Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Choline Deficiency”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 973 records · Page 54Linked to original sources
PubMed2000

Warm ischemia and reperfusion injury in diet-induced canine fatty livers.

BACKGROUND: Fatty liver is associated with primary nonfunction after liver transplantation, contributing a shortage of suitable liver grafts. Because extensive investigation of mechanisms underlying such nonfunction has been limited largely to rodents, we made a new fatty liver model in dogs and studied primary nonfunction after warm ischemia. METHODS: We developed a diet rich in fat but deficient in choline to induce fatty change in canine liver and investigated effects of 60 min of warm ischemia and reperfusion in dogs with such fatty livers. RESULTS: Microscopically evident steatosis increased with duration of dietary manipulation (up to 12 weeks), as did hepatic total lipid and triglyceride levels. No dog with >30% of steatotic hepatocytes, >445 mg/g hepatic total lipid or >145 mg/g hepatic triglyceride survived after 60 min of warm ischemia. Arterial ketone body ratios decreased and blood endotoxin increased after reperfusion in nonsurvivors. The main histologic finding in livers of nonsurvivors was marked sinusoidal congestion. CONCLUSIONS: Damage to hepatocytes and nonparenchymal cells after warm ischemia and reperfusion was thought to be closely related to sinusoidal microcirculatory disturbances in fatty livers. The canine fatty liver model reported here may be useful in studying the pathology of primary nonfunction and in establishing criteria for allowable degrees of fatty change in potential liver grafts.

Alanine Transaminase↗
PubMed2001

Increased generation of reactive oxygen species in isolated rat fatty liver during postischemic reoxygenation.

BACKGROUND: Whether fatty infiltration of the liver influences the generation of reactive oxygen species (ROS) during reperfusion is unclear. Thus, this study aimed to compare the ROS formation that occurs during postanoxic reoxygenation in isolated normal and fatty livers. METHODS: Isolated livers from fed Sprague-Dawley rats with normal or fatty livers induced by a choline-deficient diet were reperfused at 37 degrees C for 60 min with an oxygenated medium containing 10 microM of lucigenin after 1 hr of warm ischemia. Superoxide anion generation was assessed by the chemiluminescence (CLS) signal emitted from the organ surface. The hepatic content of malondialdehyde (MDA) and glutathione was determined at the end of reperfusion. Tissue injury was evaluated by the liver histology and the alanine aminotransferase (ALT) release in the perfusate. RESULTS: CLS started rapidly with reoxygenation and it diffused to the whole organ in both groups. However, CLS emission was significantly higher in fatty liver (after 10 min: 812.425+/-39.898 vs. 294.525+/-21.068 photons/cm2/sec; P<0.01). A greater concentration of MDA was measured at the end of reoxygenation in fatty liver. Finally, the liver histology and the ALT release indicated a greater injury in steatotic than normal liver. CONCLUSIONS: The CLS technique allows a direct visualization and comparison of ROS generation from the organ surface. Fatty infiltration increases ROS generation in the liver during postischemic reoxygenation, likely leading to the greater lipid peroxidation observed in these experiments. The increased oxidative stress may contribute to the reduced tolerance of steatotic livers to ischemia-reperfusion injury.

Alanine Transaminase↗
PubMed2005

Modulation of non-alcoholic steatohepatitis by pattern recognition receptors in mice: the role of toll-like receptors 2 and 4.

Toll-like receptors (TLR) recognize pathogen-derived molecules and induce downstream activation of inflammatory pathways. Fatty liver has been shown to result in increased sensitivity to lipopolysaccharide (LPS), a TLR4 ligand. In this study, we investigated the roles of TLR2 and TLR4 in liver damage and on cytokine induction in a methionine-choline deficient (MCD) diet-induced model of nonalcoholic steatohepatitis. We found that mice with nonalcoholic fatty liver had increased liver injury and inflammatory cytokine induction after challenge with a TLR4 but not with a TLR2 ligand. TLR2 deficient mice were not protected against the development of steatohepatitis after MCD diet feeding. On the contrary, TLR2 mice had significantly higher levels of serum ALT and greater TNF-alpha levels after LPS challenge suggesting increased liver injury. This was associated with reduced production of IL-6, a cytokine with hepatoprotective effects in fatty liver. Increased liver injury in the MCD diet-fed TLR2 mice was associated with reduced baseline and LPS-induced NF-kB and PPRE binding compared to MCS controls. These results demonstrate that TLR2 deficiency results in increased liver injury in association with nonalcoholic steatohepatitis and may suggest a protective role for TLR2-mediated signals in liver injury.

Animals↗
PubMed2004

Ethyl pyruvate ameliorates distant organ injury in a murine model of acute necrotizing pancreatitis.

OBJECTIVE: Ethyl pyruvate has been shown to be an effective anti-inflammatory agent in a variety of in vitro and in vivo model systems. Herein, we used a murine model of acute pancreatitis to compare the effects of treatment with either Ringer's lactate solution or ethyl pyruvate solution on several physiologic and biochemical variables related to disease severity. DESIGN: Experimental animal study. SETTING: University laboratory. SUBJECTS: C57Bl/6 mice. INTERVENTIONS: Pancreatitis was induced by feeding the animals a choline-deficient diet supplemented with 0.5% ethionine for 24 hrs and then challenging the animals with seven hourly 50 microg/kg intraperitoneal injections of cerulein and a single intraperitoneal injection of Escherichia coli lipopolysaccharide (4 mg/kg). MEASUREMENTS AND MAIN RESULTS: When mice were treated with ethyl pyruvate (40 mg/kg intraperitoneally every 6 hrs for 48 hrs) instead of Ringer's lactate solution starting 2 hrs after the injection of lipopolysaccharide, long-term survival was improved from one of ten to six of ten (p =.057). When mice were treated with a 40 mg/kg dose of ethyl pyruvate just before the first dose of cerulein and then injected with a second 40 mg/kg dose 6 hrs later, serum concentrations of alanine aminotransferase measured 10 hrs after the first cerulein dose were significantly lower than in mice with pancreatitis treated with Ringer's lactate solution. In this model of acute pancreatitis, the same dosing regimen for ethyl pyruvate also ameliorated bacterial translocation to mesenteric lymph nodes and leakage of fluorescein isothiocyanate-labeled albumin from blood into bronchoalveolar lavage fluid. Treatment with ethyl pyruvate decreased pancreatic expression of tumor necrosis factor and interleukin-6 messenger RNA and nuclear factor-kappaB DNA binding in nuclear extracts prepared from pancreatic tissue. CONCLUSION: Treatment with ethyl pyruvate ameliorated the local inflammatory response and decreased local and distant organ injury in a murine model of necrotizing pancreatitis.

Animals↗
PubMed2004

Sustained spatial disturbance of bile canalicular networks during regeneration of the steatotic rat liver.

BACKGROUND: Although it is generally considered that livers with moderate steatosis can be safely used in the setting of living-donor liver transplantation, the effect of the regenerative process of such a graft on postoperative liver function is incompletely understood. We assessed the morphologic and functional alterations during the regeneration of fatty liver, with special reference to the biliary system. METHODS: Wistar rats with normal or fatty livers induced by a choline-deficient diet were subjected to 70% partial hepatectomy (PH). The regenerated liver weight and serum parameters were compared. Furthermore, to assess the spatial alterations of bile canalicular networks, the distribution of AGp110, a fibronectin receptor that localizes on the apical (bile canalicular) membrane of the hepatocytes, was analyzed immunohistochemically. RESULTS: The serum albumin levels of the fatty-liver rats decreased significantly after 24 hours, and this continued until day 7. The increase in the total bile acid levels of the fatty-liver group was higher and more prolonged compared with that of the normal-liver group. At 24 hours after PH, discontinuity of the AGp110-positive canalicular network was evident in both groups. At 7 days after PH, the typical AGp110-positive canalicular network was almost restored in the normal-liver group. In contrast, the fatty-liver group showed sustained discontinuity of canalicular networks at the same time point. CONCLUSIONS: The livers with moderate steatosis are associated with prolonged cholestasis after 70% PH, and this was caused, in part, by sustained spatial disturbance of bile canalicular networks during the regenerative process.

Animal Nutritional Physiological Phenomena↗
PubMed1991

Initiating activity of diethylnitrosamine in a rapid production model for pancreatic carcinomas in Syrian hamsters.

The potential initiating activity of diethylnitrosamine (DEN) was studied in a rapid production model for pancreatic carcinogenesis in hamsters developed in our laboratory incorporating the principle of selection based on resistance of cytotoxicity, originally demonstrated for liver carcinogenesis in rats. Female Syrian golden hamsters were given DEN at a dose of 100 mg/kg body weight or N-nitrosobis-(2-oxopropyl)amine (BOP) at a dose of 70 mg/kg body weight as initiators followed by 3 cycles of augmentation pressure (choline-deficient diet combined with DL-ethionine, L-methionine upon return to basal diet and then administration of 20 mg/kg body weight BOP), and killed 10 weeks after the beginning of the experiment. DEN followed by the augmentation pressure induced a 65% incidence of total pancreatic lesions including 15% carcinomas, while BOP followed by the augmentation pressure induced 100% incidence of total pancreatic lesions and 84.2% for carcinomas. These yields were significantly greater than those observed for augmentation pressure alone. The results thus indicate that DEN possesses weak initiating activity for pancreatic carcinogenesis under the present experimental conditions.

Animals↗
PubMed1993

K-ras gene mutation in early ductal lesions induced in a rapid production model for pancreatic carcinomas in Syrian hamsters.

The presence of K-ras gene mutation was examined in experimentally induced preneoplastic pancreatic ductal lesions. Syrian hamsters received 70 mg/kg of N-nitrosobis(2-oxopropyl)amine (BOP) followed by repeated exposure to an augmentation pressure regimen consisting of choline-deficient diet combined with DL-ethionine and L-methionine and administration of 20 mg/kg BOP. After two augmentation pressure cycles, pancreatic ductal cell hyperplasias appeared and after three cycles, atypical hyperplasias of pancreatic ductal cells and intraductal carcinomas developed. K-ras mutations were detected by single-strand conformation polymorphism analysis of polymerase chain reaction products and nucleotide sequencing. The results showed that K-ras mutation had occurred in one of 9 simple hyperplasias of pancreatic ductal epithelium, in 5 of 9 atypical hyperplasias, and in 4 of 8 intraductal carcinomas. The findings thus suggested that K-ras is activated in association with very early stage malignant transformation of pancreatic ductal cells in hamsters.

Animals↗
PubMed2006

Methylation of neutral endopeptidase 24.11 promoter in rat hepatocellular carcinoma.

Neutral endopeptidase 24.11 (NEP), a cell-surface enzyme expressed by epithelial cells that cleaves and inactivates biologically active small peptides, is downregulated in various cancers. NEP is encoded by a gene that contains a CpG island in the promoter region, whose hypermethylation appears related to decreased expression. Altered expression of NEP has also been reported in human hepatocellular carcinoma (HCC), suggesting its possible role in hepatocarcinogenesis. To elucidate the status of NEP in HCC, methylation in the promoter region of the gene that encodes NEP in male Fischer 344 rats with HCC, induced by a choline-deficient, l-amino acid-defined diet, was investigated by methylation-specific polymerase chain reaction, combined bisulfite restriction analysis, and bisulfite genomic sequencing. These analyses together showed the promoter to be frequently methylated in HCC in contrast to its unmethylated status in normal liver, the degree of methylation being inversely related to the level of mRNA expression evaluated by reverse transcription-polymerase chain reaction (P = 0.031). In two rat liver cell lines, RLC-16 and RLC-27, the promoter was heavily methylated and NEP mRNA expression was negative. However, administration of 5-aza-2'-deoxycytidine caused NEP expression, suggesting that methylation of CpG is a factor regulating transcriptional expression. Together with the data from microarray analyses performed previously using the same animal model, the current results suggest that reduced expression of NEP or other ectopeptidases could impact on molecules involved in signal-transducing systems, including G-protein coupled receptors, via modified turnover of extracellularly active small peptides.

Animals↗
PubMedDate not supplied

Effects of a gastric mucosal protecting agent in rats with liver cirrhosis.

Male Sprague-Dawley rats were fed a 0.1% ethionine-added choline-deficient diet for 8 weeks to induce liver cirrhosis. At the same time 100 mg/kg/day teprenone was administered orally in order to evaluate its effects on the liver and gastric mucosal blood flow. Blood flow increased not only in gastric mucosa but also in liver tissues in the teprenone group. Serum transaminase levels and histopathologic findings of the liver also improved. These findings suggest that teprenone alleviates hepatocellular injuries. This effect may be partly attributable to cytoprotective effects of the catenoid isoprenoid moiety of teprenone on liver cells.

Animals↗
PubMed1989

Relation of sinusoidal stenoses following hepatocyte swelling to hepatic vascular resistance in experimental liver cirrhosis.

To investigate the significance of sinusoidal stenoses and a decrease in the sinusoidal bed due to hepatic cell swelling as a factor increasing hepatic vascular resistance in liver cirrhosis, hepatic vascular resistance in choline-deficient diet-induced cirrhotic rats was measured by an isolated liver perfusion method. In the cirrhotic rats, the swollen hepatic cells resulting from accumulation of fat droplets narrowed the sinusoids and decreased the sinusoidal bed. Consequently, the hepatic vascular resistance was increased by 2.7 times normal (8.60 +/- 2.32 mm H2O.ml-1.min; controls, 3.13 +/- 0.67 mm H2O.ml-1.min), and portal hypertension was also recognized (188.1 +/- 26.3 mm H2O; controls, 114.2 +/- 12.8 mm H2O). In the cirrhotic rats fed with ordinary rat pellets for 2 months, however, the sinusoidal stenoses and the decreased sinusoidal bed recovered to nearly normal as a result of disappearance of the fat droplets in the hepatic cells. The increased hepatic vascular resistance was decreased to 1.5 times normal (4.68 +/- 0.82 mm H2O.ml-1.min), and the elevated portal vein pressure was reduced (141.5 +/- 17.4 mm H2O). These findings clearly demonstrate that an important factor leading to an increase in hepatic vascular resistance is sinusoidal stenoses and a decrease in the sinusoidal bed resulting from swollen hepatic cells.

Animals↗
PubMed1992

Role of septal fibrosis in development of hepatic circulatory disturbance in the presence of liver cell enlargement.

The effect of septal fibrosis on hepatic circulation was examined in rats with enlarged liver cells. Septal fibrosis was produced by horse serum injections and liver cell enlargement by a choline-deficient diet. Septal fibrosis alone did not induce any disturbance of hepatic circulation. In fatty livers, a slight increase in sinusoidal vascular resistance and a slight elevation of portal vein pressure were found. However, in fatty livers with septal fibrosis, portal hypertension and sinusoidal vascular resistance were higher than in fatty livers without septal fibrosis. These experimental data clearly demonstrate that septal fibrosis alone has no effect on hepatic circulation, but septal fibrosis in the presence of liver cell enlargement markedly affects sinusoidal circulation and induces portal hypertension. The augmentation of sinusoidal vascular resistance by septal fibrosis in the presence of liver cell enlargement might be due to the severe deformation of the sinusoids by enlarged liver cells in the limited spaces surrounded by septal fibrous bands.

Animals↗
PubMed1985

Expression of c-Ki-ras, c-Ha-ras, and c-myc in specific cell types during hepatocarcinogenesis.

We examined the expression of six proto-oncogenes in (i) whole rat liver and isolated liver cell populations during the course of hepatocarcinogenesis induced by a choline-deficient diet containing 0.1% ethionine and (ii) fetal rat liver at different stages of development. The abundance of c-Ki-ras, c-Ha-ras, and c-myc transcripts in polysomal polyadenylated RNA from liver cells increased by 2 weeks after the start of the carcinogenic diet. c-Ki-ras and c-myc expression remained elevated during the 35 weeks of the diet, whereas c-Ha-ras transcripts increased transiently. A primary tumor sampled at 35 weeks after the carcinogenic diet was started contained high levels of both c-Ki-ras and c-myc RNA. The abundance of c-src transcripts was unchanged throughout carcinogenesis; c-abl and c-mos transcripts were not detected in either preneoplastic or neoplastic livers. To determine which cell types within the liver contained proto-oncogene transcripts, we isolated hepatocytes, oval cells, and bile duct cells from normal and preneoplastic livers. The results indicate that proto-oncogenes are expressed differentially in these cell types during hepatocarcinogenesis and that the expression of c-Ki-ras and c-myc is high in oval cells throughout carcinogenesis. In developing livers, c-Ki-ras, c-Ha-ras, and c-myc transcript levels were high at 17 days of gestation but reached the low values characteristic of adult rat livers between 20 days of gestation and 3 days after birth.

Animals↗
PubMed1991

Effect of a new synthetic ascorbic acid derivative as a free radical scavenger on the development of acute pancreatitis in mice.

The therapeutic effects of CV 3611, a new synthetic free radical scavenger prepared from an ascorbic acid derivative, on choline deficient, ethionine enriched (CDE) diet induced acute pancreatitis in mice were evaluated and compared with those of superoxide dismutase. Time/course studies after subcutaneous injection of CV 3611 in normal mice showed a peak plasma concentration of mean (SEM) 0.54 (0.09) micrograms/ml at one hour, with a gradual decrease over the next 10 hours, while a peak concentration in pancreatic tissue of mean (SEM) 425 (33) ng/g tissue was achieved at three hours and the drug was undetectable at 12 hours. Survival rates and activities of pancreatic enzymes (amylase, lipase, elastase I) were compared in control mice and animals that received CV 3611 before or at the time of feeding the CDE diet. The survival rate was observed in a no treatment group and mice given pretreatment or treatment with CV 3611 or superoxide dismutase. The survival rate was significantly better in the treatment group given CV 3611 (p less than 0.02), but superoxide dismutase had no significant effect on survival. The increases in the three serum enzyme activities were significantly less at 48 hours in the groups given pretreatment or treatment with CV 3611 than in the no treatment group. These results indicate that CV 3611, which has been proved to pass through the cell membrane and to have a long half life in plasma and tissue, had an important therapeutic effect on the development of acute pancreatitis. They also suggest that oxygen derived free radicals may play an important role in the development of acute pancreatitis.

Amylases↗
PubMed1975

Changes in metabolism of ethanolamine and its derivatives in liver during fasting.

The time course of incorporation of radioactivity into liver phosphatidylethanolamine and its precursors was studied following intraportal injection of [1,2-14C]ethanolamine into rats that had been fasted for 24 h and into nonfasted rats. Marked diminution in the labelling of liver phosphatidylethanolamine and CDP-ethanolamine was present in the fasted groups while the radioactivity contained in the ethanolamine and phosphorylethanolamine pools of these livers was increased. The livers of the fasted rats contained significantly higher levels of ethanolamine, phosphorylethanolamine and CDP-ethanolamine while choline and phosphorylcholine were decreased. These changes are identical to those which we have described earlier in the livers of nonfasted rats fed a choline deficient diet. In a further experiment, the duration of the fasting period necessary to bring about these changes was studied. Incorporation of radioactivity into liver phosphatidylethanolamine at 2.5 min following intraportal injection of [1,2-14]ethanolamine declined progressively up to 7.5 h of fasting and did not decrease further after that time. There was a concomitant decrease in labelling of CDP-ethanolamine with retention of radioactivity in ethanolamine and phosphorylethanolamine. These results show that the liver metabolism of ethanolamine is altered quite early in the fasting period and suggest that it may be related in some way to the metabolic response to fasting.

Animals↗
PubMed1985

The role of phosphatidylcholine biosynthesis in the secretion of lipoproteins from hepatocytes.

An investigation of the role of phospholipids in lipoprotein assembly and secretion is important since phospholipids, particularly phosphatidylcholine, are prominent components of all plasma lipoproteins. The fatty acid composition of phosphatidylcholine is virtually identical in human very low (VLDL), low, and high density lipoproteins, which supports the idea that phosphatidylcholine exchanges freely among plasma lipoproteins. However, the fatty acid composition of phosphatidylcholine from cultured rat hepatocytes is different from that in the secreted lipoproteins. In addition, the composition of molecular species of phosphatidylcholine is quite different in the rat liver, plasma, and red cells. Phosphatidylcholine is made in liver by two alternate pathways, by the CDP-choline pathway and by the methylation of phosphatidylethanolamine. Regulation of phosphatidylcholine biosynthesis by the CDP-choline pathway in rat liver is well established. In most instances, the rate of phosphatidylcholine synthesis is governed by the activity of CTP:phosphocholine cytidylyltransferase, which is present in the cytosol and also associated with microsomes. The cytosolic enzyme is inactive but can be reversibly translocated to the microsomes, where it is active. Translocation of this enzyme to the microsomes can be achieved either by a dephosphorylation reaction or by the presence of fatty acids in the cytosol. Once synthesized, how is phosphatidylcholine assembled into lipoprotein particles? The sequence of assembly of phospholipids into VLDL has been investigated in several studies. In a pulse-chase experiment, there was an initial labelling (within 15 min of the pulse) of phospholipids in secreted VLDL, which probably reflected the rapid movement of the phospholipids from their site of synthesis (the endoplasmic reticulum) to the Golgi. There appears to be a rapid exchange of phospholipid between the Golgi membranes and contents. There was also a delayed labelling (after 30 min) of the phospholipids and triacylglycerols (from [3H]glycerol) and the apoproteins (from [3H]leucine) in the secreted VLDL. This lag was attributed to the time taken for the nascent VLDL particles to move from the lumen of the endoplasmic reticulum to the Golgi and into the medium. Is phosphatidylcholine biosynthesis is required for lipoprotein secretion? This question was investigated in rats maintained on a choline-deficient diet for 10 days. The total amount of plasma phosphatidylcholine decreased by approximately 40% and the rats developed fatty livers.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Effect of kinin inhibition in experimental acute pancreatitis.

Activation of the endogenous kinin system is a consistent observation in acute pancreatitis and has repeatedly been implicated in the pathophysiology of the disease. We have studied the effect of a potent bradykinin antagonist on the onset and development of acute pancreatitis in four unrelated animal models. Pancreatitis was induced in rats by either supramaximal stimulation with caerulein, intraductal injection of sodium taurocholate, or pancreatic duct ligation with secretin infusion, and in mice by feeding a choline-deficient, ethionine-supplemented diet. The potent, long-acting bradykinin antagonist HOE-140 was administered subcutaneously (0.1 mg/kg every 5 h). Effective kinin inhibition had no effect on pancreatitis-associated mortality, the extent of morphological damage and inflammation, or the intracellular distribution of lysosomal hydrolases. Pancreatic edema was only reduced in caerulein-induced pancreatitis, the only model in which edema formation was paralleled by increased vascular permeability. We conclude that, contrary to previous suggestions, kinins do not play a predominant role in the development of acute pancreatitis. Their participation is strictly limited to vascular events and does not involve the early cell biological alterations in pancreatic acinar cells.

Acute Disease↗
PubMed2000

Simple epithelial keratins are dispensable for cytoprotection in two pancreatitis models.

Pancreatic acinar cells express keratins 8 and 18 (K8/18), which form cytoplasmic filament (CF) and apicolateral filament (ALF) pools. Hepatocyte K8/18 CF provide important protection from environmental stresses, but disruption of acinar cell CF has no significant impact. We asked whether acinar cell ALF are important in providing cytoprotective roles by studying keratin filaments in pancreata of K8- and K18-null mice. K8-null pancreas lacks both keratin pools, but K18-null pancreas lacks only CF. Mouse but not human acinar cells also express apicolateral keratin 19 (K19), which explains the presence of apicolateral keratins in K18-null pancreas. K8- and K18-null pancreata are histologically normal, and their acini respond similarly to stimulated secretion, although K8-null acini viability is reduced. Absence of total filaments (K8-null) or CF (K18-null) does not increase susceptibility to pancreatitis induced by caerulein or a choline-deficient diet. In normal and K18-null acini, K19 is upregulated after caerulein injury and, unexpectedly, forms CF. As in hepatocytes, acinar injury is also associated with keratin hyperphosphorylation. Hence, K19 forms ALF in mouse acinar cells and helps define two distinct ALF and CF pools. On injury, K19 forms CF that revert to ALF after healing. Acinar keratins appear to be dispensable for cytoprotection, in contrast to hepatocyte keratins, despite similar hyperphosphorylation patterns after injury.

Actins↗
PubMed1990

Hepatic microvascular changes associated with development of liver fibrosis and cirrhosis.

Quantitative data defining basic microvascular parameters are needed for better understanding of the relationship between liver blood flow and function under normal and pathological conditions. The present study was undertaken to quantitate the following microvascular parameters: flow velocities in sinusoids and terminal hepatic venules; the range of sizes of terminal hepatic vessels; and acinar sizes in both normal rat livers and during the development of liver cirrhosis. Fibrosis and cirrhosis were induced by either weekly administration of carbon tetrachloride (CCl4) or by choline-deficient diet. Microcirculation was observed using intravital epifluorescent video microscopy and recorded on a videotape for subsequent analysis. It was found that even early stages of liver disease, when only mild hepatic fibrosis was present, are associated with profound changes in the hepatic microvasculature. These changes include the appearance of highly fluorescent cells in the liver parenchyma (mainly in the areas where collagen is being deposited), a marked dilatation of the terminal hepatic venules, an increase in hepatic venous outflow, and appearance of sinusoids with very high flow velocities. As fibrosis progresses to cirrhosis, the proportion of these "fast sinusoids" increases from 7% in fibrotic livers to 33% in cirrhotic livers. These results demonstrate the presence of functional intrahepatic shunts in cirrhotic livers and support the hypothesis that hyperdynamic splanchnic circulation may be an important factor in the etiology of portal hypertension in liver disease.

Animals↗