Determinants of hepatic function in liver cirrhosis in the rat. Multivariate analysis.

Reichen, Jürg; Egger, Bernhard; Ohara, N.; Zeltner, Thomas; Zysset, Thomas; Zimmermann, Arthur

doi:10.1172/jci113828

Cited by 99 publications

(67 citation statements)

References 47 publications

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“…In the normal liver, this diffusion is instantaneous because the endothelium contains fenestrae of 50 -200 nm in diameter and has no basement membrane. Since the apparent molecular diameter for Gd-DOTA is 0.9 nm (38), the assumption that the extraction fraction (E) of the contrast agent equals 1.0 is reasonable in the normal liver and hepatic perfusion (F) can therefore be considered to equal k 1 . In addition to k 1 , the outflow rate constant k 2 was also estimated and with both rate constants the distribution volume of the contrast agent and its mean transit time could be determined.…”

Section: Discussionmentioning

confidence: 99%

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Assessment of hepatic perfusion parameters with dynamic MRI

Materne

Smith

Peeters

et al. 2001

Magnetic Resonance in Med

213

247

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Section: Discussionmentioning

confidence: 99%

“…Liver hemodynamics is a main determinant of hepatic function (1,2). In patients with liver cirrhosis, modifications of hepatic perfusion contribute to the deterioration of hepatic function by decreasing blood-hepatocyte exchanges (3).…”

mentioning

confidence: 99%

Assessment of hepatic perfusion parameters with dynamic MRI

Materne

Smith

Peeters

et al. 2001

Magnetic Resonance in Med

213

247

View full text Add to dashboard Cite

“…The Goresky model has previously been used to estimate the mean transit time of vascular and extravascular references in the fibrotic rat liver. 5,6,30 In general, various space-distributed models using vascular and extravascular references as a basis for drug disposition in perfused livers should be comparable although not mathematically identical. The significantly larger liver/body weight ratio for CCl 4 -treated (phenobarbital/CCl 4 treatment), CCl 4 -control (phenobarbital treatment), and alcohol-treated rats compared with alcohol-control (normal) rats (Table 1) is likely to be treatment induced.…”

Section: Discussionmentioning

confidence: 99%

Quantitative evaluation of altered hepatic spaces and membrane transport in fibrotic rat liver

et al. 2002

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Four animal models were used to quantitatively evaluate hepatic alterations in this study: (1) a carbon tetrachloride control group (phenobarbital treatment only), (2) a CCl 4 -treated group (phenobarbital with CCl 4 treatment), (3) an alcohol-treated group (liquid diet with alcohol treatment), and (4) a pair-fed alcohol control group (liquid diet only). At the end of induction, single-pass perfused livers were used to conduct multiple indicator dilution (MID) studies. Hepatic spaces (vascular space, extravascular albumin space, extravascular sucrose space, and cellular distribution volume) and water hepatocyte permeability/surface area product were estimated from nonlinear regression of outflow concentration versus time profile data. The hepatic extraction ratio of 3 H-taurocholate was determined by the nonparametric moments method. Livers were then dissected for histopathologic analyses (e.g., fibrosis index, number of fenestrae). In these 4 models, CCl 4 -treated rats were found to have the smallest vascular space, extravascular albumin space, 3 H-taurocholate extraction, and water hepatocyte permeability/surface area product but the largest extravascular sucrose space and cellular distribution volume. In addition, a linear relationship was found to exist between histopathologic analyses (fibrosis index or number of fenestrae) and hepatic spaces. The hepatic extraction ratio of 3 H-taurocholate and water hepatocyte permeability/surface area product also correlated to the severity of fibrosis as defined by the fibrosis index. In conclusion, the multiple indicator dilution data obtained from the in situ perfused rat liver can be directly related to histopathologic analyses. (HEPATOLOGY 2002;36:1180-1189 L iver fibrosis and cirrhosis represent a major worldwide health problem. In cirrhosis, the normal hepatic lobular architecture is replaced by interconnecting bands of fibrous tissue surrounding nodules of regenerating hepatocytes. The sinusoidal stellate cell is central to the fibrotic process. 1-4 Consequently, extravascular space accessible to macromolecules (e.g., albumin) decreases and the distribution of sucrose shows a barrierlimited pattern in the space of Disse instead of the normal flow-limited behavior due to 3 hepatic alterations: (1) collagenization of the space of Disse, (2) formation of a basement membrane of the sinusoid (capillarization), and (3) intrahepatic, portahepatic shunt formation. 5-8 A liver biopsy is currently mandatory to assess severity of fibrosis.We recently examined the drug structure/disposition kinetics of a series of cationic drugs in carbon tetrachloride-and alcohol-induced fibrosis in perfused rat livers. 9 In this case, cationic drug disposition in the fibrotic liver can be predicted from drug properties and liver histopathology. As a result, the question was raised of whether we could use histopathology from patient liver biopsy specimens to estimate changes in hepatic spaces and whether the active and passive transport of probes (e.g., 3 H-taurocholate, 3 H-water) across ...

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“…The second model exposes rats to CCl 4 vapors concomitantly to phenobarbital and results in cirrhosis. 14,15,32 To quantify the effect of biliary fibrosis on the expression of IP 3 R isoforms, we used four different methods, one at the protein level and three at the mRNA level. They all found that 28 days after bile duct ligation, IP 3 R isoform 2 was less abundant, IP 3 R isoform 1 more abundant, and isoform 3 was several-fold more expressed ( Table 1).…”

Section: Discussionmentioning

confidence: 99%

Expression of inositol 1,4,5-trisphosphate receptor isoforms in rat cirrhosis

et al. 1999

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Ca 2؉ signals mediate the hepatic effects of numerous hormones and growth factors. Hepatic Ca 2؉ signals are elicited by the inositol trisphosphate receptor, an intracellular Ca 2؉ channel. Three isoforms of this receptor have been identified; they are expressed and regulated differently. We investigated the effect of liver fibrosis and cirrhosis on the hepatic expression of the inositol trisphosphate receptor isoforms. Two different rat models were used: bile duct ligation (fibrosis) and chronic exposure to CCl 4 /phenobarbital (cirrhosis). Messenger RNA levels were determined by ribonuclease protection assay (RPA), competitive polymerase chain reaction (PCR) followed by Southern blotting, and real-time quantitative PCR. Protein expression was assessed by Western blotting; tissue distribution was assessed by immunohistology. In control animals, isoform 2 was the predominant isoform, isoform 1 represented less than one third, and isoform 3 less than 1%. After bile duct ligation, expression of types 1 and 3 increased 1.9-and 5.7-fold, and expression of type 2 decreased 2.5-fold at the protein level. After exposure to CCl 4 /phenobarbital, expression of types 1, 2, and 3 were 2.4-, 0.9-, and 4.2-fold their expression in control animals. Type 2 was localized to the apical domain of hepatocytes, consistent with a role for Ca 2؉ signals in canalicular function. Type 3 was detectable in intrahepatic bile duct epithelial cells and not in hepatocytes, suggesting that Ca 2؉ signals may be regulated differently in these cells. Signaling through inositol trisphosphate receptor participates in the pathogenesis of cirrhosis, because this process affects the expression of its isoforms. (HEPATOLOGY 1999;30:1018-1026.)Development of cirrhosis implies not only remodeling of the liver architecture, but also dramatic changes in the functions of hepatic cells. These changes are orchestrated by a network of receptors, protein-kinases, and transducers that compose complex signaling pathways. Among them, the inositol 1,4,5-trisphosphate receptor (IP 3 R) plays a central role. 1 Numerous hormones and growth factors bind to receptors on plasma membrane to stimulate the production of inositol 1,4,5-trisphosphate (IP 3 ) and to trigger IP 3 -dependent Ca 2ϩ release through the Ca 2ϩ channel of the IP 3 R. 2 Ca 2ϩ signals regulate many cellular functions from gene expression and cellular division to metabolic pathways and cellular secretion. 1 Both hepatocytes and biliary epithelial cells demonstrate complex Ca 2ϩ signals, which rely essentially on IP 3 R, because the ryanodine receptor, another intracellular Ca 2ϩ channel, could not be detected in liver. 3 In response to hormonal stimulation, intracellular Ca 2ϩ concentration oscillates in hepatocytes and even forms Ca 2ϩ waves through the entire lobule. 4 Hepatocellular Ca 2ϩ signals start in a specific apical location and diffuse in an apical to basal manner. 5 IP 3 -dependent Ca 2ϩ signals stimulate bile canalicular contractions, an effect blocked by nitric oxide. 6 In intrahepatic bil...

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Determinants of hepatic function in liver cirrhosis in the rat. Multivariate analysis.

Cited by 99 publications

References 47 publications

Assessment of hepatic perfusion parameters with dynamic MRI

Assessment of hepatic perfusion parameters with dynamic MRI

Quantitative evaluation of altered hepatic spaces and membrane transport in fibrotic rat liver

Expression of inositol 1,4,5-trisphosphate receptor isoforms in rat cirrhosis

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