Blood, Vol. 94 No. 4 (August 15), 1999:
pp. 1460-1464
The Significance of Hepatitis G Virus in Serum of Patients With
Sporadic Fulminant and Subfulminant Hepatitis of Unknown Etiology
By
Santiago J. Muñoz,
Harvey J. Alter,
Yoshiyuki Nakatsuji,
James W.-K. Shih,
Rajender K. Reddy,
Lennox Jeffers,
Eugene R. Schiff,
Andrea E. Reid,
Aldo Marrone,
Kenneth Rothstein,
Cosme Manzarbeitia, and
T. Jake Liang
From the Center for Liver Diseases, Albert Einstein Medical Center,
Philadelphia, PA; the Department of Transfusion Medicine and Clinical
Center, Liver Diseases Section, NIDDK, National Institutes of Health,
Bethesda, MD; the Gastrointestinal Unit, Massachusetts General
Hospital, Boston, MA; and the Center for Liver Diseases, University of
Miami, Miami, FL.
 |
ABSTRACT |
Excluding acute hepatic failure caused by drugs, the etiology of
fulminant hepatitis (FH) remains unknown in many patients. There are
conflicting data about a possible pathogenic role for the hepatitis G
virus (HGV) in patients with cryptogenic fulminant hepatitis (non-A-E
FH). We investigated the presence of circulating HGV in 36 patients
with well-documented non-A-E fulminant and 5 patients with
subfulminant hepatitis from 3 geographic locations in the United
States. Serum HGV RNA was determined by reverse transcriptase-polymerase chain reaction using primers from
the NS5 region of the HGV genome. HGV RNA was also measured before and
after liver transplantation in 5 patients and at different time points
in 7 patients. Serum samples were recoded and reanalyzed for HGV RNA
using different primer sets to assess the validity of the HGV RNA
assay. HGV was present in serum of 14 of the 36 patients (38.8%) with
non-A-E fulminant hepatitis. Twenty percent of patients from the
Northeast, 11% of the patients from the Southeast, and 50% from the
Mid-Atlantic regions of the United States had circulating HGV RNA. The
use of therapeutic blood products was significantly associated with the
presence of serum HGV RNA (P < .02). Retesting for HGV RNA
with different primers was positive in all but 1 case. HGV RNA is not
causally related to non-A-E fulminant hepatitis. The finding of HGV
RNA in serum from these patients is likely related to the
administration of blood product transfusion after the onset of
fulminant hepatitis.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
FULMINANT HEPATITIS (FH) is an uncommon
hepatic disorder characterized by the development of hepatic
encephalopathy within 8 to 12 weeks from the onset of symptoms of acute
liver disease.1 Acute infection with the hepatitis viruses
A or B can be identified as the etiologic agent in 5% to 20% of
patients with FH.2,3 It is now generally accepted that
infection with the hepatitis C virus is an exceedingly rare cause of
FH.4-14 Likewise, FH due to acute infection with the
hepatitis D or E viruses accounts for only a small number of cases in
the United States.7,10,11,13,14 Thus, excluding FH related
to acetaminophen or other drug overdose, nearly 40% to 50% of FH
cases have no discernible etiology and could possibly be due to a
yet-unidentified viral agent. The recent identification and molecular
characterization of the hepatitis G virus (HGV) has led to the
investigation of a potential role for this agent in the etiology of a
variety of chronic and acute cryptogenic hepatic
disorders.15-21 Although it is now apparent that HGV is
ubiquitous and not etiologically related to chronic liver diseases,
there are conflicting data about a putative role of HGV in patients
with cryptogenic FH.22-26 The aim of this work was to
investigate the presence of circulating HGV in a relatively large
number of patients with a sporadic and cryptogenic form of FH from 3 separate geographic locations in the United States.
| |
PATIENTS AND METHODS |
Thirty-one patients who met the diagnostic criteria for fulminant
hepatitis and 5 patients with late onset (subfulminant) hepatitis were
studied.1,27,28 The diagnosis of FH of unknown cause
(cryptogenic; non-A-E) was established by the absence of the following
markers in the patients' serum: HAV-IgM, HBsAg, HBc-IgM, HCV
antibodies (RIBA II), HCV RNA (reverse transcriptase-polymerase chain
reaction [RT-PCR] with 3 sets of primers),7
HBV DNA (PCR),7 HEV RNA (RT-PCR),7 anti-HEV
antibody, antinuclear antibody (ANA), and anti-smooth muscle antibody
(SMA). Sera from 19 patients was tested and found negative for
serologic markers of remote or past infection with HBV and HAV, by
determination of hepatitis B core and surface antibodies and hepatitis
A antibodies. Other causes of FH, such as acetaminophen overdose, other
toxic ingestion, Budd Chiari syndrome, Wilson's disease, and
Epstein-Barr virus (EBV) and cytomegalovirus (CMV)
infections were excluded by history and appropriate biochemical or
serologic assays. Serum samples from the 36 patients were stored at
70°C and aliquots were thawed for duplicate testing of HGV
RNA. HGV was detected in serum using an RT-PCR assay with primers from
the NS5 region of the HGV genome. Briefly, RNA was extracted from 125 µL of serum using RNA isolator (Genosys, Woodlands, TX). After
ethanol precipitation, the pellet was dissolved in 25 µL of
diethyl pyrocarbonate (DEPC)-treated water containing 10 U/µL of RNAsin (Promega, Madison, WI). RT-PCR was performed using an
RNA PCR Core Kit and PCR carry-over prevention kit (Perkin Elmer,
Branchburg, NJ) with primers (0.5 mmol/L each) from the NS5 region of
the HGV genome: sense, 5'-CTCTTTGTGGTAGCCGAGAGAT-3' (nucleotides 6904-6928); and antisense,
5'-CGAATGAGTCAGAGGACGGGGTAT-3' (nucleotides 7004-7036).
Forty-five cycles of PCR (94°C for 1 minute, 55°C for 1 minute,
and 72°C for 1 minute for each cycle) were performed, followed by
an extension reaction at 72°C for 7 minutes. PCR products were
analyzed by dot blot hybridization with a 32P-labeled
oligonucleotide probe: 5'-TCGGTTACTGAGAGCAGCTCAGATGAG-3' (nucleotides 6978-7054). The sensitivity of this assay is 10 HGV RNA
copies per reaction, corresponding to approximately 200 copies/mL of
serum. Positive results were confirmed by an independent assay. To
assess the validity of the HGV RNA assay, the serum samples were tested
for HGV RNA without knowledge of the patient diagnoses. Subsequently,
30 serum samples were recoded and reanalyzed for HGV RNA using
different primer sets from the NS5 region as provided by the
manufacturer (Boehringer Mannheim Gmbh, Mannheim,
Germany).29
In 5 patients, serum samples were tested for HGV RNA before and after
they underwent urgent liver transplantation for FH. Serum samples from
5 other patients were tested for HGV RNA at different time points
during their disease. HGV RNA was also determined in the serum of 10 patients with FH of known etiology (8 acetaminophen overdose and 2 fulminant Wilson's disease) and in 10 individuals without liver
disease, who served as negative controls. Twenty-two FH patients were
from a Mid-Atlantic location, 9 patients from the Southeast United
States, and 5 patients from the Northeast United States. Statistical
analysis for differences in proportions was performed using the
2 test.
| |
RESULTS |
The demographic, clinical, and laboratory characteristics of the 36 patients with sporadic non-A-E FH are presented in
Table 1. Twenty-two patients (61%)
ultimately died, and 14 (38.8%) patients underwent urgent liver
transplantation. HGV RNA was positive by duplicate assays in 14 of 36 patients (38.8%). HGV RNA was found in 1 of 5 (20%) patients from the
Northeast, in 1 of 9 (11%) from the Southeast, and in 12 of 22 (54.5%) patients from the Mid-Atlantic region
(Table 2). None of the patients from the Northeast and Southeast had received therapeutic blood transfusions before sample collection for HGV RNA, whereas 17 of 22 patients from
the Mid-Atlantic region received blood products before testing (Table
2). The distribution of patients according to HGV RNA status and blood
transfusion is shown in Table 3. The
presence of HGV RNA in serum was associated with the use of therapeutic blood transfusion (P = .0203). Of the 12 patients from the
Mid-Atlantic region who tested positive for HGV, 10 had received
transfusion of blood products (Table 3). Other than blood product
transfusion in the 10 patients from the Mid-Atlantic region, none of
the patients had risk factors associated with transmission of hepatitis
viruses before the onset of FH. Analysis of patients with non-A-E
fulminant hepatitis with respect to HGV positivity and transfusions of
blood products demonstrated a significant association of the 2 parameters (P < .02; Table 3). Serum from 5 patients was
obtained on different dates and tested for HGV RNA; in 2 patients
(patients no. 18 and 23), HGV RNA was persistently positive at
different times (samples obtained 2 and 4 days apart), whereas in 2 other patients (no. 17 and 34), HGV RNA was consistently absent in all
samples (samples also obtained 2 and 4 days apart). In a fifth patient
(no. 33), the initial serum sample was negative for HGV RNA but became
positive 12 days later after plasmapheresis and perioperative blood
transfusions. Five patients with non-A-E FH were tested before and
after liver transplantation (LTx). HGV RNA was absent from serum in 2 of these patients (no. 29 and 31) before and after LTx, whereas 2 other patients (no. 26 and 30) demonstrated circulating HGV RNA before and
after LTx. The fifth patient (no. 18) had HGV RNA in serum before LTx,
but lost it 4 weeks after the transplantation procedure. HGV RNA was
also found in 2 patients with FH of known cause and in 1 of 10 individuals without liver disease. Retesting for HGV RNA using a
different set of primers in 30 serum samples confirmed the results in
all cases but 1 patient (no. 24). Because the second set of primers
might span regions with sequence heterogeneity explaining the PCR
negativity, this patient was considered HGV RNA positive for the
prevalence analysis.
| |
DISCUSSION |
The etiology of fulminant hepatitis remains unclear in many of these
patients, because they generally lack evidence of acute infection with
known hepatotropic viruses or other known causes of acute hepatic
failure.7-11,14,30 The identification of HGV led to the hypothesis that this agent could be involved in the pathogenesis of at least some cases of cryptogenic FH. Several studies
with relatively small numbers of patients have addressed this
issue31-42; a summary of published reports is shown in
Table 4. It is clear that observations are
widely diverse among the various preliminary reports. Yoshiba et
al33 first reported the presence of HGV sequences in serum
of 3 of 6 patients with cryptogenic FH. However, the 3 HGV-positive
patients had at least 1 risk factor for acquiring hepatitis viruses
before the onset of FH. In a subsequent brief report, these
investigators expanded their series to 16 patients with non-A-E FH and
detected HGV RNA in 6 (37.5%) of these patients.38 In this
report, only 1 of the patients had received therapeutic blood product
transfusion after the onset of FH but before obtaining the serum sample
for HGV RNA. This led the investigators to conclude that the presence of HGV RNA was not the result of therapeutic transfusions in most of
their cases.38 However, the uncertain reliability of
historical transfusion data obtained from referring hospitals may have
resulted in underestimation of the true frequency of therapeutic
transfusion in these patients. There are 4 full publications to date on
the prevalence of serum HGV RNA in patients with cryptogenic FH,
describing German, Australian, Japanese, and Spanish patients,
respectively.22-25 Heringlake et al25 found
that HGV RNA was present in the serum of 50% of 10 German patients
with non-A-E FH. Although serum samples in this study were obtained on
admission and therefore presumably before transfusion of blood
products, no specific information was provided regarding risk factors
in these patients or the history of transfusion administered at the
referring hospitals. Thus, pre-existing HGV infection or passive
acquisition via blood product transfusions could explain the high
frequency of HGV RNA positivity in this study as well. In contrast,
Moaven et al24 found no trace of HGV RNA in the serum of 14 Australian patients with fulminant FH at the time of admission; most of
them became positive after liver transplantation, suggesting
acquisition of HGV via perioperative blood transfusion, but no
information on preoperative risk factors, including transfusion
history, was provided in this report. In the study by Tanaka et
al,23 only 2 of 11 patients with cryptogenic FH tested
positive for serum HGV RNA, and both patients had previously received
blood or plasma transfusion. Saiz et al22 recently reported
the presence of HGV RNA in serum of 2 of 19 Spanish patients with
idiopathic FH, but no information was provided as to previous transfusion history in this cohort of patients.
HGV RNA has been detected in up to 2% of blood donors; therefore,
there is a high probability of transmission from the large amounts of
fresh frozen plasma used to treat the severe coagulopathy of FH. Our
study included 2 cohorts of patients with sporadic FH that differed
precisely in this aspect. Our observations indicate that positivity for
HGV RNA in FH was strongly associated with the use of therapeutic blood
product transfusion. HGV RNA was rarely found in patients without this
risk factor. The presence of HGV RNA in the serum of patients with
non-A-E FH does not necessarily imply a causative role for HGV. The
critical question is whether HGV infection preceded the fulminant
hepatitis or occurred as a result of whole blood, plasma, or platelet
transfusion in these critically ill patients. Given the
unpredictability of the onset of FH, no serum samples were generally
available before the onset of FH to distinguish between the 2 possibilities. It is conceivable that some of our HGV-positive patients
are chronic HGV carriers who then developed fulminant hepatitis from
another cause. Our observation of a consistent pattern of serum HGV RNA
in patients tested on different dates supports the concept of active
viremia in these patients and a lack of causation of the FH in those
persistently negative for HGV RNA.
Our study is the first to examine the prevalence of HGV in a large
American cohort of patients with cryptogenic FH and provided an
opportunity to directly assess the role of blood product transfusion in
the significance of HGV positivity. The frequency of HGV RNA in serum
of transfused patients was much higher than those who did not receive
transfusion and is thus in agreement with the results from the reports
by Moaven et al,24 Tanaka et al,23 and Saiz et
al.22 One limitation of our study is the lack of determination of HGV RNA and HBV DNA in liver tissue, because previous
reports suggested that a few patients with non-A-E FH may actually
have HBV DNA in hepatic tissue.9,30 Only 1 report is
available on the presence of HGV RNA in liver tissue obtained at the
time of transplantation for seronegative FH.32 HGV RNA was
not detected in liver tissue in any of these patients.
Our observations, taken in the context of the reports summarized in
Table 4, strongly suggest that HGV RNA is not causally related to
non-A-E FH and that the finding of HGV RNA in patients with non-A-E
FH is most likely the result of blood product transfusions administered
after the onset of fulminant hepatitis.
| |
FOOTNOTES |
Submitted December 2, 1998; accepted April 19, 1999.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Santiago J. Muñoz, MD, Albert
Einstein Medical Center, 5401 Old York Rd, Klein Building, Suite 509, Philadelphia, PA 19141.
| |
REFERENCES |
1.
Trey C, Davidson C:
The management of fulminant hepatic failure.
Prog Liver Dis
3:282, 1970[Medline]
[Order article via Infotrieve]
2.
Lee W:
Medical progress: Acute liver failure.
N Engl J Med
329:1862, 1993[Free Full Text]
3.
Thiele DL:
Viral hepatitis and acute liver failure, in
Lee W,
Williams R
(eds):
Acute Liver Failure. Cambridge, UK, Cambridge, 1997, p 10.
4.
Wright T, Hus H, Donegan E, Feinstone S, Greenberg H, Read A:
Hepatitis C virus not found in fulminant non-A, non-B hepatitis.
Ann Intern Med
115:111, 1991
5.
Gordon F, Anastopoulos H, Khettry V, Loda M, Jenkins R, Lewis D, Trey C:
Hepatitis C infection: A rare cause of fulminant hepatic failure.
Am J Gastroenterol
90:117, 1995[Medline]
[Order article via Infotrieve]
6.
Farci P, Alter H, Shimoda A, Govindarajan S, Cheung L, Malpolder J, Sacher R, Shih J, Purcell R:
Hepatitis C-virus associated fulminant hepatic failure.
N Engl J Med
335:631, 1996[Free Full Text]
7.
Liang TJ, Jeffers L, Reddy R, Silva M, Cheinquer H, Findor A, De Medina M, Yarbough P, Reyes G, Schiff E:
Fulminant or subfulminant non-A, non-B viral hepatitis: The role of hepatitis C and E viruses.
Gastroenterology
104:556, 1993[Medline]
[Order article via Infotrieve]
8.
Yoshiba M, Dehara K, Inove K, Okamoto H, Mayumi M:
Contribution of hepatitis C virus to non-A, non-B fulminant hepatitis in Japan.
Hepatology
19:829, 1994[Medline]
[Order article via Infotrieve]
9.
Feray C, Gigou M, Samuel D, Reyes G, Bernoau J, Reyes M, Bismuth H, Brechot C:
Hepatitis C virus RNA and hepatitis B virus DNA in serum and liver of patients with fulminant hepatitis.
Gastroenterology
104:549, 1993[Medline]
[Order article via Infotrieve]
10.
Kuwada S, Patel V, Hollinger F, Yarbough P, Wiesner R, Kaese D, Rakela J:
Non-A, non-B fulminant hepatitis is also non-E, non-C.
Am J Gastroenterol
89:57, 1994[Medline]
[Order article via Infotrieve]
11.
Sallie R, Silva A, Purdy M, Smith H, McCaustland K, Tibbs C, Portmann B, Williams R:
Hepatitis C and E in non-A, non-B fulminant hepatic failure: A polymerase chain reaction and serological study.
J Hepatol
20:580, 1994[Medline]
[Order article via Infotrieve]
12.
Villamil F, Hu K, Yu C, Lee C, Rojter S, Podesta L, Makowka L, Geller S, Vierling J:
Detection of hepatitis C virus with RNA polymerase chain reaction in fulminant hepatic failure.
Hepatology
22:1379, 1995[Medline]
[Order article via Infotrieve]
13.
Sussman N:
Fulminant hepatic failure, in
Zakim D,
Boxer T
(eds):
Hepatology: A Textbook of Liver Disease. Philadelphia, PA, Saunders, 1996, pp 618-650.
14.
Mutimer D, Shaw J, Neuberger J, Skidmore S, Martin B, Hubscher S, McMaster P, Elias E:
Failure to incriminate hepatitis B, hepatitis C, and hepatitis E viruses in the aetiology of fulminant non-A, non-B hepatitis.
Gut
36:433, 1995[Abstract/Free Full Text]
15.
Linnen J, Wages J Jr, Zhang-Kech S-Y, Fry KE, Krawczynski KZ, Alter H, Koonin E, Gallagher M, Alter M, Hadziyannis S, Karayiannis P, Fung K, Nakatsuji Y, Shih W-K, Young L, Piatak M, Hoover C, Fernandez J, Chen S, Zou J-C, Morris T, Hyams K, Ismay S, Lifson J, Hess G, Foung S, Thomas H, Bradley D, Margolis H, Kim J:
Molecular cloning and disease association of hepatitis G virus: A transfusion-transmissible agent.
Science
271:505, 1996[Abstract]
16.
DiBisceglie AM:
Hepatitis G virus infection: A work in progress.
Ann Intern Med
125:772, 1996[Free Full Text]
17.
Alter HJ:
The cloning and clinical implications of HGV and HGBV-C.
N Engl J Med
334:1536, 1996[Free Full Text]
18.
Masuko K, Mitsui T, Iwano K, Yamazaki C, Okuda K, Meguro K, Murayama N, Inoue T, Tsuda F, Okamoto H, Miyakawa Y, Mayumi M:
Infection with hepatitis GB virus C in patients on maintenance hemodialysis.
N Engl J Med
334:1485, 1996[Abstract/Free Full Text]
19.
Schleicker S, Chaves R, Dehmer T, Gregor M, Hess G, Flehming B:
Identification of GBV-C hepatitis G RNA in chronic hepatitis C patients.
J Med Virol
50:71, 1996[Medline]
[Order article via Infotrieve]
20.
Karayiannis P, Hadziyannis SJ, Kim J, Pickering J, Piatak M, Hess G, Yun A, McGarvey M, Wages J, Thomas HC:
Hepatitis G virus infection: Clinical characteristics and response to interferon.
J Viral Hepatol
4:37, 1997[Medline]
[Order article via Infotrieve]
21.
Simons JN, Pilot-Matias TJ, Leary TP, Dawson GJ, Desai SM, Schlauder GG, Muerhoff A, Erker J, Buijk S, Chalmers M, Van Sant C, Mushahwar I:
Identification of two flavivirus-like genomes in the GB hepatitis agent.
Proc Natl Acad Sci USA
92:3401, 1995[Abstract/Free Full Text]
22.
Saiz J, Sans M, Mas A, Olmedo E, Forns X, Lopez-Labrador FX, Restrepo J, Costa J, Salmeron J, Guilera M, Ampurdanes S, Sanchez- Tapias J, Jimenez De Anta M, Rodes J:
Hepatitis G virus infection in fulminant hepatic failure.
Gut
41:696, 1997[Abstract/Free Full Text]
23.
Tanaka M, Nishiguchi S, Tanaka T, Enomoto M, Fukuda K, Takeda T, Nakajima S, Shiomi S, Kuroki T, Monna T, Yano Y, Otani S:
Prevalence of GBV-C and hepatitis G virus variants in patients with fulminant hepatitis in Japan.
J Hepatol
27:966, 1997[Medline]
[Order article via Infotrieve]
24.
Moaven L, Locarnini S, Bowden D, Kim J, Breschkin D, McCaw R, Yun A, Wages J, Jones B, Angus P:
Hepatitis G virus and fulminant hepatic failure: Evidence for transfusion-related infection.
J Hepatol
27:613, 1997[Medline]
[Order article via Infotrieve]
25.
Heringlake S, Osterkamkp S, Trautwein C, Tillmann H, Boker K, Muerhoff S, Mushahwar I, Hunsmann G, Manns M:
Association between fulminant hepatic failure and a strain of GBV virus C.
Lancet
348:1626, 1996[Medline]
[Order article via Infotrieve]
26.
Tameda Y, Kosaka Y, Tagawa S, Takase K, Sawada N, Nakao H, Tsuda F, Tanaka T, Okamoto H, Miyakawa Y, Mayumi M:
Infection with GB virus (GBV-C) in patients with fulminant hepatitis.
J Hepatol
25:842, 1996[Medline]
[Order article via Infotrieve]
27.
Gimson A, O'Grady J, Ede R, Portmann B, Williams R:
Late onset hepatic failure: Clinical, serological and histological features.
Hepatology
6:288, 1986[Medline]
[Order article via Infotrieve]
28.
Bernuau J, Rueff B, Benhamou J:
Fulminant and subfulminant liver failure: Definitions and causes.
Semin Liver Dis
6:97, 1986[Medline]
[Order article via Infotrieve]
29.
Schlueter V, Schmolke S, Stark K, Hess G, Ofenloch-Haehnle B, Engle AM:
Reverse transcription PCR detection of hepatitis G virus.
J Clin Microbiol
34:2660, 1996[Abstract]
30.
Laskus T, Rakela J, Wiesner R, Steers R, Persing D:
Lack of evidence for hepatitis B virus (HBV) infection in fulminant non-A, non-B hepatitis.
Dig Dis Sci
39:1677, 1994[Medline]
[Order article via Infotrieve]
31.
Kanda T, Yokosuka D, Ehata T, Maro Y, Tagawa M, Imazeki F, Saisho H, Shiratori Y, Omata M:
GBV-C is unlikely to be the cause of non-A-E fulminant hepatitis in Japan.
Hepatology
24:531A, 1996
32.
Sallie R, Shaw J, Mutimer D:
GBV-C virus and fulminant hepatic failure.
Lancet
347:1552, 1996[Medline]
[Order article via Infotrieve]
33.
Yoshiba M, Okamoto H, Mishiro S:
Detection of the GBV-C hepatitis virus genome in serum from patients with fulminant hepatitis of unknown aetiology.
Lancet
346:1131, 1995[Medline]
[Order article via Infotrieve]
34.
Mishiro S, Yoshiba M, Okamoto H:
GBV-C in the aetiology of fulminant hepatitis (letter).
Lancet
348:120, 1996[Medline]
[Order article via Infotrieve]
35.
Heringlake S, Tillmann H, Trautwein C, Hunsmann G, Manns MP:
GBV-C Is not the major cause of autoimmune and cryptogenic hepatitis but a certain subtype seems to be frequently associated with fulminant hepatic failure in German patients.
Hepatology
24:290A, 1996
36.
Haydon GH, Jarvis LM, Simmonds P, Simpson KJ, Hayes PC:
Clinical significance of the detection of GBV-C virus in the serum of patients with acute liver failure of unknown aetiology.
Hepatology
24:292A, 1996
37.
Fukumoto T, Berg T, Naumann U, Bechstein WO, Lobeck H, Ku Y, Hopf U, Neuhaus P:
Role of GB virus C in patients with fulminant non A non B hepatitis-A in liver transplant recipients.
Hepatology
24:419A, 1996
38.
Yoshiba M, Inoue K, Sekiyama K:
HGV-C in fulminant hepatitis.
N Engl J Med
335:1392, 1993[Free Full Text]
39.
Kao J-H, Chen P-J, Chen D-S, Tokushige K, Yamauchi K, Hayashi N:
GBV-C in the aetiology of fulminant hepatitis (letter).
Lancet
347:120, 1996[Medline]
[Order article via Infotrieve]
40.
Ishikawa K, Hasegawa K, Kojima S, Nahanishi T, Takatsu K, Shizuma T, et al:
HGV is rare but possible causative agent of non-A-C fulminant hepatitis.
Hepatology
24:527A, 1996
41.
Sheng L, Nevens F, Pirenne J, Aerts R, Kosala H, Setioso E, Fevery J, Yap S:
Hepatitis G virus infection in patients with fulminant hepatitis.
Hepatology
26:601A, 1997
42.
Kuroki T, Nishiguchi S, Tanaka M, Enomoto M, Kobayaski K:
Does GBV-C cause fulminant hepatitis in Japan?
Lancet
347:908, 1996[Medline]
[Order article via Infotrieve]
TOP
ABSTRACT
INTRODUCTION
