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.

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),7HBV 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 χ2 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 (Table2). 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.

Table 1.

Clinical and Laboratory Features of Patients With Non–A-E FH

Patient No. Age (yr) Race Sex DurationAST/ALT Protime Bilirubin HGV RNA Therapeutic Transfusion Other Risk Factors OLT Outcome
1  49 W  M  2  200/475  51.0  451  +  −  − +  Died  
2  57  A  F  14  2,200/2,500  14.9 238  −  −  −  −  Died  
3  18  F  10  1,800/2,100  17.0  386  −  −  − +  Died  
4  35  W  F  20  825/628  16.3 408  −  −  −  +  Alive  
5  55  M  45  1,336/550  21.1  350  −  −  − −  Died  
6  33  W  F  >120  1,165/600 33.4  400  −  −  −  +  Alive  
7  56 W  F  68  2,152/2,242  22.8  84  −  − −  +  Died  
8  65  W  M  >120 695/1,030  18.2  561  −  −  −  −  Died 
9  55  W  M  68  275/372  23.6  401  − −  −  −  Died  
10  16  W  F  25 3,660/9,980  23.7  51  −  −  −  − Alive  
11  26  W  M  20  548/913  >50 679  −  −  −  −  Died  
12  50  F  15  2,800/3,700  24.0  306  +  −  − +  Died  
13  25  W  F  7  2,974/3,752  26.5 645  −  −  −  −  Died  
14  58  M  21  2,493/3,133  15.9  238  −  −  − −  Alive  
15  38  W  F  18  954/1,012 31.0  197  −  FFP  −  −  Died  
16  26 W  M  37  4,881/3,471  22.0  85  −  − −  −  Died  
17  14  W  F  1,900/2,580  17.3  425  −  −  −  − Died  
18  28  W  F  5  939/747  61.9  527 +  Plasmapheresis  −  −  Died  
19  58  F  42  143/170  16.2  394  −  FFP  −  Alive  
20  32  B  M  3  4,620/7,460  29 459  +  −  −  −  Died  
21  33  F  18  1,664/643  26.6  85  +  Plasmapheresis −  −  Alive  
22  19  W  F  1,810/2,112  31.5  78  −  Plasmapheresis  − −  Died  
23  28  B  F  4  10,749/6,996 45  213  +  Plasmapheresis  −  −  Died  
24 69  W  F  10  909/960  40.7  391  −  FFP −  −  Died  
25  31  B  F  8  784/548 42.1  612  +  Plasmapheresis  −  −  Died 
26  16  B  F  21  207/142  33  352  Plasmapheresis  −  +  Alive  
27  18  W  35  386/570  23  765  +  FFP  −  − Alive  
28  26  B  F  3  2,580/5,460  40  62 +  FFP  −  +  Alive  
29  39  W  F  70 450/280  23  330  −  −  −  +  Alive 
30  49  W  F  50  267/234  22.6  323  − FFP  −  +  Died  
31  18  W  F  54 809/818  15.0  204  +  Plasmapheresis  −  Alive  
32  47  W  F  7  568/436  35.5  374 +  Plasmapheresis  −  +  Alive  
33  30  F  14  1,028/984  52.4  391  +  Plasmapheresis −  +  Died  
34  15  W  F  22  324/365 23.4  476  −  Plasmapheresis  −  −  Alive 
35  33  W  M  7  6,274/4,721  28.4  54  − Plasmapheresis  −  −  Alive  
36  20  B  2  255/1,413  38.4  340  +  −  −  − Died  
Total  35.7 ± 16  W: 89% F: 73%  27.7 ± 30  1,823 ± 2,114 29.7 ± 12  342.6 ± 186  (+): 38.8% 17/36 (47.2%)  0%  14/36 (38.8%)  Died: 62.2% 
     2,058 ± 2,356 
Patient No. Age (yr) Race Sex DurationAST/ALT Protime Bilirubin HGV RNA Therapeutic Transfusion Other Risk Factors OLT Outcome
1  49 W  M  2  200/475  51.0  451  +  −  − +  Died  
2  57  A  F  14  2,200/2,500  14.9 238  −  −  −  −  Died  
3  18  F  10  1,800/2,100  17.0  386  −  −  − +  Died  
4  35  W  F  20  825/628  16.3 408  −  −  −  +  Alive  
5  55  M  45  1,336/550  21.1  350  −  −  − −  Died  
6  33  W  F  >120  1,165/600 33.4  400  −  −  −  +  Alive  
7  56 W  F  68  2,152/2,242  22.8  84  −  − −  +  Died  
8  65  W  M  >120 695/1,030  18.2  561  −  −  −  −  Died 
9  55  W  M  68  275/372  23.6  401  − −  −  −  Died  
10  16  W  F  25 3,660/9,980  23.7  51  −  −  −  − Alive  
11  26  W  M  20  548/913  >50 679  −  −  −  −  Died  
12  50  F  15  2,800/3,700  24.0  306  +  −  − +  Died  
13  25  W  F  7  2,974/3,752  26.5 645  −  −  −  −  Died  
14  58  M  21  2,493/3,133  15.9  238  −  −  − −  Alive  
15  38  W  F  18  954/1,012 31.0  197  −  FFP  −  −  Died  
16  26 W  M  37  4,881/3,471  22.0  85  −  − −  −  Died  
17  14  W  F  1,900/2,580  17.3  425  −  −  −  − Died  
18  28  W  F  5  939/747  61.9  527 +  Plasmapheresis  −  −  Died  
19  58  F  42  143/170  16.2  394  −  FFP  −  Alive  
20  32  B  M  3  4,620/7,460  29 459  +  −  −  −  Died  
21  33  F  18  1,664/643  26.6  85  +  Plasmapheresis −  −  Alive  
22  19  W  F  1,810/2,112  31.5  78  −  Plasmapheresis  − −  Died  
23  28  B  F  4  10,749/6,996 45  213  +  Plasmapheresis  −  −  Died  
24 69  W  F  10  909/960  40.7  391  −  FFP −  −  Died  
25  31  B  F  8  784/548 42.1  612  +  Plasmapheresis  −  −  Died 
26  16  B  F  21  207/142  33  352  Plasmapheresis  −  +  Alive  
27  18  W  35  386/570  23  765  +  FFP  −  − Alive  
28  26  B  F  3  2,580/5,460  40  62 +  FFP  −  +  Alive  
29  39  W  F  70 450/280  23  330  −  −  −  +  Alive 
30  49  W  F  50  267/234  22.6  323  − FFP  −  +  Died  
31  18  W  F  54 809/818  15.0  204  +  Plasmapheresis  −  Alive  
32  47  W  F  7  568/436  35.5  374 +  Plasmapheresis  −  +  Alive  
33  30  F  14  1,028/984  52.4  391  +  Plasmapheresis −  +  Died  
34  15  W  F  22  324/365 23.4  476  −  Plasmapheresis  −  −  Alive 
35  33  W  M  7  6,274/4,721  28.4  54  − Plasmapheresis  −  −  Alive  
36  20  B  2  255/1,413  38.4  340  +  −  −  − Died  
Total  35.7 ± 16  W: 89% F: 73%  27.7 ± 30  1,823 ± 2,114 29.7 ± 12  342.6 ± 186  (+): 38.8% 17/36 (47.2%)  0%  14/36 (38.8%)  Died: 62.2% 
     2,058 ± 2,356 

Total values are the means ± SD.

Abbreviations: W, caucasian; B, Afro-American; A, Asian; Duration, days from onset of jaundice to encephalopathy; AST, aspartate aminotransferase; ALT, alanine aminotransferase; Protime, prothrombin time in seconds; Bilirubin, in micromoles per liter (normal, 5 to 17 μmol/L); HGV RNA, qualitative HGV RNA in serum; FFP, fresh frozen plasma; plasmapheresis, exchange plasmapheresis (removal of plasma and replacement with FFP); OLT, orthotopic liver transplantation.

Table 2.

HGV RNA in Serum of Patients With Non–A-E FH

Patient Source Serum HGV RNA (+) Patients With Transfusion*
Northeast (n = 5)  1 (20)  0 (0) 
Mid-Atlantic (n = 22)  12 (55)  17 (77)  
Southeast (n = 9)  1 (11)  0 (0)  
 
FH with known etiology (n = 10) 2 (20)  3 (30)  
Healthy controls (n = 10) 1 (10)  0 (0) 
Patient Source Serum HGV RNA (+) Patients With Transfusion*
Northeast (n = 5)  1 (20)  0 (0) 
Mid-Atlantic (n = 22)  12 (55)  17 (77)  
Southeast (n = 9)  1 (11)  0 (0)  
 
FH with known etiology (n = 10) 2 (20)  3 (30)  
Healthy controls (n = 10) 1 (10)  0 (0) 

Values are the numbers of patients with percentages in parentheses.

*

Patients with non–A-E FH with a history of transfusion of plasma or exchange plasmapheresis.

Eight therapeutic drug-induced FH: 6 acetaminophen, 1 isoniazide, and 1 progabide. Two Wilson’s FH.

Table 3.

Therapeutic Blood Transfusion and Serum HGV RNA in Cryptogenic FH

Blood Transfusion No Blood Transfusion Total
HGV RNA (+)  10   4  14  
HGV RNA (−)   7  15 22  
Total  17  19  36 
Blood Transfusion No Blood Transfusion Total
HGV RNA (+)  10   4  14  
HGV RNA (−)   7  15 22  
Total  17  19  36 

χ2 Test: P < .0203.

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.

Table 4.

Reports on HGV RNA in Cryptogenic FH

Reference Serum HGV RNA [no. (+)/ total no.]% Positive HGV in Liver Transfusion or Other Risk Factors4-150
Heringlake et al25 5/10 50  ND  Unknown  
Kuroki et al42 0/7  0  ND  0/7  
Sallie et al32 0/20 0  0/20  Unknown  
Yoshiba et al33,38  6/16  38  ND  1/16  
Fukumoto et al37 1/12  8  ND  2/12  
Haydon et al36 5/23 22  ND  5/5  
Tanaka et al23 2/19  11 ND  9/19  
Moaven et al24 0/144-151 0  ND Unknown  
Saiz et al22 2/19  11  ND Unknown  
 
Total  21/140  15.6 ± 18 0/20  17/59 
Reference Serum HGV RNA [no. (+)/ total no.]% Positive HGV in Liver Transfusion or Other Risk Factors4-150
Heringlake et al25 5/10 50  ND  Unknown  
Kuroki et al42 0/7  0  ND  0/7  
Sallie et al32 0/20 0  0/20  Unknown  
Yoshiba et al33,38  6/16  38  ND  1/16  
Fukumoto et al37 1/12  8  ND  2/12  
Haydon et al36 5/23 22  ND  5/5  
Tanaka et al23 2/19  11 ND  9/19  
Moaven et al24 0/144-151 0  ND Unknown  
Saiz et al22 2/19  11  ND Unknown  
 
Total  21/140  15.6 ± 18 0/20  17/59 

Abbreviation: ND, not done.

F4-150

Including but not limiting to recent or remote history of hepatitis; transfusion of whole blood, platelets, or fresh plasma; intravenous drug use; and health-related occupation.

F4-151

Eight of the 11 patients who went on to liver transplantation became HGV RNA positive postoperatively, in association with perioperative blood transfusions.

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.

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.

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Author notes

Address reprint requests to Santiago J. Muñoz, MD, Albert Einstein Medical Center, 5401 Old York Rd, Klein Building, Suite 509, Philadelphia, PA 19141.