Our research interest is focused on the study of the molecular mechanisms underlying the most severe paediatric liver disorders, namely cholestasis, which results from the impaired secretion of bile from the liver to the intestine.
As such, it represents a clinical and biochemical syndrome that is produced by a wide variety of disease processes that affect the liver. Individuals with cholestasis manifest jaundice, severe itching, malabsorption of fats and lipidsoluble vitamins and, in many cases, progressive liver damage. These clinical manifestations are due to the accumulation in blood and tissues of substances normally secreted in the bile, such as bilirubin, bile acids, and cholesterol and to the absence of bile from the intestine.
When manifested in early infancy, cholestasis is often life threatening and usually requires liver transplantation. Extrahepatic biliary atresia (EHBA), Alagille syndrome and progressive familial intrahepatic cholestasis (PFIC) constitute the main paediatric cholestatic disorders. EHBA is an enigmatic disease of unknown aetiology, characterised by a precocious and accelerated obstruction of the biliary tree. Alagille syndrome is associated with mutations in the Jag1 gene and is characterised by a paucity or absence of intrahepatic bile ducts. PFIC encompasses a heterogeneous group of autosomal recessive diseases that exhibit similar clinical features. These diseases are caused by mutations in proteins located in the canalicular membrane of the hepatocyte and in proteins involved in bile secretion, such as the bile salt export pump (BSEP; ABCB11), the phospholipid transport protein MDR3 (ABCB4) and the aminophospholipid translocase FIC1 (ATP8B1). These cholestatic disorders constitute the most common indication for liver transplantation in childhood.