Cytokine profiles in high risk injection drug users suggests innate as opposed to adaptive immunity in apparent resistance to hepatitis C virus infection.

A cohort of injection drug users (IDU) have been identified who despite a long history of IDU and sharing of injecting equipment remain seronegative and aviraemic for hepatitis C virus (HCV). They have been termed HCV exposed uninfected (EU). The study of potential innate or adaptive immune mechanisms of resistance to HCV infection in this group is of interest. The aim of this study was to determine the levels of a broad range of cytokines in serum of exposed, uninfected individuals to ascertain whether there is a specific cytokine profile associated with apparent resistance to HCV. Sera from 22 EU individuals were analysed for a range of cytokines and chemokines, and compared to 16 treatment-naive chronic HCV cases (HCV Ab+ RNA+), 16 individuals with spontaneous resolution of HCV (HCV-Ab+ and HCV-RNA-) and 10 healthy unexposed controls. EU subjects had strikingly higher levels of both IL-6 (on average more than 100-fold, P = 0.001) and IL-8 (on average more than 10-fold, P < 0.001) than the comparison groups. Additionally higher levels of tumour necrosis factor-alpha (TNF-α; on average up to threefold, P = 0.02) were seen in EU individuals. The levels of interferon-alpha (IFN-α) were upregulated in all HCV exposed groups in comparison to healthy controls (P = 0.013). Adaptive immune cytokine levels were no different between the groups. Cytokine profiling demonstrated raised levels of pro-inflammatory innate immune cytokines and chemokines in EU IDU, in particular interleukin-6 and interleukin-8. These findings suggest innate immune activation may be the key to prevention of infection in this cohort.

Incidence and characterization of serum transaminases elevations in pegylated interferon and ribavirin treated patients with chronic hepatitis C.

BACKGROUND: A virological response to pegylated-interferon and ribavirin is typically associated with a prompt fall in serum transaminases. For some patients, transaminases rise during treatment. AIM: To assess the frequency and define factors associated with elevations of serum transaminases. METHODS: A total of 169 treated patients were studied. Transaminase elevations were graded by WHO criteria - grade 0: no value > baseline, grade 1: 1-2x baseline, grade 2: 2.1-5x baseline, grade 3: >5x, grade 4: any rise with evidence of liver failure. Results 60/169 (35%) patients experienced transaminase elevations: 52 grade 1, 6 grade 2, 1 grade 3, 1 grade 4. Overall, end of treatment response and sustained virological response rates were 72% and 55%. Lower rates were observed in the grade 1 elevation group (63% and 40%) compared with patients with grade 0 (79% and 65%) and grade > or =2 elevations (85% and 71%). Grade 1 elevations tended to occur earlier during treatment than grade > or =2 elevations. Transaminase elevations were associated with greater pre-treatment body weight (P = 0.006), steatosis (P = 0.008) and poorer sustained virological response rates (P = 0.007). CONCLUSIONS: Transaminase elevations during treatment of chronic Hepatitis C virus with pegylated interferon and ribavirin are common but rarely severe. Mild rises may reflect ongoing viral activity in treatment non-responders. More significant rises are frequently observed despite a virological response, and may be because of an immuno-modulating effect of interferon in susceptible patients.

The role of hepatitis E virus testing in drug-induced liver injury.

BACKGROUND: Locally acquired hepatitis E is an emerging infection in developed countries and can be misdiagnosed as drug-induced liver injury. AIM: To study the role of hepatitis E virus (HEV) testing in drug-induced liver injury. METHODS: Retrospective review of a cohort of patients with suspected drug-induced liver injury (n = 69) and hepatitis E (n = 45). The standard criteria for drug-induced liver injury were applied. Patients with suspected drug-induced liver injury who met these criteria were retrospectively tested for HEV on stored sera taken at the time of presentation. The two cohorts were compared to determine variables that predicted either of the diagnoses. RESULTS: Forty-seven out of 69 patients had criterion-referenced drug-induced liver injury. 22/47 were HEV negative and thus had confirmed drug-induced liver injury. 19/47 were not tested for HEV, as there was no sera available from the time of presentation. 6/47 were HEV positive and thus did not have drug-induced liver injury, but had hepatitis E infection. Compared to patients with confirmed drug-induced liver injury, patients with hepatitis E were significantly more likely to be male (OR 3.09, CI 1.05-9.08); less likely to present in November and December (0.03, CI 0.01-0.52); have lower serum bilirubin (P = 0.015); and higher serum alanine aminotransferase (P < 0.001) and alanine aminotransferase/alkaline phosphatase ratio (P < 0.001). CONCLUSION: The diagnosis of drug-induced liver injury is not secure without testing for HEV.

Autochthonous hepatitis E in southwest England.

Although autochthonous hepatitis E has been reported in developed countries, its extent and nature in the United Kingdom are unclear. The aim of the present study was to report the natural history, lifestyle risk factors and molecular epidemiology of autochthonous hepatitis E infection in southwest England. Three hundred and thirty-three patients with unexplained hepatitis were tested for markers of hepatitis E virus (HEV) infection over a 7-year period. HEV RNA isolated from the cases was amplified and characterized. Of the 333 patients, 21 had autochthonous hepatitis E. Patients were middle-aged or elderly and males were more commonly affected. Clinical manifestations ranged from asymptomatic infection to severe hepatitis. Of the 21 patients, 20 recovered within 6 weeks. None of the cases had travelled to an area endemic for HEV. None of the patients were vegetarian and all ate pork. Of the 21 cases, 20 occurred in the spring, summer and autumn months. All polymerase-chain-reaction-confirmed cases carried HEV genotype 3, which bore close sequence homology to HEV circulating in UK pigs. In the United Kingdom, autochthonous hepatitis E may be more common than previously recognized. Although the mode of transmission remains to be determined, it may be a zoonosis with pigs as a reservoir. Hepatitis E should be considered a public health issue in the United Kingdom.