IFN-λ3 as a host immune response in acute hepatitis E virus infection.

BACKGROUND AND AIM: Hepatitis E virus (HEV) is mainly transmitted orally, either waterborne or zoonotic foodborne. Intestinal viruses such as rotavirus are known to induce type III interferon (IFN) in the gastrointestinal (GI) tract where type III IFN dominantly functions in comparison with type I IFN. Therefore, the aim of this study is to investigate the significance of type III IFN (IFN-λ3) in acute hepatitis E. METHODS: IFN-λ3 and HEV RNA levels in the sera of patients with acute HEV infection and in the supernatant of HEV-inoculated cells were measured, using an in-house high-sensitivity method and reverse transcription-polymerase chain reaction, respectively. RESULTS: High serum IFN-λ3 levels were found in the early phase of acute HEV infection, which normalized after resolution. Interestingly, serum IFN-λ3 levels correlated well with serum HEV RNA titers in the same sera, both of which showed the peak before the robust increase of transaminases. In vitro experiments demonstrated that HEV replicated well in the cells with little IFN-λ3 induction (Caco-2, A549) and recombinant IFN-λ3 inhibited HEV replication in a dose-dependent manner. In contrast, in HT-29 cells, a colon cancer cell line, HEV poorly replicated and induced IFN-λ3 in a titer-dependent manner. CONCLUSIONS: These clinical and experimental observations suggest that HEV induced IFN-λ3 as a host innate immune response, which may play a protective role against HEV.

Hepatitis E virus genotype 3 is a common finding in liver-transplanted patients undergoing liver biopsy for elevated liver enzymes with a low De Ritis ratio and suspected acute rejection: A real-world cohort.

BACKGROUND: Hepatitis E virus (HEV) infection is a potential reason for elevated liver enzymes after liver transplantation (LT). Our aim was to analyze a real-world cohort of LT patients, who underwent liver biopsy for elevated transaminases and suspected acute rejection, to evaluate frequency of post-transplant HEV infection. PATIENTS: Data from 160 liver biopsies were analyzed. Seventy-one patients were biopsied on schedule after LT without elevated liver enzymes. A subgroup of 25 patients with elevated liver enzymes and suspected rejection was chosen for further analysis. Patient demographics and data were retrieved from a clinical database, patients' charts, and reports. RESULTS: Hepatitis E virus infection was diagnosed in five of 25 patients with suspected acute rejection (20%). HEV genotype 3 was detected in three of the five HEV-infected patients. Patients with HEV infection showed higher ALT levels (P = 0.014), lower De Ritis ratio (P = 0.021), and more frequent glucocorticoid therapy (P = 0.012) compared to HEV-negative patients. CONCLUSION: We found a rate of 20% HEV infections in LT patients undergoing liver biopsy for elevated liver enzymes and suspected acute rejection. These data indicate the necessity for HEV testing in all LT patients with elevated liver enzymes and suspected acute rejection.

Lack of persistent hepatitis E virus infection as a cause for unexplained transaminase elevation in renal transplant recipients in India.

BACKGROUND: Hepatitis E virus (HEV) infection is highly endemic in India, being the most common cause of acute hepatitis; however, no case of chronic infection has been reported. All the human isolates of HEV from India till date have belonged to genotype 1. In contrast, in non-endemic areas, genotype 3 is the most prevalent, and persistent HEV infection has been reported among solid-organ transplant recipients. Whether persistent infection occurs with genotype 1 HEV is unclear. We therefore looked for evidence of HEV infection among renal transplant recipients with elevated alanine transaminase (ALT). METHODS: Renal transplant recipients receiving immunosuppressive therapy were screened for ALT levels, irrespective of time duration since renal transplant. For those with ALT levels equal to or exceeding 50 IU/mL on at least two occasions ≥3 weeks apart, serum was tested for HEV RNA using a sensitive real-time reverse transcription polymerase chain reaction assay. For those testing positive, HEV genotyping and follow up for duration of viral persistence were planned. RESULTS: Of the 275 patients studied, 49 (17.8 %, 44 male, median age = 39.5 years) had elevated ALT levels (median = 62 [range = 50-477] IU/L). None of these 49 patients had detectable HEV RNA in the serum using an assay with detection sensitivity of 300 copies of RNA/mL of specimen. CONCLUSION: Our data indicate that persistent HEV infection is an infrequent cause of ALT elevation in Indian renal transplant recipients who are receiving immunosuppressive drugs. This suggests that infection with genotype 1 HEV may have either no or low potential to cause persistent infection.

Role of nitric oxide synthase genes in hepatitis E virus infection.

Hepatitis E virus (HEV) is the most common cause of endemic and epidemic acute hepatitis. A correlation between iNOS, eNOS polymorphisms, levels and severity of disease has been reported, and here, we examined the role of iNOS and eNOS gene polymorphisms and their levels in HEV-related acute viral hepatitis and acute liver failure. Hepatitis E virus-related cases of acute hepatitis (294 patients) and liver failure (82 patients) and age- and sex-matched healthy controls (331 subjects) were included in the study. PCR-RFLP was performed to identify the polymorphisms in the iNOS and eNOS genes. iNOS and eNOS levels were studied using ELISA assays and HEV viral load, genotype and combined effects of iNOS genotype, levels and parameters for disease severity were examined. The frequency of iNOS (CT + TT) and eNOS (GT + TT) genotypes was higher in subjects with liver failure compared with controls. iNOS and eNOS levels in patients with acute liver failure (55.51 ± 6.33 IU/mL, 60.2 ± 3.69) cases were significantly increased as compared to patients with acute viral hepatitis (17.8 ± 6.08 IU/mL, 23.7 ± 6.57) and controls (P < 0.05). A significant positive correlation was observed between the iNOS and eNOS levels in our study population when compared with the severity of disease parameters. Hence, the iNOS C150T polymorphism and the eNOS G894T polymorphism and high levels of iNOS and eNOS are associated with an increased risk of HEV-related acute hepatitis and liver failure. This study supports the possible role of nitric oxide synthase genes (iNOS and eNOS) in determining the severity of HEV infection.

A nationwide survey for hepatitis E virus prevalence in Japanese blood donors with elevated alanine aminotransferase.

BACKGROUND: Although we reported two cases of transfusion-transmitted hepatitis E in Japan, the prevalence of hepatitis E virus (HEV) in Japanese blood donors is not very clear. STUDY DESIGN AND METHODS: Blood samples of donors who were deferred from donation because of elevated alanine aminotransferase (ALT) levels were collected from all Japanese Red Cross Blood Centers and subjected to HEV tests. RESULTS: Among the 41 donors with elevated ALT levels higher than 500 IU per L in Hokkaido, HEV RNA was detected in 8 (19.5%) samples. In 1389 donor samples with ALT levels of higher than 200 IU per L in nationwide Japan, the numbers of positive HEV RNA, immunoglobulin M (IgM) anti-HEV, and immunoglobulin G (IgG) anti-HEV samples were 15 (1.1%), 14 (1.0%), and 45 (3.2%), respectively. Although RNA-positive donors were predominantly male and found in any geographic area of Japan, they tended to be higher in number in eastern Japan including Hokkaido and lower in number in western Japan. Of the 23 HEV-positive samples, 19 were Genotype 3 and 4 were Genotype 4. DNA sequences of the 9 isolates showed more than 98.5 percent homology with the known swine HEV isolates. In 1062 donor samples with ALT levels of 61 to 199 IU per L, the percentages of IgM and IgG anti-HEV-positive samples were 0.1 and 2.7 percent, respectively, although there was no HEV RNA-positive sample. CONCLUSION: HEV markers (HEV RNA and anti-HEV) were detected in donors with elevated ALT levels who were widely distributed over Japan. The prevalence and incidence were higher in eastern Japan than in western Japan.

Transfusion-transmitted hepatitis E caused by apparently indigenous hepatitis E virus strain in Hokkaido, Japan.

BACKGROUND: In industrialized countries, sporadic cases of hepatitis E have been reported in individuals who have never been in an endemic area. Hepatitis E virus (HEV) infection commonly occurs via the fecal-oral route but a potential risk of transfusion transmission route has been suggested. STUDY DESIGN AND METHODS: A 67-year-old Japanese male patient who had never been abroad received a transfusion of blood from 23 voluntary donors and developed acute hepatitis with unknown etiology after transfusion. His blood samples were tested for viral markers of hepatitis viruses. RESULTS: HAV, HBV, HCV, CMV, and EBV were ruled out as causative agents in this case. The patient's blood sample in the acute phase contained HEV RNA as well as IgM and IgG anti-HEV. HEV RNA was also detected in one of the FFP units transfused. The donor had no history of traveling abroad and had a normal ALT level at the time of donation. The PCR products from the patient and the donor showed complete identity for two distinct regions of HEV within open reading frame 1. CONCLUSION: The patient was infected with HEV via transfused blood from a volunteer donor. A potential risk of posttransfusion hepatitis E should be considered even in nonendemic countries.

Non-A, non-B, non-C hepatitis: its significance in pediatric patients and the role of GB virus-C.

OBJECTIVES: To delineate the importance of non-A, non-B, non-C (non-ABC) hepatitis, and the role of GB virus C (GBV-C) in children. METHODS: From 1980 to 1995, acute-onset viral hepatitis was diagnosed in 166 inpatients and categorized into type A, B, C, and non-ABC hepatitis according to the serologic markers or the results of polymerase chain reaction assay for HBV DNA or HCV ribonucleic acid (RNA) in the National Taiwan University Hospital. Non-ABC hepatitis was diagnosed in 57 patients (34%). GBV-C RNA was investigated by reverse transcription and nested polymerase chain reaction in 32 of the 57 patients with non-ABC hepatitis. The clinical and laboratory features of patients with acute non-ABC hepatitis were compared with the features of those with acute hepatitis A and B. RESULTS: The degree of abnormality in aminotransferase activities was milder in patients with non-ABC hepatitis than in those with hepatitis B; chronicity was noted in 12%. Fulminant hepatitis occurred in 16%, and the mortality rate was 56%. Young age carried a significantly higher risk of having a fulminant course (1.9 +/- 0.2 years of age vs 6.4 +/- 5.1 years of age in acute course; p < 0.05). Compared with fulminant hepatitis B, fulminant non-ABC hepatitis had a trend of a longer interval from onset to death (119.2 +/- 144.8 vs 15.2 +/- 8.4 days; p = 0.079). GBV-C RNA was detected in only two of the patients tested, both of whom had received transfusions; one had persistent viremia and fluctuating aminotransferase values. CONCLUSIONS: Non-ABC hepatitis plays an important role in the etiology of pediatric viral hepatitis; however, the role of GBV-C is minor. A search for other unknown viral agent(s) responsible for non-ABCG hepatitis is needed.

A comparison of three interferon alfa-2b regimens for the long-term treatment of chronic non-A, non-B hepatitis. Multicenter Study Group.

BACKGROUND: We studied the effects of long-term treatment with interferon on histologic features of the liver and serum alanine aminotransferase concentrations in patients with chronic non-A, non-B hepatitis. METHODS: Consecutive patients who met the inclusion criteria were enrolled in the study. The diagnosis of chronic non-A, non-B hepatitis was established on the basis of the liver-biopsy findings and an abnormal serum alanine aminotransferase value (greater than 1.5 times the normal value) for at least one year. All patients were treated for six months with 3 million units of interferon alfa-2b given subcutaneously three times a week and were then randomly assigned to the same treatment for an additional 12 months (group 1), a regimen of 1 million units three times a week for 12 months (group 2), or no further treatment (group 3). Patients in group 3 who had elevated serum alanine aminotransferase concentrations for three consecutive months underwent the initial regimen once again. Follow-up continued for two years after the discontinuation of treatment. Histologic improvement was defined as a decrease of at least one grade in the score for necroinflammatory activity (0, no activity; 1, mild; 2, moderate; or 3, severe) between the first liver biopsy and a biopsy performed at 18 months. RESULTS: Of the 329 patients initially treated, 303 were randomized: 103 to group 1, 101 to group 2, and 99 to group 3. Of the 286 patients tested, 252 (88.1 percent) had antibodies to hepatitis C virus. In an intention-to-treat analysis, 46 of the patients in group 1 (44.7 percent) had normal serum alanine aminotransferase values at 18 months, as compared with 27 of the patients in group 2 (26.7 percent, P = 0.008) and 30 of those in group 3 (30.3 percent, P = 0.04). Between 19 and 42 months, 23 of the patients in group 1 (22.3 percent) continued to have normal serum alanine aminotransferase values (measured every six months), as compared with 10 of the patients in group 2 (9.9 percent, P = 0.02) and 8 of those in group 3 (8.1 percent, P = 0.005). Among the 176 patients with repeated liver biopsies at 18 months, more patients in group 1 had improved histologic-activity scores (69.6 percent) than in group 2 (47.6 percent, P = 0.02) or group 3 (38.6 percent, P < 0.001). CONCLUSIONS: Among patients with chronic non-A, non-B hepatitis, a regimen of 3 million units of interferon alfa-2b given three times a week for 18 months produced better histologic findings and serum alanine aminotransferase values than regimens involving a lower dose or a shorter duration of treatment.

[An experimental infection in lambs by the hepatitis E virus]. / Eksperimental'naia infektsiia iagniat virusom gepatita E.

Lambs were experimentally infected with a pool of 10% hepatitis E (HE) patient fecal suspension containing HE virus (HEV) isolates Osh-225 and Osh-228 which caused an infection closely resembling experimental HE in primates. Clinical manifestations consisted of acute biochemical and histological hepatitis, virus shedding in feces, the presence of virus-like particles in the peripharyngeal lymph nodes and the contents of small intestine, of HEV RNA in the parenchymal organs of lambs. Susceptibility of lambs to HEV derived from the infected piglets and the possibility of passaging the piglets' HEV in lambs was demonstrated. This passaging led to shortening of the incubation period.

Elevated serum thymidine kinase activity in patients with acute viral hepatitis.

To evaluate the clinical applications of serum thymidine kinase (TK) activity, we compared the results obtained with this parameter with those of other liver function tests in 27 patients with acute viral hepatitis and 16 normal controls. In those in the acute stage, the serum TK activity increased significantly to 55.5 +/- 66.5 U/L. There was no significant correlation between serum TK activity and findings for serum albumin, bilirubin, alkaline phosphatase or r-glutamyl transpeptidase. However, it did correlate significantly well with the serum activity of aspartate aminotransferase (AST) (r = 0.621, P < 0.01), alanine aminotransferase (ALT) (r = 0.551, P < 0.01), and lactate dehydrogenase (LDH) (r = 0.620, P < 0.01). Serum TK activity reached higher than 70 U/L in 8 of 11 patients with hepatitis A; however, no patients with the other types of hepatitis reached such a high level. During the recovery stage, the serum TK activity decreased significantly to 5.9 +/- 1.7 U/L (P < 0.01), and did not correlate with AST, ALT, LDH or other conventional liver function parameters. The data suggest that an elevation of serum TK in patients with acute viral hepatitis results from hepatocellular damage. A marked elevation of serum TK activity may thus provide a marker for acute hepatitis A infection.