Histopathology of cholestasis.
ABSTRACT Cholestasis may be extrahepatic or intrahepatic in origin. The block in bile secretion may be complete or incomplete to variable extent. Complete cholestasis occurs in case of primary parenchymal disease (intrahepatic cholestasis) or total obstruction of extrahepatic bile ducts (extrahepatic cholestasis). Incomplete block in bile secretion is due to incomplete obstruction of intra- or extrahepatic bile ducts (intra- or extrahepatic cholestasis or both). Histologically, it is useful to distinguish between bilirubionstasis and cholate-stasis. Complete secretory block causes as early changers: bilirubinostasis (in hepatocytes, canaliculi and Kupffer cells) in acinar zone 3, and "ductular reaction" in acinar zone 1. The latter refers to an increase in periportal ductular profiles, associated with neutrophil infiltration. With longer duration of cholestasis, further lesions ensue: feathery degeneration of hepatocytes due to retention of detergent bile acids, cholestatic liver cell rosettes representing a shift from hepatocellular to biliary differentiation, xanthomatous cells reflecting hyperlipidemia, cholate stasis in acinar zone 1 due to overload of membrane-damaging bile acids, eventually paraportal bile infarcts, and progressive ductular reaction. The latter may be due to multiplication of pre-existing ductules, to metaplasia of periportal hepatocytes, or to activation of progenitor cells. It is invariably associated with periductular fibrosis: the pacemaker for increasing matrix deposition, resulting in biliary fibrosis and eventually in true biliary cirrhosis. Incomplete cholestasis (e.g. PBC, PSC) is characterized by absence of bilirubinostasis during long periods of time, whereas the afore mentioned features of chronic cholestasis do appear. Hence follows that the most reliable markers of chronic incomplete cholestasis are cholate stasis, cholestatic rosettes and ductular reaction. Bilirubinostasis is only a late and often ominous sign.
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ABSTRACT: Sandwich-cultured hepatocytes (SCH) are used commonly to investigate hepatic transport protein-mediated uptake and biliary excretion of substrates. However, little is known about the disposition of endogenous bile acids (BAs) in SCH. In this study, four endogenous conjugated BAs common to rats and humans [taurocholic acid (TCA), glycocholic acid (GCA), taurochenodeoxycholic acid (TCDCA), and glycochenodeoxycholic acid (GCDCA)], as well as two BA species specific to rodents (α- and β-tauromuricholic acid; α/β TMCA), were profiled in primary rat and human SCH. Using B-CLEAR® technology, BAs were measured in cells+bile canaliculi, cells, and medium of SCH by LC-MS/MS. Results indicated that, just as in vivo, taurine-conjugated BA species were predominant in rat SCH, while glycine-conjugated BAs were predominant in human SCH. Total intracellular BAs remained relatively constant over days in culture in rat SCH. Total BAs in control (CTL) cells+bile, cells, and medium were approximately 3.4, 2.9, and 8.3-fold greater in human than in rat. The estimated intracellular concentrations of the measured total BAs were 64.3±5.9 μM in CTL rat and 183±56 μM in CTL human SCH, while medium concentrations of the total BAs measured were 1.16±0.21 μM in CTL rat SCH and 9.61±6.36 μM in CTL human SCH. Treatment of cells for 24h with 10 μM troglitazone (TRO), an inhibitor of the bile salt export pump (BSEP) and the Na⁺-taurocholate cotransporting polypeptide (NTCP), had no significant effect on endogenous BAs measured at the end of the 24-h culture period, potentially due to compensatory mechanisms that maintain BA homeostasis. These data demonstrate that BAs in SCH are similar to in vivo, and that SCH may be a useful in vitro model to study alterations in BA disposition if species differences are taken into account.Toxicology and Applied Pharmacology 02/2012; 261(1):1-9. DOI:10.1016/j.taap.2012.02.002 · 3.63 Impact Factor
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ABSTRACT: To determine whether protoporphyric liver injury affects hepatic dendritic cells (DC) and Kupffer cells, we examined liver tissues of griseofulvin-induced protoporphyric mice using histological and immunohistochemical methods. After 1 week of griseofulvin feeding, the protoporphyric liver showed prominent hepatomegaly and a gradual in- crease in histopathological changes such as hepatocellular hypertrophy, focal necrosis and brown pigment deposits. After 4 weeks of treatment, marked ductular reaction was observed in the liver tissue. Immunohistochemical analyses indicated that the den- sity of NLDC-145-positive hepatic DC gradually decreased during griseofulvin feeding. However, the index of the number of DC in the whole liver appeared to fall sharply after 6 weeks. In contrast, the density of F4/80-positive Kupffer cells gradually increased during griseofulvin feeding. In the spleen and lung, no significant differences were noted in the distribution of NLDC-145-positive DC between experimental and control mice. These results suggested that griseofulvin-induced protoporphyria leads to a specific decrease in the density of hepatic DC due to hepatomegaly until 4 weeks of treatment and is substantial after 6 weeks. This substantial decrease of hepatic DC might have been induced by some alterations in protoporphyric liver injury including ductular reaction at a later stage in this experiment. Since hepatic DC were reduced in number, they seemed to have no significant relation to the progression of griseofulvin- induced protoporphyric liver injury. However, the decrease of hepatic DC might affect the cellular immune response in protoporphyria.
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ABSTRACT: Previous studies have demonstrated that the organic cation 1-methyl-4-phenylpyridinium (MPP+) is avidly taken up by rat freshly isolated hepatocytes through at least two distinct transport mechanisms: the type I hepatic transporter of organic cations and P-glycoprotein. In this study, the effects of extrahepatic cholestasis induced by bile duct ligation for 4 days on the uptake of [3H]MPP+ by rat freshly isolated hepatocytes and liver slices were determined. Bile duct ligation produced no significant alterations in the characteristics of [3H]MPP+ uptake by freshly isolated hepatocytes. The strong correlation found between the effect of various drugs on [3H]MPP+ uptake by hepatocytes from control and treated rats (r = 0.958; P < 0.0001; n = 15) suggests that neither the type I hepatic transporter of organic cations nor P-glycoprotein were affected by bile duct ligation. On the contrary, uptake of [3H]MPP+ by liver slices was markedly changed after bile duct ligation: (1) there was a significant increase (approximately equal to 40%) in the amount of [3H]MPP+ taken up by liver slices from bile duct-ligated rats; (2) there was no correlation between the effect of various drugs on [3H]MPP+ uptake by liver slices from control and treated rats (r = 0.772; P= 0.072; n = 6). On the basis of (1) the lack of effect of bile duct ligation on [3H]MPP+ uptake by isolated hepatocytes; and (2) the profound morphological alterations of liver tissue observed 4 days after bile duct ligation (increase in volume density of bile ductules, ductular cells and infiltration of inflammatory cells), we suggest that non-parenchymal liver cells have an important participation in the hepatic uptake of [3H]MPP+ after bile duct ligation in the rat.Pharmacological Research 07/1998; 37(6):497-504. DOI:10.1006/phrs.1998.0325 · 3.98 Impact Factor