[Contribution to the study of intraphepatic cholestasis: the role of cholangiolitis].
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The role of transient obstructive cholestasis on liver histology remains undetermined.To investigate whether transient cholestasis impairs liver histology.Cross-sectional study at a public university hospital (UNICAMP), Brazil.169 individuals undergoing cholecystectomy, with or without cholestasis. were enrolled. Histopathological findings were correlated with clinical and biochemical characteristics.Biliary hepatopathy was more frequent in individuals with resolved cholestasis than in those with active obstruction or no jaundice (P < 0.01), as also were fibrosis and ductular proliferation (P = 0.02). Cholestasis was commoner in individuals with resolved obstruction than in those with no history (P < 0.01) or active cholestasis (P < 0.05). Biliary hepatopathy was associated with longer duration of cholestasis (P < 0.001) and higher bilirubin levels (P = 0.02) in individuals with active obstruction; with lower body mass index (P = 0.02) and longer cholestasis (P < 0.001) in individuals with resolved obstruction; and with longer cholestasis (P < 0.001) and longer interval between endoscopic retrograde cholangiopancreatography and surgery (P = 0.03) overall. In individuals with active obstruction, duration of cholestasis (R = 0.7; P < 0.001) and bilirubin levels (R = 0.6; P = 0.004) were independently correlated with cholestasis severity. Duration of cholestasis (R = 0.7; P < 0.001) was independently correlated with ductular proliferation severity.Transient cholestasis was associated with significant histopathological changes, even after its resolution. Longer duration of obstruction correlated with greater severity of histopathological changes, especially cholestasis and ductular proliferation. This emphasizes the need for early treatment of obstructive cholestasis.
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Abstract Cholestasis is a clinically significant symptom and widely associated with liver diseases, however, there are very few effective therapies for cholestasis. Danning tablet (DNT, a Chinese patent medicine preparation) has been clinically used to treat human liver and gallbladder diseases for more than 20 years in China. However, which ingredients of DNT contributed to this beneficial effect and their mechanistic underpinnings have been largely unknown. In the present study, we discovered that DNT not only demonstrated greater benefits for cholecystitis patients after cholecystectomy surgery in clinic but also showed protective effect against alpha-naphthylisothiocyanate (ANIT)-induced cholestasis model in rodent. Curcumin, one major compound derived from DNT, exerted the protective effect against cholestasis through farnesoid X receptor (FXR), which has been focused as potential therapeutic targets for treating cholestasis. The underlying mechanism of curcumin against cholestasis was restoring bile acid homeostasis and antagonizing inflammatory responses in a FXR-dependent manner and in turn contributed to overall cholestasis attenuation. Collectively, curcumin can be served as a potential treatment option for liver injury with cholestasis.
Farnesoid X receptor
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γ-glutamyl transpeptidase(GGT) is an important index of cholestasis.Most patients with cholestasis liver diseases have high GGT level, but some of the patients are characterized by low GGT level.This paper summarizes the progress of cholestasis liver diseases with low GGT level in order to improve the understanding of these diseases.
Key words:
γ-glutamyl transpeptidase; Cholestasis; Cholestasis liver diseases
Gamma-glutamyltransferase
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Cholestasis, caused by the interrupted excretion of bile, resulting in an accumulation of bile products in the body fluids is characteristic of many human liver diseases (Sherlock & Dooley, 1997). Experimental animal models of cholestasis allow the understanding of pathophysiological mechanisms involved and their clinical correlates (Chang et al., 2005; Chandra & Brower, 2004). The most common experimental models of intrahepatic cholestasis are estrogen-induced, endotoxin-induced and drug-induced cholestasis (Rodriguez-Garay, 2003). Drug-induced cholestasis was described during treatment by different drugs in medical clinic and in experimental research. In experimental medicine, αnaphthylisothiocyanate (ANIT) treatment has been extensively used, permitting to describe not only cholestatic alterations but also compensatory mechanisms. The animal model and transport protein studies are necessary for the progressive understanding of congenital and acquired human cholestasis, and regulatory mechanisms which operate on liver cells. Continuous bile formation is an important function of the liver, and bile is used as a vehicle for the secretion of bile acids and the excretion of lipophilic endoand xenobiotics (Meier and Stieger, 2000; Hsien et al., 2006). Molecular and cellular mechanisms of intrahepatic cholestasis development are important for understanding of role of different factors in this process and effective therapy. Lysosomes are connected with bile secretion, however their role in cholestasis development is still not clear. Human bile revealed high activity of lysosomal enzymes (β-galactosidase, β-N-acetylglucosaminidase, acid phosphatase) which are suggested to be secreted from lysosomes localized in peribiliar zone of hepatocytes (Korolenko et al., 2007). We tested the hypothesis that impaired lysosomal secretion is related to cholestasis development. Earlier in some works it was shown that in mice and rats increased activity of lysosomal enzymes in bile was connected with their increased secretion.
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To clarify the mechanisms of systemic endotoxemia in extrahepatic cholestasis and the pathogenesis of aggravation of multiorgan failure after external biliary drainage (EBD)--for elaborating of the curative tactics.The results of experimental studies performed on 208 Wistar rats and 90 dogs were implemented in the surgical clinic in treatment of 150 patients with cholestasis. In experiments--Histological, Transmission and Scanning Electron Microscopic, and Biochemical (Malonic Dialdehide--the end product of Peroxide Oxidation of Lipids of cell membrane) methods have been used. Perfect model of EBD in cholestasis was created. In clinic--the measurement of Mitochondrial ferments, Bilirubin concentration, Creatinin clearance and Psychometric tests were used for evaluation of liver, kidney and brain functions.Destruction of 7.2% and 8.1% of villi in 6 and 7 days cholestasis and 17.3% and 23.5% of villi consequently in 12-14 days cholestasis (compared with 1.1%-1.4% in control [P < 0.01]) resulted in denudation of lacteals was observed. Malonic Dialdehide concentration is significantly increased in plasma after EBD in cholestasis, especially under rapid decreasing of biliary pressure.Gut barrier failure in cholestasis "lets" gram-negative bacteria and their endotoxins to penetrate the systemic circulation via the lymphatic system avoiding the liver filter. This process, which is partially suppressed by bile salts existed in lymph due to bilio-lymphatic reflux, precipices just after EBD with all consequences. Aggravation of hepatic failure after one-stage rapid biliary decompression is also promoted by activation of Peroxide Oxidation of Lipids (caused by blood reflow into portal system under falling the pressure in bile compartment) injuring the liver cells. Administration of "Duphalac" ("Solvey Pharmaceuticals")--with antiendotoxic, and "Plapheron LB" (Georgian Industry)--with anti-free-radicals properties is suggested in cholestasis not only before the operation, but after the biliary drainage as well.
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Properties differentiating 13 biochemical indexes of cholestasis within a group of patients suffering from acute virus hepatitis were examined. It has proved the existence of a set of parameters of optimal properties differentiating separate states of cholestasis. This set includes concentrations of bilirubin and cholesterol esters, together with the activity of alkaline phosphatase. The variables formed a function enabling to differentiate mathematically+ the states with and without cholestasis.
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