Cholestatic liver disease metabolism

Modes of action The mechanisms of UDCA and its effects in cholestatic liver diseases are not yet fully understood - even though a number of different effects have been demonstrated. These include (i.) hepatopro-tective (92, 97, 98), (2.) cytoprotective (89), and (3.) biliary-metabolic effects (84, 93, 104, 105), as well as (4.) an influence on the immune system. In ligature of the bile duct in rats, UDCA was found to reduce the occurrence of histological changes and biliary cirrhosis as well as of portal hypertension. (98) (s. tab. 40.7)... 

In patients on home parenteral nutrition, hypermangane-semia can be facilitated through (1) cholestatic liver disease and thereby reduced manganese biliary excretion, (2) high nutritional requirements (responsible for increased manganese supply), and/or (3) altered manganese metabolism or body distribution (12). 

In 1972, large amounts of THCA were firund in the bile of two unrelated young children with intrahepatic bile duct abnormalities (E5), suggesting a block in the biosynthesis of cholic acid. Tliree years later, this bile acid intermediate was also found in the bile, serum, and urine of a brother and sister with a similar paucity of intrahepatic bile ducts and cholestatic liver disease, which proved fotal (H3). DHCA or varanic acid could not be detected in these patients, so that the metabolic defect in this condition appeared to be specific for the enzyme involved in the conversion of THCA to varanic acid. Hanson et a/, speculated that THCA might have caused the... 

Taken together, FXR not only regulates bile acid homeostasis but also greatly impacts on transporters and enzymes involved in drug metabolism. Effects on phase I—III genes by bile acid-activated FXR may therefore at least in part explain alterations of drug metabolism in cholestatic liver disease [62, 85, 86]. 

Vitamin E deficiency was first described in children with fat malabsorption syndromes, principally abe-talipoproteinemia, cystic fibrosis, and cholestatic liver disease. Subsequently, humans with severe vitamin E deficiency with no known defect in lipid or lipoprotein metabolism were described to have a defect in the a-TTP gene. 

A wide range of conditions fall into this gronp. They can be roughly categorised further into those causing cholestatic disease, chronic liver disease, acute liver failure/metabolic crisis, storage disorders, disorders of bilirubin metabolism. Table 3.5 snmmarises the types of liver disease that fall into each group. 

Disturbances of Bile Acid Metabolism in Hepatocellular Disease. Fasting plasma bile acid concentrations are elevated in hepatocellular diseases, such as hepatitis and cirrhosis. The mechanisms responsible are regurgitation of bile acids from cholestatic hepatocytes and portosystemic shunting. These defects allow the plasma concentrations to rise proportionately much higher than normal following meals, suggestmg that the postprandial rise in plasma bile acids may be a sensitive test for the detection of liver disease. 

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