing, acupuncture,
surgery, and dental procedures within
6 months before the onset of
acute hepatitis. Other inapparent
parenteral routes such as
heterosexual transmission should be
considered (
16).
It is noteworthy that the relative frequency of acute HAV, HCV, HDV,
and HEV superinfection showed no significant difference
between
patients with fulminant hepatitis and those with nonfulminant
hepatitis. Furthermore, the relative risk of fulminant hepatitis
in
HBsAg carriers with acute HAV, HCV, HDV, or HEV superinfection
was not
significantly different from the risk for those with acute
reactivation
of chronic HBV infection (Table
2). These data thus
highly suggest that
viral superinfection with HAV, HCV, HDV, or
HEV and acute reactivation
of chronic HBV infection might contribute
to the development of
fulminant hepatitis with a similar risk.
It seems that the varied
etiology of fulminant hepatitis superimposed
upon chronic HBsAg
carriers in the previous studies (
1,
9,
19,
26,
28,
29)
might reflect only the different geographic
and ethnic origins of the
study
patients.
Another important finding of the present study is that 8% of
HBsAg carriers with fulminant hepatitis had simultaneous
acute
HCV and HDV superinfection, compared to none of those with
nonfulminant
hepatitis (
P = 0.02). Our previous study
has shown that 0.5 to
1% of HBsAg carriers in Taiwan had serological
evidence of concurrent
infection with both HCV and HDV (
24).
The most important clinical
implication of the present study is that
HBsAg carriers might
acquire acute HCV and HDV infection simultaneously
from a carrier
of HBV, HCV, and HDV and that simultaneous acute HCV and
HDV superinfection
significantly increases the severity of liver cell
damage (Table
2).
Finally, only 1 (3.6%) of 28 HBsAg carriers with fulminant hepatitis
was HGV RNA positive (this one also had acute HCV infection),
as were
3.3% (3 of 90) of those with nonfulminant hepatitis (two
had acute HCV
infection and one had acute hepatitis of unidentified
cause),
suggesting that the role of HGV infection in HBsAg carriers
with
superimposed acute fulminant or nonfulminant hepatitis is
limited, if
any.
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ACKNOWLEDGMENTS |
Grant support was received from the National Institute of Health
(DOH85-HR-522) and the National Science Council
(NSC87-2315-B-182-003-MH), Taiwan, Republic of China.
We thank S. C. Chen for preparing the manuscript and W. C. Shyu for technical assistance.
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FOOTNOTES |
*
Corresponding author. Mailing address: Liver Research
Unit, Chang Gung Memorial Hospital, 199, Tung Hwa North Rd., Taipei, Taiwan. Phone: 886-3-3281200, ext. 8120. Fax: 886-3-3282824. E-mail: gi31208108{at}adm.cgmh.com.tw.
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Journal of Clinical Microbiology, January 1999, p. 235-237, Vol. 37, No. 1
0095-1137/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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