Role of cytokines in the assessment of the severity of chronic hepatitis C and the prediction of response to therapy.

AIMS: (i) To characterize serum levels of pro/anti-inflammatory cytokines in non-cirrhotics with hepatitis C; (ii) to correlate levels of these cytokines with degree of disease at baseline; and (iii) to characterize the immuno-modulatory effects of therapy with response. METHODS: We studied 103 patients that were part of randomized, controlled, clinical trials. Serum cytokines were measured using enzyme-linked immunosorbent assay. RESULTS: Using standard therapy in the presence and absence of ribavirin, the sustained responders had lower baseline tumor necrosis alpha (TNF-alpha) levels as compared to relapsed responders and non-responders. In patients receiving pegylated therapy, the degree of inflammation as determined by histology was paralleled by high TNF-alpha levels at baseline. In pegylated combination therapy with high dose ribavirin, lower levels of TNF-alpha, transforming growth factor beta (TGF-beta) and fibrosis scores were seen when comparing baseline with follow up. In sustained responders, regardless of therapy, the histological activity scores were lower at follow up as compared to baseline. CONCLUSIONS: Pegylated combination therapy reduces and sustains TNF-alpha levels and liver inflammation as shown by the histological activity index. In addition, it is able to reduce fibrosis as judged both by TGF-beta levels and fibrosis scores as compared to standard therapy.

Cytokine--chemokine and apoptotic signatures in patients with hepatitis C.

Cytokines and chemokines are proteins that play a critical role in the regulation of immunity and inflammation in patients with chronic Hepatitis C. The aim of our study was to correlate serum cytokines, chemokines and apoptosis in non-treated chronic hepatitis C patients with various degrees of inflammation and fibrosis. We studied 778 patients: 59 had low Knodell fibrosis score and low Knodell histological activity index; 372 had mild fibrosis and low histological activity index; 270 had moderate fibrosis and moderate histological activity index; and, 77 had high fibrosis and high histological activity index on their biopsy. Serum cytokines, chemokines and apoptosis were measured by enzyme-linked-immunosorbent-assay. Multivariate analysis was employed for statistical purposes. A positive correlation was seen between the degree of inflammation and tumor necrosis factor-alpha (TNF-alpha) levels (r = 0.92) in non-cirrhotic patients and between interleukin 2 in all patients (r = 0.85). Interleukin-8 increased significantly at higher histological activity indices and continued to increase in patients with cirrhosis. Transforming growth factor-beta (TGF-beta) levels increased significantly with the severity of fibrosis, but decreased in cirrhotics. In conclusion, cytokines, chemokines and apoptosis levels reflect the progression of inflammation and fibrosis in hepatitis C infected patients, but their signatures differ.

Serum tumour necrosis factor-alpha and transforming growth factor-beta levels in chronic hepatitis C patients are immunomodulated by therapy.

Our aims were: (i) to characterize serum levels of tumour necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta) in non-cirrhotics with hepatitis C; (ii) to correlate levels of theses cytokines with degree of disease at baseline; (iii) to characterize the immunomodulatory effects of therapy with response and (iv) to compare profiles of cytokines in patients treated with pegylated-interferon alpha-2b monotherapy (PMT) vs its combination with ribavirin (PCT1-low dose ribavirin and PCT2-high dose ribavirin). We studied 56 patients that were part of two randomized, controlled, clinical trials. At baseline, high TNF-alpha levels paralleled the degree of inflammation as determined by histology. In PCT2, a significant reduction was seen in levels of TNF-alpha, TGF-beta and fibrosis scores when comparing baseline with follow-up. In sustained responders, regardless of therapy, the histological activity scores were lower at follow-up as compared to baseline. In conclusion, PCT2 is able to constantly reduce and sustain TNF-alpha levels, which is responsible for the sustained decline in liver inflammation as shown by the histological activity index and it is also able to reduce fibrosis as judged both by TGF-beta levels and fibrosis scores.