Hepatitis G virus co-infection in liver transplantation recipients with chronic hepatitis C and nonviral chronic liver disease

Hepatitis G virus (HGV) is a newly described RNA virus that is parenterally transmitted and has been found frequently in patients with chronic hepatitis C infection. To determine the impact of hepatitis G virus co-infection on morbidity and mortality following liver transplantation, we measured HGV RNA by polymerase chain reaction in pre and posttransplantation sera from a cohort of patients transplanted for chronic hepatitis C and a control group of patients transplanted for nonviral causes who were negative for hepatitis C virus (HCV) RNA in serum. The overall prevalence rate of HGV RNA in transplanted patients with chronic hepatitis C was 20.7%. HGV infection was present before transplantation in 13% while it appeared to have been acquired at the time of transplantation in 7.4%. Mean serum alanine aminotransferase activity, hepatic histological activity, and patient and graft survival were similar between HGV-positive and HGV-negative patients. The prevalence rate of HGV RNA in transplanted controls was 64% (P < .01) with a significantly higher rate of acquisition of HGV infection following transplantation (53%, P < .001) when compared with patients with chronic hepatitis C. Mean serum alanine aminotransferase activity was significantly lower in the control patients with HGV infection alone following transplantation than in patients co-infected with hepatitis C (37 +/- 9 vs. 70 +/- 33 U/L, P < .01). Thus, HGV is frequently found in transplantation patients co-infected with hepatitis C although it appears to have minimal clinical impact. In patients transplanted for nonviral causes of end-stage liver disease, a high rate of hepatitis G acquisition at the time of transplantation may occur but does not appear to predispose to chronic hepatitis.     

Hepatitis C--associated glomerular disease in liver transplant recipients

Hepatitis C virus (HCV) infection may be associated with extrahepatic illness including renal disease. We investigated the clinical and virological characteristics of three patients who developed a mesangial proliferative and sclerosing glomerulopathy alone or in association with membranoproliferative glomerulonephritis after liver transplantation for end-stage liver disease secondary to HCV infection. Using polymerase chain reaction technology and the IgM RIBA assay, viral load, genotype and IgM antibody response to HCV in the setting of glomerulonephritis was evaluated. Within 1 year of transplantation, the patients showed decreased renal function, proteinuria and recurrent hepatitis C liver disease. Likewise, HCV viral load increased following transplantation, whereas the viral genotypes remained unchanged. Although the first patient presented with classic type II cryoglobulinemia in association with glomerulonephritis, the second patient developed an IgM directed specifically against the hepatitis C core antigen. The third patient developed a low-titered IgM directed against the hepatitis C core antigen with rheumatoid factor activity but without cryoglobulinemia. All of the patients show IgM in glomerular capillary walls by biopsy. One patient has shown a clinical response to interferon (IFN) alfa-2b therapy without evidence of hepatic allograft rejection. The second and third patients have not responded to IFN or developed hepatic rejection. This study suggests that HCV-associated glomerulonephritis may complicate liver transplantation in conjunction with the production of increased amounts of IgM of variable specificity. The posttransplant setting may provide a unique situation in which to investigate the specific requirements for the onset of renal disease.     

Human immunodeficiency virus and hepatitis C virus coinfection

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) share the same parenteral, sexual and vertical routes of transmission (McNair et al. 1992). This common epidemiology explains the high frequency of combined infections by hepatotropic viruses in HIV-infected patients. The aim of the present review is to clarify some important issues dealing with the reciprocal interactions between HIV and hepatitis C virus infections. The main topics include epidemiology, virological markers of HIV-infection, histopathology, natural course and treatment of hepatitis C in HIV-infected individuals.     

Hepatitis G virus infection among liver graft recipients: anatomoclinical correlations

Hepatitis G virus (HGV) causes persistent infection in man, but its disease association is controversial. We studied the HGV disease association in 25 liver transplantation (LT) recipients without evidence of hepatitis B and C infection. HGV RNA was tested by semiquantitative RT-PCR in serial serum samples and its presence was correlated with the biochemical and histological evidence of liver damage. The overall prevalence of HGV infection in this population was 9/25 (36%), one patient being HGV RNA positive since before LT, while the other eight apparently acquired de novo infections after LT. In five cases, appearance of HGV was followed by biochemical and histological evidence of liver damage: the liver biopsy showed acute rejection in two cases, acute cholangitis in two, and acute hepatitis in one. At the end of follow-up, histological evidence of chronic hepatitis was found in one HGV-positive patient but also in three HGV-negative patients, whereas the only patient with acute hepatitis at the time HGV RNA was first detected in serum developed an intralobular gigantocellular granuloma. In conclusion, HGV infection after LT may be seldom associated with acute and chronic liver damage, but comparable histological features can be observed also among HGV-negative controls.     

Hepatitis B vaccination results in 140 liver transplant recipients

BACKGROUND/AIMS: Human autologous liver transplantation is possible due to an adequate suppression of the body's immune response. This also causes a higher hepatitis infection rate, making hepatitis prevention very important. MATERIALS AND METHODS: We describe our experience with hepatitis B virus vaccination in 140 adult liver transplant recipients, transplanted from 1986 to 1994 with more than one year of follow-up. Excluded were those who had hepatitis B surface antigens or antibodies to those antigens before the transplant. The vaccination schedule was 0-1-2 months with a double dose of recombinant vaccine. RESULTS: The total response rate (surface antigen antibodies > 10 U) was 40% (56/140); the rate was 47.7% in men and 26% in women. At the end of the study, only 17.1% (24/140) of the patients had antibodies > 10 U. The response rate was higher in patients with antibodies to hepatitis B core antigen (66.6%) than in those lacking antibodies (31.7%), and more long lasting (42.4% vs 11.2%). The response rate in 116 patients with booster doses was 12.9%. Six correctly vaccinated patients (4.28%) acquired new hepatitis B virus infections after the operation. CONCLUSIONS: The total response rate in these patients is much lower than in the general population, and there is a rapid decline of titers, probably due to immunosuppression. The role of booster doses in these patients should be clarified.     

GB virus C/hepatitis G virus infection in autoimmune liver diseases

Cutaneous necrosis may occur as a complication of treatment with interferon. Here we report the first case of cutaneous necrosis developing in a patient receiving interferon alpha-2b for the treatment of chronic hepatitis C viral infection. The patient developed two necrotic lesions while receiving high doses of interferon. We suggest that discontinuation of treatment may be necessary to permit healing of such lesions. Although the exact mechanism involved in cutaneous necrosis remains unknown, our observations support earlier findings suggesting that intraarterial injection may be a factor.     

Comparative analysis of three nucleic acid-based detection systems for hepatitis C virus RNA in plasma from liver transplant recipients

The early detection of hepatitis C viraemia (HCV) following liver transplantation is important for monitoring disease recurrence and planning antiviral chemotherapy. In the current study, the sensitivity, specificity, and concordance of three HCV RNA assays were compared using a random sample of 84 plasma specimens from 23 transplant recipients. Two of the assays were prototype commercial tests: Roche Molecular Diagnostic's RT-PCR HCV Amplicor system; and Chiron's Quantiplex HCV-RNA assay. The third was a 'home brew' PCR-liquid hybridization/gel retardation assay developed at the University of Pittsburgh Medical Center (UPMC). On all criteria the PCR-based assays out-performed the Quantiplex assay and displayed an overall concordance of 87%. A high percentage of specimens in the Quantiplex assay gave indeterminate results (12%) or high coefficients of variance (13%). The specificities of all RNA assays were determined using HCV serostatus as the gold standard. Both of the PCR-based assays had specificities of 100%, whereas the Chiron Quantiplex HCV assay had a specificity of 88%, if indeterminates were counted as negatives, and a specificity of 64% if indeterminates were counted as positives. The calculated sensitivities of the PCR-based assays were 56% and 48% for the 'home brew' and the Roche assays, respectively. The UPMC HCV assay, however, was determined to be capable of reproducibly detecting four or fewer chimpanzee infectious doses, suggesting that HCV viraemia was not present in the PCR-negative cases. The sensitivity of the Quantiplex assay was 41% counting indeterminates as negatives and 46% counting them as positives. The high cost of the Quantiplex assay combined with the number of uninterpretable results, the lack of sensitivity, and reduced specificity may limit the usefulness of this assay for monitoring HCV recurrence.     

Chronic hepatitis in children after liver transplantation: role of hepatitis C virus and hepatitis G virus infections

BACKGROUND/AIMS: Chronic graft hepatitis occurs in 20-30% adults after liver transplantation but the prevalence and causes in children are not known. In adults, hepatitis C virus infection is prevalent prior to transplantation and recurrent infection is a frequent cause of graft dysfunction. The significance of the recently described hepatitis G virus infection remains unproven. The aim of this study was to examine the role of hepatitis C virus and hepatitis G virus infection in chronic graft hepatitis after paediatric liver transplantation. METHODS: The prevalence of graft hepatitis and the role of hepatitis C virus and hepatitis G virus infections in 80 children after liver transplantation have been studied, with a median follow up of 4.4 years (range 0.4 to 10.7), and the persistence of hepatitis G infection in the presence of immunosuppression has been determined. RESULTS: Chronic graft hepatitis was diagnosed in 19/80 (24%) children and was most frequently seen in children transplanted for cryptogenic cirrhosis (71%). There was no significant difference in the prevalence of chronic hepatitis in those transplanted before or after donor anti-HCV screening. Hepatitis C infection occurred in three children transplanted prior to donor screening but in only one was associated with chronic hepatitis. Hepatitis G infection was found in 22/79 (28%) transplant recipients but was not associated with graft hepatitis. In 17/21 children hepatitis G infection persisted for a median of 5.2 years after transplantation. CONCLUSION: Chronic hepatitis occurred in 24% of children after liver transplantation, a similar prevalence to that in adults. Cryptogenic liver disease predisposed to graft hepatitis, but neither hepatitis C nor hepatitis G infection was associated. Hepatitis G virus caused a frequent and usually persistent infection after transplantation.     

Hepatitis C virus genotypes in liver transplant recipients: impact on posttransplant recurrence, infections, response to interferon-alpha therapy and outcome

BACKGROUND: End-stage liver disease due to hepatitis C virus (HCV) is the most common indication for liver transplantation in U.S. veterans. We investigated the influence of HCV genotypes on the incidence and timing of recurrent HCV hepatitis, survival, infectious morbidity, and response to interferon-alpha therapy in this unique patient population. METHODS: HCV genotype was determined by direct sequencing of the NS5 region of HCV with type-specific primers. RESULTS: Genotype 1a (66%, 32/47) was the predominant genotype. Type 1b was found in 25% (12/47) of patients and type 2b was found in 9% (4/47). Histopathologically recurrent HCV hepatitis developed in 53% (25/47) of the patients after transplantation. This group included 45% (14/31) of the patients with type 1a, 67% (8/12) of the patients with type 1b, and 25% (1/4) of the patients with type 2b (P>0.5). The time to recurrence and the severity of HCV recurrence as defined by aminotransferase levels or Knodell scores were not different among the three genotypes. There was a trend toward a higher incidence of major infections in patients with type 1b (75%) versus type 1a (48%) and type 2b (50%) (P=0.11). The response to interferon-a therapy did not differ significantly among the genotypes. Mortality at 5 years was 16% (5/31) in patients with genotype 1a, 42% (5/12) in patients with genotype 1b, and 50% (2/4) in patients with genotype 2b (P=0.06). CONCLUSIONS: The incidence, time to recurrence, and response to interferon-alpha therapy did not differ between the various genotypes in our liver transplant recipients. However, there was a trend toward higher infectious morbidity and overall mortality in patients with genotype 1b after transplantation.     

Quantitation of hepatitis G virus RNA in allogeneic bone marrow transplant recipients. Stem Cell Transplantation Team

In thermolysin, tryptophan 115 seems to be at the S2 subsite. Trp-115 was replaced with tyrosine, phenylalanine, leucine, and valine during site-directed mutagenesis in order to evaluate the role of Trp-115 in the proteolytic activity of thermolysin. The mutant enzymes with Tyr-115 or Phe-115 had as much proteolytic activity as the wild-type enzyme, but the other two mutant enzymes had no activity. We found earlier that the substitution of Trp-115 with alanine, glutamic acid, lysine, and glutamine causes the enzyme to lose all activity, so an aromatic amino acid at position 115 seems to be essential for thermolysin.     

GB virus C/hepatitis G virus infection: a favorable prognostic factor in human immunodeficiency virus-infected patients?

Lung disease is a rare complication of inflammatory bowel disease (IBD). Herein is a series of seven IBD patients who developed new, persistent and unexplained symptoms of respiratory disease, particularly chronic productive cough. Using a CT scan of the chest, a diagnosis of bronchiectasis was made in five patients, while the diagnosis of chronic bronchitis was made in two patients. Factors, other than IBD, that could account for pulmonary disease in these patients were absent. Several important clinical patterns for IBD-associated large airway disease were uncovered and are reviewed in light of earlier case reports in the medical literature. A discussion regarding the possible pathogenesis of IBD-associated airway disease follows.     

Hepatitis C virus and liver diseases

Pigmented villonodular synovitis is an uncommon synovial disease which only rarely involves the hip. In a multicenter retrospective study, we identified 58 histologically-proven cases. There were 33 females and 25 males. Mean age at diagnosis was 38 years. In all but two cases, only one hip was involved; the right hip was affected somewhat more often (33 cases) than the left. Two patients probably had bilateral hip disease. Mean delay to diagnosis was four years. Pain was the presenting symptom in most cases. A palpable mass in the groin was found in six patients. Plain roentgenograms were considered normal in only three patients. Bony cysts were seen in 39 patients and kissing cysts in 19. Joint space narrowing was found in 40 patients and was diffuse in half the cases. Roentgenograms suggested pigmented villonodular synovitis in 63% of cases, osteoarthritis of the hip in 16%, and inflammatory hip disease in 14%. Additional imaging studies included opaque arthrography in 21 subjects, computed tomography in 23, magnetic resonance imaging in 11, and arthroscopy in 9. Initial treatment was osmic acid synoviorthesis in 14 patients, partial synovectomy in 9, and total synovectomy in 21; in addition, eight patients had insertion of a cup prosthesis and 13 had total arthroplasty of the hip. Treatment was successful in 65% of cases after a mean follow-up of three years; among the 35% of failures, there were seven recurrences (14%). Total hip arthroplasty was performed secondarily in nine patients. This study illustrates the diversity of roentgenological changes in pigmented villonodular synovitis of the hip and the high frequency of osteoarticular lesions precluding conservative treatment. Magnetic resonance imaging and/or arthroscopy should be used to establish the diagnosis at an early stage when conservative treatment with total synovectomy and synoviorthesis is most likely to be successful.     

Quantitation of hepatitis G and C viruses in the liver: evidence that hepatitis G virus is not hepatotropic

Hepatitis G virus (HGV) is prevalent in patients with chronic liver disease and has been previously detected in liver specimens. However, it is unknown whether the virus is replicating in the liver or is simply a contaminant from serum. We sought to determine whether HGV was hepatotropic and to determine whether coinfection with HGV and hepatitis C virus (HCV) influenced the level of either virus. Virus was quantitated using branched DNA (bDNA) assay for both HGV and HCV in the liver explants and pretransplant serum samples from 30 transplant recipients: Group I, HGV/HCV coinfection (n = 10); group II, HCV infection alone, (n = 8); group III, HGV alone (n = 12). In patients with coinfection HCV (RNA) titers in liver were consistently higher than those for HGV RNA (median 1.13 x 10(8) and 360,000 Eq/g respectively, P < .01). The ratio of liver/serum viral RNA was significantly higher for HCV than for HGV (median 129 and 0.3 respectively, P < .01). Levels of HCV RNA were similar in patients with HCV infection alone versus those with HGV/HCV coinfection (median; liver = 1.15 x 10(7) vs. 1.13 x 10(8) Eq/g, serum = 500,000 vs. 200,000 Eq/mL) and levels of HGV RNA in liver and serum were similar in patients with HGV infection alone compared to those with HGV/HCV coinfection (median; liver = 1.2 x 10(6) vs. 4.0 x 10(5) Eq/g, serum = 4.5 x 106 vs. 2.6 x 10(6) Eq/mL). Levels of either virus appeared unaffected by the presence of an additional virus. The high ratio of HCV RNA levels in liver compared to serum is consistent with its known hepatotropism, but this pattern was not observed for HGV. The median liver/serum ratio of HGV RNA was less than unity, a finding consistent with serum contamination of liver tissue. Thus we conclude that the liver is not the main site of HGV replication.