The canaliculi join each other to form larger and larger structures, sometimes referred to as the canals of Hering, which themselves join to form small bile ductules that have an epithelial surface. The ductules join to form bile ducts that eventually form either the right main hepatic duct that drains the right lobe of the liver, or the left main hepatic duct draining the left lobe of the liver. The two ducts join to form the common hepatic duct, which in turn joins the cystic duct from the gall bladder, to give the common bile duct. This duct then enters the duodenum at the ampulla of Vater. In cholestasis, bile accumulates in the hepatic parenchyma.One of the most common causes of extrahepatic, or obstructive cholestasis, is biliary obstruction. This is better known as choledocholithiasis where gallstones become stuck in the common bile duct. Mechanisms of drug-induced cholestasis
Drugs may induce cholestasis by interfering with 1) hepatic transporters, 2) bile canaliculi dynamics, and/or 3) cell structure and protein localization. Hepatic transporters are essential for maintaining enterohepatic bile flow and bile acid homeostasis. Therefore, their direct inhibition by certain drugs may lead to cholestasis. Relevant transporters implicated  include BSEP, MDR3, MRP2-4, and NTCP.Cholestasis can result from competitive inhibition of BSEP by several drugs, including cyclosporine A, rifampicin, nefazodone, glibenclamide, troglitazone, and bosentan. BSEP is the main transporter in hepatocytes responsible for exporting bile salts across the apical membrane into bile canaliculi.
Therefore, it is hypothesized that a reduction in secondary bile acid production, as a result of dysbiosis, could lead to bile duct damage via decreased activation of FXR and TGR5. Indeed, lower levels of secondary bile acids were found in PSC patients, but a causal relationship is yet to be confirmed. Familial intrahepatic cholestasis
Familial intrahepatic cholestasis (FIH) is a group of disorders that lead to intrahepatic cholestasis in children. Most often, FIH occurs during the first year of life, with an incidence rate of 1/50,000 to 1/100,000. There are three different versions of FIH, with each causing a different severity of jaundice. Typically, children exhibit recurrent jaundice episodes, which eventually become permanent. Diagnosis usually occurs by analyzing laboratory features, liver biopsy results, DNA/RNA sequences, and biliary lipid analysis. The definitive treatment for FIH is liver transplant which usually results in a high recovery rate. Each type of FIH is a result of a different mutation. The three genes thought to be involved include APT8B1, which encodes for the FIC1 protein. The ABCB11 gene encodes for the bile salt export pump (BSEP) protein, and the ABCB4 gene encodes for the multidrug resistance 3 (MDR3) protein. BSEP and MDR3 are respectively responsible for transporting bile salt and phospholipid, two major constituents of bile, across the apical membrane of hepatocytes. Alagille syndrome
Alagille syndrome is an autosomal dominant disorder that impacts five systems, including the liver, heart, skeleton, face, and eyes.