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[Liver regenerative capacity after partial hepatectomy in rats with nonalcoholic fatty liver disease].

OBJECTIVE: To explore the changes of liver regeneration after partial hepatectomy on rats with nonalcoholic fatty liver disease (NAFLD) caused by a high fat diet. METHODS: One hundred Wistar rats were randomly divided into a control group (group C, n = 45), fed with normal diet, and a NAFLD group, fed with fat-rich diet (group F, n = 55). All rats had a 70% partial hepatectomy at the end of the 12th week. They were sacrificed at postoperative 0, 1, 12, 24, or 36 hours and the percentages of their regenerated liver masses were calculated. The mitosis index was measured microscopically and the changes of cell ultrastructure were observed under an electron microscope. The expression of proliferating cell nuclear antigen (PCNA) was detected using immunohistochemistry. The expression of mRNA of cyclin D1 was measured by RT-PCR. RESULTS: The light and electron microscopy showed that the hepatic sinusoids expanded at an early period after the partial hepatectomy. The mitochondria and rough endoplasmic reticulum (RER) expanded and their number increased. The mitosis index was increased. The sinusoids of the livers in group F were narrow and irregular. The nuclei were smaller and the necrotic cells increased. As compared with the control group, the mitosis index was significantly decreased (P < 0.01), and the regenerative liver weight ratio in group F was lower at postoperative 12 h, 24 h, 36 h (P < 0.01). PCNA labeling index in group F also was lower than that in group C. The peak of the PCNA in group F was later than that of the control group (P < 0.01). In group C, the mRNA of cyclin D1 peaked at the 24th hour after the partial hepatectomy, and then decreased afterwards. In group F, it was lower than that of group C at the same time (P < 0.01). CONCLUSION: After NAFLD rats had partial hepatectomies, the capacity of their liver regeneration decreased and the peak of DNA synthesis was delayed, and at the same time the morbidity of the rats increased.

Animals↗

Evaluation of inferior right hepatic vein-preserving hepatectomy with resection of the superior right hepatic vein.

BACKGROUND/AIMS: If the superior right hepatic vein (SRHV) is resected, segment 6 will be drained by the inferior right hepatic vein (IRHV) and congestion will not occur. However, early postoperative liver function and long-term regeneration of segment 6 after IRHV-preserving hepatectomy remains unclear. METHODOLOGY: Three patients undergoing IRHV-preserving hepatectomy were examined. One (case 1) had liver metastasis from sigmoid colon cancer and two (cases 2 and 3) had hepatocellular carcinoma. Resection of segments 7 and 8 along with the SRHV was performed in cases 1 and 2. Anterior sectionectomy and resection of segment 4a along with the SRHV and middle hepatic vein (MHV) was performed in case 3. The volume of each sector was calculated by summation of each CT area. RESULTS: The warm ischemic time of the three cases was 50-78 min, operative blood loss was 496-914 g, and operating time was 4-7 h. There was no significant change in diameter of the IRHV and MHV before and after surgery. Intraoperative color Doppler ultrasonography was a useful technique for evaluating intrahepatic venous communication. Part of segment 6 had previously been resected in case 1, and at outpatient follow-up this segment was found to have become atrophic. In cases 2 and 3, the remnant posterior sector became hypertrophic. CONCLUSIONS: IRHV-preserving hepatectomy can retain a greater proportion of liver parenchyma than right hepatectomy. Postoperative liver function was well maintained in our patients and there were no serious complications. Long-term follow-up showed hypertrophy of the remnant posterior sector except in one case. To minimize surgical damage, for example in patients with poor liver function or preoperative complications, IRHV-preserving hepatectomy should be considered.

Carcinoma, Hepatocellular↗

Feasibility and effectiveness of chemical bile duct embolization for chemical hepatectomy: a preliminary study.

BACKGROUND: The high operative risk of hepatectomy for specially located intrahepatic stones is still a problem to be solved. This study was undertaken to investigate the feasibility and effectiveness of chemical bile duct embolization for chemical hepatectomy. METHODS: Oxybenzene or absolute ethanol plus N-butyl-cyanoacrylate was employed for embolization. The feasibility, effectiveness and mechanism of chemical hepatectomy were preliminarily analyzed histologically or by Fas, TIMP-1, TGF-beta(1), and collagen I. RESULTS: Oxybenzene plus cyanonacrylate can preferably destroy and embolize the intrahepatic biliary duct, leading to the disappearance of hepatocytes in the periphery of embolized lobe and the achievement of effective chemical hepatectomy. The expressions of Fas, TIMP-1 and TGF-beta(1) in oxybenzene embolism group (88.90 +/- 38.10, 619.43 +/- 183.42, 185.22 +/- 70.39) and ethanol embolism group (72.39 +/- 29.51, 407.55 +/- 134.74, 163.56 +/- 51.75) were higher than those of biliary duct-ligated group (26.31 +/- 12.07, 195.31 +/- 107.67, 74.84 +/- 40.73) (P<0.05). The collagen I-positive percentage in the oxybenzene embolism group was also greater than that of the ethanol embolism group (33.97 +/- 12.51% vs. 20.67 +/- 8.09%, P<0.05). CONCLUSION: The effect of chemical hepatectomy may be achieved by chemical bile duct embolization.

Animals↗

[Preoperative portal embolization increases safety of hepatectomy].

Postoperative liver failure following major hepatectomy is a frightened complication. In order to increase safety of major hepatectomy, a study evaluating preoperative portal embolization (PE) was performed. Between 1983 and 1990, PE was performed in 71 patients (41 with hepatocellular carcinoma (HCC), 8 with other liver tumors, and 22 with biliary carcinoma), in 63 cases to the main branch, prior to hepatectomy. Out of these 63 patients 42 (extended) hemihepatectomies were performed. For comparison 77 patients with the same extent of hepatectomy, but without PE, were studied. Liver volume was evaluated by CT examination. Portal venous pressure was elevated by 73 mmH2O just after embolization of the main portal branch. However, no complications were associated to the PE procedure except for temporary elevation of transaminases. Volume of the unembolized lobe increased by 8.8% in average following PE. Prominent volume gain was observed in the patients with prior arterial embolization and long observation period. In patients with PE prior to major hepatectomy, postoperative bilirubin values were significantly lower (p less than 0.01). In the group with PE, no fulminant liver failure was seen and no operative mortality was encountered, as compared to 11.7% (9/77) in the control group. Preoperatively performed PE was a safe procedure decreasing postoperative liver failure and mortality.

Adult↗

Preoperative estimation of surgical risk of hepatectomy in cirrhotic patients.

In order to improve the results of hepatectomy in cirrhotic patients, functional resectability of the liver was evaluated before surgery, in 119 cases of hepatectomy, including 85 cases with cirrhosis, over the last 10 years. Our total risk, measured by multivariate analysis of hepatic function tests, was very useful in selecting the suitable operative method. Functional reserve of the remnant liver and that of per unit volume of the liver evaluated by ICGRmax, were also good indicators for estimating long-term prognosis and liver regeneration following hepatectomy. Furthermore, from our experience with 4 cirrhotic patients who developed disseminated intravascular coagulopathy after hepatectomy, the preoperative evaluation of function in the coagulation-fibrinolysis system was also important for estimating the operative risk of hepatectomy in cirrhotic patients.

Adult↗

[The effect of partial hepatectomy on glucose-stimulated insulin release from the isolated perfused pancreas in rats].

To investigate the functional changes of endocrine pancreas in the early stage after partial hepatectomy, we evaluated the changes in the secretion of insulin to glucose load in perfused rat pancreas at 4 and 7 days after about 70% hepatectomy. Insulin responses to glucose load were significantly augmented at 4 days compared with both the normal and sham-operation rats and at 7 days also significantly augmented compared with the normal rats. These results are in accordance with the morphological changes of islet and indicate that in the early stage after hepatectomy, the response of islet B-cells to glucose load are increased in order to support the glucose metabolism in this stage. Thus, insulin seems to play an important role in the regenerating liver after hepatectomy and these changes seem to be one of the adaptation of endocrine pancreas after hepatectomy to support the regenerating liver.

Animals↗

[Changes in arterial thromboxane B2 and 6-keto-prostaglandin-F1 alpha levels in cirrhotic and non-cirrhotic patients after hepatectomy].

Following hepatectomy, arterial concentrations of thromboxane B2(TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), which are stable metabolites of thromboxane A2(TXA2) and prostaglandin I2(PGI2), were measured by radioimmunoassay in 17 cirrhotic and 9 non-cirrhotic patients to assess the role of TXB2 and PGI2 in patients with liver dysfunction during hepatectomy. In both cirrhotic and non-cirrhotic patients, arterial TXB2 and 6-keto-PGF1 alpha levels significantly increased during hepatectomy and decreased to preoperative levels at the 1st postoperative day (1-POD). The TXB2/6-keto-PGF1 alpha ratio significantly decreased during hepatectomy and at 1-POD. There were no significant differences in changes of TXB2 and PGI2 levels between cirrhotic and non-cirrhotic patients. In cirrhotic patients with poor hepatic reserve, whose ICG K values were less than 0.08, arterial 6-keto-PGF1 alpha levels were significantly higher and the ratio were significantly lower than in cirrhotic patients with good hepatic reserve and non-cirrhotic patients before and after operation. Based on these results, it is concluded that the TXA2/PGI2 ratio becomes low after hepatectomy and the ratio is lower in cirrhotic patients with poor hepatic reserve.

6-Ketoprostaglandin F1 alpha↗

Endocrine and exocrine pancreatic functions following partial pancreatectomy + partial hepatectomy.

Comparative studies were performed on changes in endocrine and exocrine responses of the pancreas after partial hepatectomy, partial pancreatectomy or combination of these procedures in rats, in order to clarify the effect of the combined operation on the remnant pancreatic parenchyma. Three days after partial (60%) pancreatectomy with partial (70%) hepatectomy, endocrine function was better preserved than after partial pancreatectomy alone, suggesting that hypersecretion of insulin initiated by partial hepatectomy may ameliorate the defective glucose-induced insulin secretion following partial pancreatectomy. Further, exocrine function in terms of amylase output was relatively well maintained 3 days after partial pancreatectomy + partial hepatectomy as compared with partial pan after partial pancreatectomy + partial hepatectomy as compared with partial pancreatectomy alone.

Amylases↗

[Influence of hepatic ischemia on liver regeneration following hepatectomy, with special reference to the therapeutic choice for ruptured hepatoma].

The influence of partial hepatic ischemia (32%) prior to partial hepatectomy (68%) has been studied in the rat. 3H-thymidine incorporation into the hepatic DNA was significantly suppressed in both 20 min and 30 min ischemia depressed the survival following partial hepatectomy (p less than 0.001). Three cases of ruptured hepatocellular carcinomas were treated: one case by emergency hepatectomy, and two cases by hepatectomy following TAE. Hepatic insufficiency and post-operative death occurred to only the case given an emergency hepatectomy. Thus, it is felt that a ruptured hepatoma should first be treated by TAE and then surgically resected.

Adult↗

[Experimental studies on bile acid metabolism after extended hepatectomy, with special reference to mechanism of an early increase of bile acids in the serum].

The purpose of this study was to evaluate an early increase of bile acids in the serum after the extended hepatectomy, namely 84% hepatectomy in normal dogs and 70% hepatectomy in dimethylnitrosamine-induced cirrhotic dogs. Many dogs died due to hepatic insufficiency caused by severe intrahepatic cholestasis and functional disturbance of the remnant liver within 7 days after extended hepatectomy. Serum total bile acids increased with the peak at 12 hours after surgery, accompanied by an increase of taurine-conjugated bile acids, and each concentration of them was higher in the hepatic vein than in the portal vein. These results suggested that an early increase of bile acids in the serum after the extended hepatectomy resulted from the reflux to systemic circulation from the remnant liver due to disturbance of bile excretion into biliary tract and the decrease of hepatic functional mass with decrease of blood perfusion.

Animals↗

[Reappraisal of hepatectomy in traumatic rupture of the liver].

From our experiences, the causes of high mortality rate in hepatectomy for hepatic rupture may be attributed to improper application of this procedure to trauma victims under suboptimal conditions, as most of the deaths were related to coagulopathy and uncontrollable bleeding. Accordingly, a protocol of indication for emergent hepatectomy was established in March, 1985, which included the following criteria: PH greater than 7.2, body temperature greater than 32.0 degrees C, systolic blood pressure greater than 60mmHg and no presence of coagulopathy. Of 14 cases which underwent hepatectomy before March, 1985, 9 cases died of exsanguination, coagulopathy and multiple organ failure with the mortality rate of 63.7% whereas only two of 10 cases which underwent hepatectomy after March, 1985, died, the mortality rate being markedly decreased to 20%. Considering the fact that there were no differences between these two groups of the patients regarding severity of liver trauma and clinical back ground, it indicates that the appropriate selection of the patients for hepatectomy based on the criteria has definitely decreased the mortality rate of hepatic rupture victims.

Adult↗

Ability of partial hepatectomy to induce gamma-glutamyltranspeptidase in regenerated and transplanted hepatocytes of Fischer 344 and Wistar-Furth rats.

The purpose of this study was to investigate the effect of a two-thirds partial hepatectomy on the expression of gamma-glutamyltranspeptidase (GGT) in parenchymal hepatocytes. Two to 3-month-old Fischer 344 (F344), Wistar-Furth (WF), and WF X F344 F1 rats of both sexes were used in this investigation. Partial hepatectomy in the F344 female rat significantly increased the percent of liver area positive for GGT from 1.3 to 20.4%, a 15-fold increase. In contrast, GGT was not induced by partial hepatectomy in either the female WF or WF X F344 F1 hybrid rat or in the male animals of these three strains of rats. This phenomenon, which was only observed in the F344 female rat, was blocked by oophorectomy 2 weeks prior to partial hepatectomy, indicating that the induction of GGT is in part dependent upon female sex hormones. By transplanting both F344 and WF hepatocytes into the axillary fat pads of isogeneic and WF X F344 F1 rats, we showed that the observed strain difference did not result from a variation in the animal hormonal environment but rather was due to the hepatocyte from the F344 rat being intrinsically more susceptible to GGT induction than that from the WF rat. Further, the extent of the enzyme induction was significantly greater when the F344 liver cells were transplanted into female recipient animals. Since hepatectomy is often used in hepatocarcinogenesis studies, it is important to note that in the F344 female animal, the surgical procedure itself increases hepatic GGT levels in both transplanted hepatocytes and the liver in situ. Thus, the F344 female rat should be used with caution in investigations where the carcinogenic potential of chemicals is based upon the formation of GGT-positive hyperplastic nodules in the liver.

Animals↗

Accumulation and release of triglycerides by rat liver following partial hepatectomy.

Regenerating liver accumulates lipid for about 20 hr following partial hepatectomy. During this time incorporation of intravenously administered palmitate-9, 10-(3)H into beta-lipoprotein increased. 13 hr after partial hepatectomy, there was no change in the level of serum beta-lipoproteins, but the specific activities of the triglycerides in the liver and beta-lipoproteins were significantly diminished. Extension of these studies to the isolated perfused liver system demonstrated that 13 hr after partial hepatectomy the regenerating liver is capable of secreting greater quantities of the lipid, but not the protein, moiety of the beta-lipoproteins in comparison with liver taken immediately from a partially hepatectomized animal, although there was no difference between the weights of the livers. However following addition of palmitate-(3)H and (14)C-labeled amino acids to the perfusate, the specific activity of the hepatic and beta-lipoprotein triglycerides of the liver excised 13 hr after partial hepatectomy was diminished, but that of the protein was not affected. Prelabeling of the accumulated triglyceride with palmitate-1-(14)C in vivo revealed that the proportions of the accumulated triglyceride secreted as beta-lipoproteins by perfused livers excised immediately and 13 hr after partial hepatectomy were identical. It is concluded that regenerating liver rapidly acquires the ability to mobilize triglycerides at a rate equal to that of the much larger normal liver, so that it can handle all free fatty acids presented to it.

Amino Acids↗

[Treatment of post-hepatectomy hepatic cellular energy crisis in cirrhosis with ATP-MgCl2 administration].

The present study was undertaken to investigate the effect of ATP-MgCl2 for hepatic cellular energy crisis following hepatectomy in cirrhosis. In experimental study, cirrhotic rats, induced by subcutaneous injection of CCl4 twice a week for 10 weeks, received ATP-MgCl2 (12.4 mumoles) (ATP group) or saline (control group) at 2 hours after 68% hepatectomy. The hepatic cellular energy charge (EC) and arterial ketone body ratio (AKBR), which were good indicators to evaluate the hepatic cellular metabolism, and reticuloendothelial system (RES) function were significantly improved among ATP group at 24 hours after hepatectomy compared to the control group. Survival at one week was also significantly improved with ATP-MgCl2 treatment. In clinical study, ATP-MgCl2 (30-50 mumoles/kg) was infused intravenously to twenty hepatectomized cirrhotic patients. The hepatic cellular energy metabolism, studied using AKBR, and RES function as well as the clinical course were improved with ATP-MgCl2) treatment compared to those of the conventionally treated controls. These data indicate that ATP-MgCl2 is beneficial as one of the therapeutic approaches to improve the hepatic cellular energy crisis after hepatectomy which is the major cause of death following hepatectomy among cirrhotic patients.

Adenosine Triphosphate↗

Effect of 3,5,3'-L-triiodothyronine on hepatic ornithine decarboxylase and thymidine kinase activity in rat after partial hepatectomy.

Partial hepatectomy (60%) led to the biphasic increase (first one at 4 h and second one at 48 h) of ornithine decarboxylase activity in the remnant rat liver. Daily administration of 3,5,3'-L-triiodothyronine (T3) (10 micrograms/100 g) to rats for 7 days before partial hepatectomy had little effect on the enzyme activity. At five days, ornithine decarboxylase activity declined to control level (sham operated controls) and its activity was significantly enhanced by T3. Ornithine decarboxylase gene expression in the rat liver (examined by Northern blot analysis using poly A+ mRNA) started to increase 4 h after partial hepatectomy, remained elevated for 48 h and decreased after 5 days. Its activity was not altered by T3 treatment. The activity of thymidine kinase increased progressively after partial hepatectomy, but its peak value was delayed by T3 administration. Plasma prolactin levels increased within 5-15 min after liver resection, then declined to control values and increased 24 h after the surgery. The data demonstrate that the changes in ornithine decarboxylase activity in the rat liver after partial hepatectomy might result from the direct effect of prolactin on the activity of enzyme rather than from its induction by hormone. Triiodothyronine administration altered both ornithine decarboxylase and thymidine kinase activities suggesting that T3 appears to regulate ornithine decarboxylase activity at post-translational level.

Animals↗

Hepatic collagen synthesis and degradation during liver regeneration after partial hepatectomy.

To elucidate hepatic collagen metabolism during liver regeneration after partial hepatectomy, we measured collagen content, collagen synthesis, and collagen-degrading enzyme activity in the remnant livers of rats 3, 5, 7, and 14 days after a partial hepatectomy of 68%. Hepatic collagen synthesis was significantly higher 3, 5, and 7 days after partial hepatectomy than it was in sham-operated control rats, but there was no such difference 14 days after surgery, the maximal hepatic collagen synthesis being observed 5 days after surgery. Although the collagen concentration in the remnant liver was similar to that in the control liver, the total collagen content of the remnant liver increased rapidly with liver regeneration until 7 days after partial hepatectomy. Hepatic collagenase activity was similar to the control; however, hepatic cathepsin B and cathepsin L activity and the intracellular degradation of newly synthesized collagen were markedly decreased 3, 5, and 7 days after partial hepatectomy compared with the controls. Hepatic collagen synthesis was significantly and inversely correlated with cathepsin L activity and with the intracellular degradation of newly synthesized collagen. These findings suggest that a combination of increased collagen synthesis and decreased intracellular collagen degradation contributes to the rapid supply of collagen that is observed during the early phase of liver regeneration.

Animals↗

[Effect of RES on liver regeneration and survival after 90% partial hepatectomy].

In previous studies, 90% partial hepatectomy in the rat was invariably accompanied by 100% mortality within 40 hr. This paper describes the effect of enhanced reticuloendothelial system (RES) on liver regeneration after 90% partial hepatectomy. RES was activated using 5 K.E. of OK-432 injected intraperitoneally 24 hr before 90% partial hepatectomy. Ninety per cent of the liver mass was resected and rats were provided with tap water or 20% glucose orally and subcutaneously. Survival time was strikingly different. In rats provided with tap water only; 100% of rats died before 42 hr. In rats provided with 20% glucose; 44.2% of rats survived beyond 42 hr. In rats pretreated with OK-432 and provided with 20% glucose; 87.0% of rats survived beyond 42 hr. This regimen results in severe hypoglycemia and dead within 42 hr. When RES was activated before 90% partial hepatectomy, significantly higher blood glucose level was observed. BrdU labeling index was significantly higher in rats pretreated with OK-432 than in control rats. The results indicate that enhancement of RES before 90% partial hepatectomy provides acute metabolic support and enhancement of liver regeneration resulting in improved survival.

Animals↗

[Two-stage hepatectomy with preoperative portal vein embolization in rats].

We studied the functional reserve and ability to regenerate of non-embolized liver made hypertrophic by portal vein embolization (PVE) to evaluate the usefulness of two-stage hepatectomy with preoperative PVE. Rats underwent one of four treatments: 1, 70% hepatectomy; 2, 70% hepatectomy 7 days after PVE; 3, 30% hepatectomy; and 4, sham operation. Liver weight, the bromodeoxyuridine labeling index (LI), and the mitotic index (MI) were calculated after surgery. The lipid peroxide level of the liver, serum hepatic enzyme activities, total bilirubin concentration, prothrombin time, and antithrombin-3 activity were also assayed after surgery in each group. Non-embolized lobes made hypertrophic by PVE regenerated further after resection of the embolized portion of the liver. The increases in liver weight, LI, and MI in group 2 were significantly lower than in group 1, but tended to be higher than in group 3. In group 2, lipid peroxidation in the liver and postoperative disorders of liver function and the coagulation system were significantly less than in group 1, and were similar to those in group 3. Preoperative PVE increases not only the weight but also the function of the residual liver, which makes extended hepatectomy safer.

Animals↗