Cholestatic disease

The potential role of the RIA technique in the analysis of BAs was investigated some time ago in a study about the development of a method for the detection of 3/I-hy-droxy-5-cholenoic acid [41]. This technique was considered by the authors to be important in the evaluation of oxidation of the cholesterol side chain, a minor pathway of BA biosynthesis. 3/THydroxy-5-cholenoic acid was found in human meconium [42] and in amniotic fluid [43], suggesting an important role in foetal life. In healthy subjects this compound was found in urine [44] but not in serum [45]. The kidney probably excretes it and its serum concentration is too low to be detected. The aim of this report was to provide a new method for the investigation of the role of 3/T hydroxy-5-cholenoic acid in cholestatic disease. 

Another problem relates to the use of ursodesoxycholic acid to treat cholestatic diseases, such as primary biliary cirrhosis. The mechanism of its action remains poorly understood. However, it is significant that tauroursodesoxycholic acid,... 

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. 

GGT does not nsnally form part of the standard LFTs in most laboratories. It is an enzyme fonnd in hepatocytes and biliary epithelial cells, and also in kidney, pancreas, intestine and prostate. It has a higher sensitivity for indicating a problem of liver origin than alkaline phosphatase, but tends to follow a similar pattern. It is released in all types of liver dysfunction and therefore cannot generally be used to differentiate between types. However, a raised GGT with an isolated raised alkaline phosphatase can be suggestive of cholestasis. GGT levels can be ten to 20 times normal in cholestatic disease. 

Secondary hypercholesterolaemia can occur in cholestatic disease. However, medical treatment is usually not indicated. 

Cholangiodestmctive cholestasis is caused by bile duct obstruction which may be intrahepatic or extrahepatic. Bile duct injury may lead to sloughing of epithelial cells into the lumen, cell edema, and inflammation, which may contribute to obstruction (Treinen-Moslen, 2001 Plumlee, 2004). Chronic lesions associated with cholangiodestmctive cholestasis typically include bile duct prohferation and periductular fibrosis. Vanishing bile duct syndrome, characterized by a loss of bile ducts, has been seen in chronic cholestatic disease in humans (Zimmerman, 1999 Treinen-Moslen, 2001) and has been produced experimentally in dogs (Uchida, 1989). 

The Increase In AP activity is stimulated by bile acids. A rise in bile acids, which is considered to be the most sensitive and earliest marker of cholestasis, precedes any elevation in AP. The latter derives from enzyme synthesis with increased secretion into the blood. Under pathological conditions, bile duct AP is formed, which is a sensitive marker for hepatobiliary diseases, cholestasis and space-occupying lesions of the liver. The sensitivity is 80-100% in cholestatic diseases. AP activity is usually higher in obstructive jaundice and cholangitis than in intrahepatic obstructions, and it is highest in the vanishing bile duct disease or in complete obstruction. (13, 39, 41) (s. tabs. 5.9 13.2-13.4)... 

Elevated LAP values are found predominantly in biliary and cholestatic diseases - in accordance with AP. In liver diseases due to alcohol abuse, LAP values are exhibited both more frequently and with higher values than AP. In hepatitis mononucleosa, LAP is generally also more clearly elevated than AP. Significant increases in LAP are found in pancreatic and breast cancer as well as in collagenoses of the vascular type. LAP is not found in bone there is no evidence of elevated LAP in bone diseases. Normal LAP in connection with an increase in AP consequently rules out hepatobiliary diseases and requires further investigation. In these cases, parallel determination of AP and LAP is advisable. 

Colombo, C., Okolicsanyi, L., Strazzabosco, M. Advances in familial and congenital cholestatic diseases. Clinical and diagnostic implications. Dig. Liver Dis. 2000 32 152-159... 

Imaging techniques (with the exception of ERC, e. g. in PSC) are generally of no diagnostic value in chronic hepatitis prior to the development of cirrhosis. Sonography is regarded as a basic, routine examination and is always indicated in cholestatic diseases or suspected cirrhosis. (9) There is often evidence of abdominal lymphadenopathy (especially of the hepatoduodenal ligament), which points to a more severe histological... 

The liver synthesizes fibrinogen factors V, VIII, XI, and XII, and the vitamin K-dependent factors II, VII, IX, and X. Furthermore the liver plays an important role in platelet growth and function. The vitamin K-dependent proteins contain y-carboxy-glutamic acid. Vitamin K is necessary for the carboxylation of these proteins, which facilitate the conversion of prothrombin to thrombin. Patients with severe hepatocellular disease have decreased synthesis of the vitamin K-dependent clotting factors, especially factor VII. Furthermore, patients with cholestatic disease have decreased bile salt secretion, which is necessary for the absorption of vitamin K, leading to failure of activation of factors II, VII, IX, and X. In these patients, unlike those with hepatocellular disease, the prothrombin time can be corrected with an injection of vitamin K. 

Cholangiocarcinoma, or primary carcinoma of the bile ducts, can arise at any point in the biliary tree, including the small intrahepatic bile duct radicals. This lesion is typically associated with underlying liver disease, such as (1) PSC, (2) congenital cystic lesions, or (3) chronic infestation with Clonorchis sinensis. The clinical picture presentation is that of cholestasis, including jaundice, dark urine, tan-colored stool, and pruritus. Differentiation from other cholestatic diseases is made by visualizing the biliary tree. 

In practice, the plasma aminotransferases and ALP are the most useful tests as they allow differentiation of hepatocellular disease from cholestatic disease. The importance of this distinction cannot be overstated failure to recognize cholestatic disease caused by extrahepatic biliary obstruction will result in liver failure if the obstruction is not quickly corrected. It is also important to recognize that there may be a gray zone of mixed hepatocellular and cholestatic disease where the tests do not distinguish one disease from the other. In this case, it is wise to assume that the problem is cholestatic and rule out biliary obstruction. 

Traditional Chinese medicine draws heavily on animal products to the point at which it threatens the survival of tigers, rhinoceros and other large animals. It none the less has provided a number a leads for new drugs. Black bear bile is a particular source of active compounds. Tauroursodeoxycholic acid is already in use against human cholestatic disease, and 4-phenylbutyric acid has been approved for treatment of urea-cycle disorders. Other bile compounds could be used to treat type 2 diabetes, but all these materials, if they are to be widely used, require synthetic methods rather than the mass slaughter of black bears. 

Vitamin E deficiency is seen rarely in humans. However, there may be a risk of vitamin E deficiency in premature infants because the placenta does not transfer a-tocopherol to the fetus in adequate amounts. When it occurs in older children and adults, it is usually a result of lipoprotein deficiencies or a lipid malabsorption syndrome. These include patients with abetalipoproteinemia or homozygous hypobeta-lipoproteinemia, those with cholestatic disease, and patients receiving total parenteral nutrition. There is also an extremely rare disorder in which primary vitamin E deficiency occurs in the absence of lipid malabsorption. This disorder is a rare autosomal recessive neurodegenerative disease caused by mutations in the gene for a-TTP. This disorder is known as ataxia with vitamin E deficiency (AVED). Patients with AVED have extraordinary low plasma vitamin E concentrations (<5pgml ) and have an onset between 4 and 18 years, with progressive development of peripheral neuropathy,... 

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