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.
If 5 nucleosidase and ALP enzymes are elevated, imaging studies such as computed tomography (CT) scan, ultrasound, and magnetic resonance imaging (MRI) are used to differentiate intrahepatic cholestasis from extrahepatic cholestasis. Additional imaging, laboratory testing, and biopsies might be conducted to identify the cause and extent of cholestasis. Biomarkers
ALP enzymes are found abundantly within the bile canaliculi and bile. If a duct is obstructed, tight junctions permit migration of the ALP enzymes until the polarity is reversed and the enzymes are found on the whole of the cell membrane. Serum ALP levels exceeding 2-3 times the upper baseline value may be due to a variety of liver diseases. However, an elevation that exceeds 10 times the upper baseline limit is strongly indicative of either intrahepatic or extrahepatic cholestasis and requires further investigation. Cholestasis can be differentiated from other liver disorders by measuring the proportion of ALP to serum aminotransferases, where a greater proportion indicates a higher likelihood of cholestasis. Typically, aminotransferase enzymes are localized within hepatocytes and leak across the membrane upon damage. However, measurement of serum aminotransferase levels alone is not a good marker to determine cholestasis. In up to a third of patients, ALP levels may be elevated without the presence of cholestasis. As such, other biomarkers should be measured to corroborate findings. Measurement of 5 nucleosidase levels may be used to identify cholestasis in conjunction with ALP. Levels of ALP may rise within a few hours of cholestasis onset while 5 nucleosidase levels may take a few days.