الفهرس 
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Abstract
SUMMARY
Biliary atresia is a progressive cholestatic and fibrotic disease of unknown etiology which occurs only in infants. Children often appear normal at birth but become jaundiced in the first weeks of life. Those diagnosed BA early receive HPE, which removes the obstructed extra-hepatic bile ducts in an attempt to restore normal bile flow. Some Kasai operations are successful; however, many will fail.
Children with a “failed Kasai” will require liver transplant in infancy to survive. In addition, infants who are diagnosed late often have too much liver damage to benefit from the Kasai operation and will also require an early transplant, usually in the first year of life. The Kasai operation’s success rate may be influenced by at least 4 factors: (1) time of Kasai; (2) surgeon experience; (3) post-operative nutrition; and (4) post-operative medications.
Early diagnosis and successful portoenterostomy establishing sufficient bile flow are the key events for extended native liver survival in BA. Even though the majority of BA patients end up with LTx due to progressive hepatic fibrosis and associated portal hypertension it is essential to increase the proportion of BA patients, who survive with their own liver into adolescence or even adulthood.
Liver transplantation carries well-known risk of allograft ageing and the side effects of long-term immunosuppression.
Inflammatory cytokines, specifically IFNγ, and hepatic lymphocytes, including NK cells and CD8 lymphocytes, were shown to be critically important for initiation and progression of the disease process in the murine model.
The predominant cellular immune response in BA at diagnosis encompasses activated CD4+ and CD8+ T cells within portal tracts that produce Th1 cytokines (IL-2, IFN-γ) and macrophages secreting TNF-α and IL-18. These lymphocytes have been found invading between bile duct epithelia, leading to degeneration of intrahepatic bile ducts
The immune response to a viral infection or an autoimmune response is generally mediated by a T helper cell (CD4+) type 1 (Th1) inflammatory process. When naïve CD4+ T cells encounter antigen, they have the potential to differentiate into either Th1 cells (cell-mediated immunity) or Th2 cells (humoral-mediated immunity). Cytokines characteristic of a Th1 response include IL-2, IFN γ, TNF-α, and IL-12, IL-18 (from macrophages), whereas Th2 cytokines include IL-4 and IL-5.
Interferon-gamma has been shown to regulate the biliary tropism of lymphocytes to the biliary system, and to play a critical role in the inflammatory obstruction of extrahepatic bile ducts. The ability to combine human studies with a laboratory model of neonatal biliary injury and obstruction opens a new era of opportunities to advance the field of BA, and to develop new therapeutic strategies to improve long-term outcome with the native liver of children with BA.
The immune response, especially the predominant TH1 and IFN γ responses, genetic susceptibility and disorders related to the embryonic development of the biliary tree can play a role in the etiopathogenesis of BA.
Immunologically mediated injury of the bile ducts triggered by as yet unidentified infectious agents is likely to play a critical role. Interleukin-18 is a proinflammatory cytokine that plays an important role in immune, infectious, and inflammatory diseases because of its induction of IFN γ.
It has also been suggested that IL-18 contributes to infection through the induction of IFN γ production by NK cells, but not through the development of T helper 1cells, under the condition in which IL-12 synthesis is deficient. So, IL-12, IL-18, and IFN γ are closely related to each other.
Cytokine production and activity is usually localized within the target organ, however with increased severity of inflammation and cytokine production, the cytokines may enter the circulation and can be detected within the sera or plasma.
Despite intensive research, understanding of mechanisms that regulate disease progression following HPE is scarce. Further understanding of pathogenesis of BA is critical concerning development of more effective treatment strategies.
The study aimed to measure the level of IL-18 and interferon γ in patients with BA.
This study included 60 infants with NC who were recruited from the attendants of pediatric hepatology department, National Liver Institute, Menoufia University and 30 apparently healthy infants as a control group.
These infants were divided into three groups:
group I : 30 infants complaining of BA
group II : 30 infants complaining of NC other than BA including:
• 11 patients complaining of PFIC.
• 5 patients complaining of insspasited bile syndrome.
• 2 patients complaining of galactosemia.
• 2 patients complaining of Alagille syndrome.
• 10 patients complaining of INH.
group III : 30 apparently healthy neonates as the control group.
All cases were subjected to measurement of IL 18 and INF γ level.
Data were collected, coded and processed by statistical analysis (SPSS) statistical package version 21 on IBM compatible computer, and the results were put in tables and graphs.
Our results showed that:
• Both patients and controls were sex matched (P-value >0.05).While there was significant statistically difference between patients and controls as regard mean age (P-value < 0.05).
• There was significant statistically difference between BA and other types of cholestasis groups as regard color of stool (P-value < 0.05) also, there was significant statistically difference between BA and other types of cholestasis groups as regard splenomegaly (P-value < 0.05). There was no significant statistically difference between BA and other types of cholestasis groups as regard hepatomegaly (P-value >0.05).
• There was no significant statistically difference between patients as regard TORCH (P-value >0.05).
• There was significant statistically difference between BA and other types of cholestasis groups as regard DTA (P-value < 0.05).
• There was significant statistically difference between BA and other types of cholestasis groups as regard ultrasonographic findings of liver, spleen and gall bladder contractility (P-value < 0.05).
• There was significant statistically difference between BA and other types of cholestasis groups as regard GGT (P-value < 0.05). There was no significant statistically difference between BA and other types of cholestasis groups as regard other laboratory findings (P-value >0.05).
• There was no significant statistically difference between BA and other types of cholestasis groups as regard CBC paramters (P-value > 0.05).
• There was significant statistically correlation between IFN γ and (AST, ALT) (P-value <0.05). There was no significant statistically correlation between age, other investigations done (CBC, liver enzymes, PC%, histopathological grade, serum bile acids and bilirubin level) and both (IL-18 ,IFN γ) (P-value >0.05).
• There was no significant statistically difference between BA, other types of cholestasis and control groups as regards IL-18 (P-value > 0.05). There was significant statistically difference between BA and other types of cholestasis groups as regard IFN γ (P-value < 0.05).
• There was significant statistically difference between IL-18 and degree of fibrosis (P-value < 0.05). While there was no significant statistically difference between IFN γ and degree of fibrosis (P-value >0.05).
• There was no significant statistically difference between degree of fibrosis in BA and other types of cholestasis groups (P-value > 0.05).
• The performance of IFN γ in differentiation between BA and other cholestatic liver disease as Specificity 70% and Sensitivity 76.7% (P-value < 0.05).
• IFN γ found to be increased in BA patients than other cholestatic liver disease and control groups therefore IFNγ may play a role in the pathophysiology of BA.
• This study concluded that increased production of IFNγ in BA was shown to be critically important for initiation and progression of the disease process.
• This study recommended that IFNγ inhibitors could reduce intrahepatic and extrahepatic bile duct inflammation and injury so, block the progression of the disease and foster long-term survival with the native liver in children with BA.
• Future research into the role of IFNγ and of other cytokines is necessary in order to assess whether these aspects should be potential targets for therapeutic intervention on a greater numbers of patients.
• The findings in this study may shed light on the potential therapeutic use of immunosuppressive therapy in the treatment of BA.
• Also, the findings in this study may shed light on the potential therapeutic use of high dose Immunoglobulins (IgG) therapy to cause significant reduction in IFN-γ and protection from biliary injury.
• We recommend to do more studies on other cytokines ( IL-10, IL-12, IL-15) and their effect on IFN-γ in patients with BA.