Evaluation of th1 and th2 cytokine patterns and their diagnostic accuracies in hepatitis b infection

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The host immune response to hepatitis B viral (HBV) infection affects the clinical outcome of HBV infection and cytokines have been shown to directly inhibit HBV replication. The type of T helper (Th) cytokine which predominates at the onset of HBV infection is likely to determine the clinical outcome of HBV infection. Various liver diseases are associated with HBV infection but the percentage of HBV patients with HBV associated liver disease is not well known among Ghanaians. This study sought to define the disease pattern of Th1, Th2 and immunosuppressive cytokines, their diagnostic accuracy in classifying various stage of HBV infection as well as describing its associated liver disease. In a case-control study, patients with HBV infections and healthy blood donors were screened for HBV serological markers, HCV and HIV. Those positive with HCV and HIV were excluded. Finally, 120 HBV infected patients and 105 healthy blood donors were recruited as cases and control respectively. Th1 cytokines (IL-12p70, IFN-γ and TNF-α), Th2 cytokines (IL-4, IL-6) and immune suppressive cytokine (IL-10) were assayed by sandwich enzyme-linked immunosorbent assay. Their diagnostic performance were established by using receiver operating characteristics (ROC) curve and the area under the curve (AUC). Serum liver function tests were also performed. Data was analysed using GraphPad Prism version 6.01 and a P value <0.05 was considered significant for all statistical comparisons. The HBV serological profile results gave 3 acute infections, 12 HBV recovery, 5 HBeAg positive chronic hepatitis B (CHB) and 100 HBeAg negative CHB. Median levels of IL-12p70, TNF-α and IFN-γ were elevated in HBV infections compared to controls (p>0.05). Median concentration of IL-4 was significantly elevated in HBeAg negative CHB and HBV recovery compared to controls (p=0.0196) whilst IL-10 was significantly elevated in HBeAg negative CHB infection (p=0.0253). At 95% confidence interval, the best diagnostic markers with AUC, sensitivity and specificity were IL-10 (0.72, 66.67% and 86.67%) for acute infection and 0.66, 67.0% and 60.0% for HBeAg negative CHB respectively, IL-4 (0.72, 66.67% and 84.44%) respectively for HBV recovery and IL-6 (0.75, 80.0% and 71.1%) respectively for HBeAg positive CHB respectively. Median alanine aminotransferase concentration were significantly elevated in HBeAg positive CHB compared to controls; median albumin concentrations were significantly reduced while median globulin and median direct bilirubin concentrations were significantly elevated in HBeAg negative compared to controls. Median globulin concentrations were also significantly elevated in HBV recovery compared to controls. 30% of cases had elevated aspartate aminotransferase (AST), 23.3% had elevated ALT whilst 5.8% had combined elevated AST, ALT, alkaline phosphatase (ALP) and γ-glutamyl transferase (GGT). Nine cases of non-alcoholic fatty liver disease (NAFLD), two intrahepatic cholestasis and one case of extrahepatic cholestasis were identified. HBeAg negative was the most common form of HBV infection among the adult population in Ghana. Hepatic injury was common among HBV patients although no severe form of liver disease was found among them. The Th2 cytokines (IL-4, IL-6) and immune suppressive cytokine (IL-10) are better diagnostic markers for classifying the various stages of HBV infections. IL-4 is associated with both HBV recovery and HBeAg negative CHB whilst increased IL-10 is associated with HBeAg negative CHB. This could provide useful information to improve the clinical management of HBV infected patients based on the diagnostic value of well-defined cytokine profiles.
A thesis submitted in fulfillment of the requirements for the degree of Master of Philosophy (Immunology) in the Department of Molecular Medicine, School of Medical Sciences.