Genetic CHolestatic disorders

The knowledge of the underlying aetiology of neonatal idiopathic hepatitis and the so-called “intrahepatic” cholestasis has been rapidly expanding in the last decade, and great advances in genetic testing have clarified that the vast majority of these conditions are monogenic liver disorders. Among those referred to as progressive familial intrahepatic cholestases (PFICs), the level of serum GGT is a good discriminant to guide the initial evaluation, being low/normal in Byler disease, BSEP deficiency, TJP2 deficiency, FXR deficiency and MYO5B deficiency, and increased only in MDR3 deficiency; however genetic testing is needed to reach a definite categorisation. In bile acid synthesis defects, normal serum bile acid is a clue to the diagnosis, although mass spectrometry is required to characterise the type of defect. Other well-known conditions such as Alagille syndrome and alpha-1 antitrypsin deficiency are more common and less challenging to recognise. In this chapter we discuss the clinical features of canalicular transport and tight junction defects, bile acid synthesis defects, biliary developmental defects and metabolic disorders that can present with neonatal/infantile cholestasis, providing also a rational approach to the diagnosis of the rarest forms as well as information on their current standard of care.