Extrahepatic Biliary Atresia is an Aflatoxin Induced Cholangiopathy in Infants with Null GSTM1 Genotype with Disrupted P53 and GSTPi to Mothers Heterozygous for GSTM1 Polymorphism: Damage Control is Mediated through Neutrophil Elastase and CD14+ Activated Monocytes: Kotb Disease

Extrahepatic biliary atresia (EHBA) has long been defined as a progressive cholangiopathy of infancy of obscure aetiology. It is a grave disease with serious morbidity, mortality and economic burden. EHBA is currently treated surgically by Kasai portoenterostomy. In 10 years post-portoenterostomy the survival does not exceed 30%, and 60-80% of children with EHBA eventually develop liver cirrhosis. EHBA is the leading indication for liver transplantation in children. Evidence supports that immune mediated destruction of extrahepatic portal tracts that extends to intrahepatic bile ductules is an integral part of pathogenesis of EHBA. Yet initiator of immune mediated pathogenesis was still unknown. Evidence supports that the aetiology of EHBA is an aflatoxin induced cholangiopathy in glutathione S transferase (GST) M1 deficient infants having disrupted p53 and GSTPi, whose mothers are heterozygous for GSTM1. Neutrophil elastase and CD14+ mediated damage control and integral in EHBA. These factors combined result in hepatotoxicity and bile duct damage followed by defective regeneration, and disruption of ontogeny respected development. EHBA is a multiple hit disease. Aflatoxins B 1 and B2 are transmitted through foods, they are highly substituted coumarins with short half life that need timely cytochrome P450 family and GST detoxification. Bacterial lipopolysaccharide increase aflatoxins induced hepatocyte and bile duct damage up to 20 folds. Evidence supports that placental intrauterine transfer of aflatoxins is recognized, and that maternal detoxification of aflatoxins protects foetus during pregnancy, which will be lost post-partum. Postpartum infantile incompetent detoxification of the aflatoxin hepatic stores would result in hepatic toxicity, in proliferated bile ducts and fibrosis hence EHBA. Maternal detoxification products of aflatoxins delivered in breast-milk punctuate the course of infants with EHBA by attacks of cholangitis. EHBA is potentially preventable. We recommend prompt diagnosis by assessment of aflatoxins and GSTM1 phentoype in any neonatal Correspondence to: Professor Magd A. Kotb E-mail: [email protected] hepatitis. Stringent monitoring of upper limits of mycotoxins in our food, and in food of poultry and cattle is a must.