Cholestasis Pathogenesis

Schreiber AJ, Simon FR (1983) Estrogen-induced cholestasis clues to pathogenesis and treatment. Hepatology 3 607-613. 

Tilg H, Diehl A M 2000 Cytokines in alcoholic and non-alcoholic steatohepatitis. New England Journal of Medicine 343 1467-1476 Trauner M et al 1998 Molecular pathogenesis of cholestasis. New England Journal of Medicine 339 1217-1227... 

It is justified to assume that cholestatis-related pruritus is caused by substances that are normally excreted in the bile. Nevertheless, it has not been possible to detect a specific causative substance up to now. Under experimental and clinical conditions, raised bile acid levels in the serum or in the skin are found both with and without pruritus - but no adequate correlation could be established. Recent findings point to an increased tonus of the opioid system in the CNS (endorphins) as being of prime importance in the pathogenesis of cholestasis-related pruritus. Endogenous lipophilic bile acids possibly effect the release of hitherto unknown prurito-... 

Cholestasis-linked osteopathy (M. Loeper et al., 1939), which occurs much more frequently in the form of osteoporosis than osteomalacia, can be expected in up to 50% of cases. The pathogenesis is complex. Vitamin D status can be examined by determining 25-OH-cholecal-ciferol in the serum. Intestinal calcium loss and reduced calcium absorption due to vitamin D deficiency are key pathogenetic factors. It is still a matter of debate whether vitamin K deficiency (which can lead to reduced osteocalcin synthesis) and deficiencies in IGF I and II (which can cause dysfunction of the osteoblasts) are possible causes of this condition. Muscle and bone pain are frequent clinical symptoms, occurring mainly in the wrists and ankles. 

Schirrmacher, S., Blnmenstein, I., Stein, J. Pathogenesis and treatment of pruritus in patients with cholestasis (review). Zschr. Gastroenterol. 2003 41 259 -262... 

Boswellinic acids Leukotrienes appear to play a special role as inflammation mediators in the pathogenesis of PBC they also correlate closely with the increase in cholestasis-indicating enzymes. Boswellinic acids are selective non-redox inhibitors of 5-lipoxygen-ase and therefore inhibit leukotriene biosynthesis. So far, they have not been used in PBC treatment. Based on existing pharmacological data, their application should now be considered. 

Jones E, Bergasa N. Evolving concepts of the pathogenesis and treatment of the pruritus of cholestasis. Can J Gastroenterol 2000 14 33-40. 

Trauner M, Meier P, Boyer J. Molecular pathogenesis of cholestasis. N Engl J Med 1998 339 1217-27. 

Lithocholic acid and its conjugates are bile acids which are not choleretic, but have the opposite effect in causing intrahepatic cholestasis in experimental animals (F5, Jl, 02), and presumably man. The cholestatic effect of these bile acids is abolished if cholic acid is administered simultaneously, probably because of the ability of cholic acid to solubilize lithocholic acid in micelles (K2, L5). To explain the pathogenesis of lithocholate-induced cholestasis, it has been suggested that lithocholate binds to the bile canalicular membrane, increases its cholesterol content and reduces its permeabflity to water and ions (Kl, K2). 

Kl. Kaksis, C., Phillips, M. J., and Yousef, I. M., The respective roles of membrane cholesterol and of sodium potassium adenosine triphosphatase in the pathogenesis of lithocho-late-induced cholestasis. Lab. Invest. 43, 73-81 (1980). 

Witzleben CL, Boyer JL, Ng OC. 1987. Manganese-bilirubin cholestasis. Further studies in pathogenesis. Lab Invest 56 151-154. 

Kullak-Ublick GA. Drug-induced cholestatic liver disease. Molecular Pathogenesis of Cholestasis. Landes Bioscience, Georgetown, Tx. 2004 256-265. 

It originates mainly from bacterial 7a-dehydroxylation of chenode-oxycholic acid in the intestine, but can also be formed in the liver by an alternative pathway involving 26-hydroxylation of choles-terol[9]. Little is known about the significance of lithocholic acid in the pathogenesis of cholestasis in man. It has been claimed that the human liver is protected from lithocholic acid-hepatoxicity by the efficient sulfation of the 3a-hydroxy group[10], which increases the bile acids polarity. Sulfated bile acids are poorly absorbed from the intestine[11,12] and their renal clearance is relatively high[13]. Therefore, sulfation of lithocholic acid should promote its elimination from the body[14]. 

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