Research review: DNA polymerases as molecular markers of the regenerating capacity of hepatocytes

Hepatocyte regeneration has been widely investigated, with the mitotic index and the incorporation of [³H]thymidine being used as regeneration markers. We focused on the induction of DNA replication enzymes, particularly DNA polymerases (pol) α, δ, and ε. Using rat models, we have shown that the activity of pol α in crude liver extract well represents the regenerating capacity of hepatocytes. Using pol α as an indicator, we analyzed liver regeneration in rat models under various conditions: obstructive jaundice, external or internal biliary drainage, and the obstruction of portal vein branches. It has been revealed that the ligation of the common bile duct alone induces a certain amount of hepatocyte proliferation. It was striking that external biliary drainage suppressed regeneration capacity in cholestatic rat liver after partial hepatectomy. The strong regeneration in nonligated lobes induced by portal branch ligation was similar to the liver regeneration seen after partial hepatectomy with respect to the induction of DNA polymerases. Taken together, the aspects of DNA replication, particularly the induction of DNA polymerases, may contribute to shedding new light on the regeneration of human liver. This work was supported in part by a Grant-in-Aid for General Scientific Research and for Cancer Research from the Ministry of Education, Science and Culture, Japan, and by grants from the Uehara Memorial Foundation     

Mechanism of postoperative liver failure after excessive hepatectomy investigated using a cDNA microarray

Background/Purpose: Excessive hepatectomy often causes fatal liver failure. We have reported that this is mainly mediated by apoptosis, characterized pathologically by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL) assay-positive hepatocytes and a ladder pattern in DNA fragmentation assays. Methods: To investigate the mechanism, we used cDNA microarray analysis to compare clearly differentiated rat partial hepatectomy (PHx) models (90%PHx, and 95%PHx). All 90%PHx rats survived, but the 95%PHx animals died of hepatic failure within 96 h. Remnant liver was obtained at four time points (1, 3, 12, and 24 h after PHx). After RNA extraction, two samples were labeled with different fluorescent dyes and hybridized to the Institute of Physical and Chemical Research (RIKEN) set of 18 816 full-length enriched mouse cDNA arrays. Scanning for fluorescent dye signals was performed, and the mRNA expression ratio of the two models was examined. Results: Genes of the p21 cyclin-dependent kinase (CDK) inhibitor, Fas, interleukin (IL)-18, and many caspases were upregulated at 1 h after PHx in the 95%PHx group. On the other hand, genes of Bcl-2, heat shock proteins, and glutathione-S-transferase were downregulated. Conclusions: We concluded that fatal hepatic failure after excessive hepatectomy was characterized by increased apoptosis and diminished liver regeneration. Received: July 25, 2001 / Accepted: November 16, 2001     

Immediate increase of portal pressure, reflecting sinusoidal shear stress, induced liver regeneration after partial hepatectomy

The mechanisms whereby hepatocytes in the normal liver can be primed for replication following partial hepatectomy (PHx) are poorly understood. To determine whether "shear stress," which is induced by acute portal hypertension after PHx, is involved in liver regeneration, we studied liver regeneration in rats with splenic transposition (SPT) in which we can minimize the postoperative elevation of portal pressure. Rats underwent 70% PHx following splenic transposition or sham surgery and were killed at various time points to measure portal pressure and other factors. In the control groups, the portal pressure was significantly increased immediately after surgery, peaking at 48 h, and returning to near the preoperative levels by 168 h after PHx. In the SPT group, although portal pressure increased immediately, it decreased to the control levels 6 h after PHx and thereafter repeatedly increased. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels peaked at 24 and 6 h after PHx, respectively. Proliferative cell analysis was done using MIB-5 antibody, and there were no significant differences between the two groups. Furthermore, liver weight was restored in the same way in both groups. Taken together, the results suggest that an immediate increase in portal pressure is necessary for the initiation of liver regeneration. Received for publication on Jan. 20, 1999; accepted on Feb. 25, 1999     

Role of shear stress and immune responses in liver regeneration after a partial hepatectomy

This report reviews studies addressing the new concepts in liver regeneration after a partial hepatectomy (PHx). The review begins with an overview of the immunologic mechanisms of liver regeneration after PHx, especially regarding Kupffer cells and extrathymic T cells of the regenerative liver in the cell-mediated immunity, based on major histocompatibility complex I and II antigens. Attention is then devoted to “on and off” studies in liver regeneration after PHx, by hypothesizing the shear stress based on the fact that the portal flow against hepatocytes or sinusoidal endothelial cells triggers their regeneration after a partial hepatectomy and controls the volume of the regenerating liver by the stimulating the cell surface modulator (CSM) of hepatocytes and sinusoidal endothelial cells (SEC). We propose that the acute elevation of shear stress after PHx influences the adhesion between SEC and intrahepatic leukocytes. These concepts are expected to positively contribute to the future research on liver regeneration after PHx.     

Acute portal hypertension reflecting shear stress as a trigger of liver regeneration following partial hepatectomy

The concept of injury in liver regeneration after partial hepatectomy (PHx), and the reason hepatocytes that have not been directly injured regenerate, remain unclear. It is known that shear stress resulting from blood flow plays an important role in the mechanism of remodeling blood vessels, and portal pressure reflects shear stress. This study was conducted to determine whether acute portal hypertension (APH) can become a trigger of liver regeneration as shear stress following PHx in a rat model. Portal pressures became elevated immediately after 70% and 90% PHx, peaking on postoperative day (POD) 3, and thereafter decreasing in proportion to the diminution of liver regeneration. The portal pressures after 90% PHx were significantly higher than those after 70% PHx even on POD 7, while those of the portocaval (PC) shunt groups decreased following PC shunting both with and without 70% PHx. The liver/body weight (LW/BW) ratio also decreased in the PC shunt both with and even without 70% PHx. The gradient expressions of class I antigen on sinusoidal endothelial cells (SEC) were found only in the periportal area, which has the highest portal pressure in the healthy rat liver. However, after hepatectomy these expressions were detected from the periportal area to the central venous area. These results suggest that APH as shear stress following PHx may not only become a trigger of hepatocyte regeneration, but also of SEC regeneration, and that surplus APH induces liver dysfunction.     

Anti-transforming growth factor-β1 antibody transiently enhances DNA synthesis during liver regeneration after partial hepatectomy in rats

The regulation of liver regeneration after partial hepatectomy (PHx) is complex and involves many different cytokines. We investigated the role of one of these, transforming growth factor-β1 (TGF-β1), an inhibitor of liver regeneration, in a Wistar male rat model, in which anti-TGF-β1 antibody was injected immediately or 24 h after 70% PHx. Livers from treated animals contained an increased number of cells in S phase, according to 5-bromo-2′-deoxyuridine (BrdU) labeling 36 h after PHx. Antibody administration 24 h after PHx resulted in the highest peak of proliferation; moreover, peak MIB-5 labeling was also observed at that time. However, neither residual liver-weight-to-body-weight ratios nor regeneration rates differed significantly between any of the animals. Therefore, we also measured levels of serum TGF-β1 and hepatocyte growth factor (HGF; an activator). With antibody administration at 0 or 24 h, TGF-β1 levels were diminished at 24 or 36 h as compared with levels in control rats, but then rebounded, reaching a delayed peak at 48 or 72 h after PHx, respectively. Interestingly, there were also similar trends in HGF levels. These results indicate that TGF-β1 may inhibit the G1 checkpoint, and serum TGF-β1 concentration may influence HGF to regulate liver regeneration and to maintain homeostasis of proliferation after PHx. Received: November 15, 2000 / Accepted: February 15, 2001     

Comparison of the stress response after laparoscopic and open cholecystectomy

Background: We designed a prospective controlled animal study to compare the stress response induced after laparoscopic and open cholecystectomy. Methods: Twelve female pigs (20–25 kg body weight) were anesthetized with ketamine, pentobarbital, and fentanyl. The animals were randomized into the following four groups: control (C), pneumoperitoneum with CO₂ at 14–15 mmHg (P), laparoscopic cholecystectomy (LC), and open cholecystectomy (OC). The average duration of the procedure in each group was 35 min. Results: Central venous pressure, mean arterial pressure, pulmonary capillary wedge pressure, and cardiac output were monitored. Measurements were recorded when animals were anesthetized (baseline), immediately before and after surgery, and thereafter every 30 min for a maximum of 3 h. White blood cell count (WBC) was determined from blood samples taken before and after 3 h of surgery. Ultrasound-guided liver biopsies were done preoperatively and after 3 h of surgery. Total RNA was isolated from the liver biopsy specimens. Steady-state mRNA levels of β-fibrinogen (β-fib), α 1-chymotrypsin inhibitor (α1-CTI), metallothionein (MT), heat shock protein 70 (Hsp70), and polyubiquitin (Ub) were detected by Northern blot/hybridization. There were no statistical differences in the hemodynamic parameters among the groups. The number of circulating neutrophils and monocytes decreased only after LC. Expression of Hsp70 was not induced after any surgical procedure, and the mRNA levels of Ub did not change after surgery. The expression of α1-CTI and β-fib (acute phase genes) were similarly increased after LC and OC. Steady-state mRNA levels of MT were slightly increased after P and LC but not after OC. Conclusion: These data indicate that there are no significant differences between LC and OC in terms of induction of the stress response. Received: 19 March 1999/Accepted: 2 July 1999/Online publication: 20 September 2000     

Changes in T-cell receptor subsets after cardiac surgery in children

T cells are divided into two subsets, αβ and γδ, according to the T-cell receptor (TCR) expressed. Recent findings indicate that γδ T cells serve as the first defense against microbial pathogens, and represent a link between innate and acquired immunity. We conducted a study to investigate the changes in circulating TCR subsets after cardiac surgery in children. Blood samples from 24 children who underwent cardiac surgery with cardiopulmonary bypass (CPB) were collected serially to analyze TCR subsets by flow cytometry. The αβ T cells reached a nadir on postoperative day (POD) 1, but recovered to pre-CPB levels on POD 3. On the other hand, the γδ T cells decreased after CPB and did not recover to pre-CPB levels even after POD 7. The αβ/γδ T-cell ratio was increased after POD 3. In children, γδ T cells recover more slowly than αβ T cells after cardiac surgery. These changes in TCR subsets may contribute to postoperative immunosuppression. Received: August 23, 1999 / Accepted: May 30, 2000     

A new surgical strategy for cirrhotic patients with hepatocellular carcinoma and hypersplenism

Background: Hepatectomy for cirrhotic patients with hypersplenism is a high-risk operative procedure. We report herein a new strategy for high-risk patients with hepatocellular carcinoma (HCC). Methods: Six cirrhotic patients with HCC and hypersplenism received a partial hepatectomy after first undergoing a laparoscopic splenectomy. We then compared the variables for these patients before splenectomy and before hepatectomy. Results: The platelet count and the white blood cell count were found to be significantly elevated before hepatectomy. The ammonia value decreased significantly before hepatectomy. The albumin value tended to be elevated before hepatectomy. Furthermore, the Child's classification of all patients improved significantly before hepatectomy. However, other variables—such as the indocyanine green dye excretion test at 15 min and the bilirubin value—did not change after splenectomy. For hepatectomy patients who first underwent a laparoscopic splenectomy, operation time ranged from 265 to 440 min (average time, 361 min), and blood loss ranged from 500 to 2,200 ml (median volume, 1,300 ml). Four of six patients did not require any blood transfusion; furthermore, no patient needed a platelet-rich plasma transfusion. All but one patient, who suffered postoperatively from an intractable duodenal ulcer, had an uneventful postoperative course. Conclusion: Partial hepatectomy after an initial laparoscopic splenectomy is a new and effective choice of treatment for cirrhotic patients with HCC and hypersplenism. Received: 1 May 1998/Accepted: 30 June 1999     

Impact of hepatic vein deprivation on liver regeneration and function after major hepatectomy

Background and aims In extended liver resections, the preservation of vascular and biliary structures of the entire remnant liver is of paramount importance. The impact of venous outflow impairment and its consequences for liver regeneration and function are still a matter of debate. Materials and methods Rats (n = 75) were subjected to a 90% partial hepatectomy (PH), to a 70% liver resection with narrowing of the hepatic outflow of an additional 20% parenchyma (70%+ PH) or to an anatomic 70% PH. Postoperatively hepatocyte proliferation (Ki-67), liver function and survival were assessed. Gene expression analysis for markers of regeneration was determined by in-house complementary (DNA) arrays and quantitative real-time polymerase chain reaction (RT-PCR). Results Ninety percent PH led to a greater regenerative response as shown Ki-67 compared to animals with a 70%+PH (p < 0.05). However, liver function was equally impaired in both groups. Rats with 70% PH showed a greater proliferation index with less hepatic injury and better liver function. While mortality was 0% in the group of 70% PH, rats with 90% PH and 70+PH had a reduced survival of 75% (p < 0.05) Conclusion Venous outflow obstruction leads to an impairment of liver regeneration and liver function. In cases with critically small liver remnants, restoration of an adequate venous outflow may be mandatory.     

Effects of ischemic preconditioning on regenerative capacity of hepatocyte in the ischemically damaged rat livers

BACKGROUND: Liver regeneration after partial hepatectomy is regulated by several factors that activate or inhibit hepatocyte proliferation. A short period of ischemia-reperfusion (IR), called ischemic preconditioning (IPC), protects the liver against subsequent sustained ischemic insults. The present study investigated the effects of IPC on liver regeneration after partial hepatectomy under IR in rats. MATERIALS AND METHODS: Male Wistar rats were subjected to 45 min of total hepatic ischemia, and 70% hepatectomy was performed just before reperfusion. Animals were pre-treated with either IPC (10/15 min) (IPC + PHx group) or not (ischemia + PHx). The survival rate, serum transaminases, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6 levels, hepatocyte proliferation and histological change of the remnant liver were measured in both groups and compared with non-ischemic controls subjected to 70% hepatectomy alone (PHx group). RESULTS: The survival rate was significantly better in the IPC + PHx group than in the ischemia + PHx group. Furthermore, IPC reduced liver injury determined by liver histology and serum transaminases. There was an early rise in serum TNF-alpha and IL-6 levels in the ischemia + PHx group. Compared with non-ischemic controls, IPC significantly decreased TNF-alpha, but not IL-6 during the late (24 and 48 h) phases of reperfusion. Rats subjected to 70% hepatectomy and 45 min of hepatic ischemia showed significantly reduced hepatocyte proliferation (mitotic index, proliferating cell nuclear antigen, and relative liver weight) when compared with animals subjected to hepatectomy alone. However, hepatocyte proliferation was markedly increased in rats pretreatment with IPC when compared with ischemic controls. CONCLUSION: These results suggest that ischemic pre-conditioning ameliorates the hepatic injury associated with ischemia-reperfusion and has a stimulatory effect on liver cell regeneration that may make it valuable as a hepatoprotective modality. Il-6 appears to be key mediator in promoting regeneration after combined ischemia and hepatic resection.     

Effects of Ozone Oxidative Preconditioning on Liver Regeneration after Partial Hepatectomy in Rats

ABSTRACT

Aim: Similar protective effect of ischemic and ozone oxidative preconditioning (OzoneOP) in hepatic ischemia–reperfusion (I/R) injury was demonstrated, providing evidences that both preconditioning settings shared similar biochemical mechanisms of protection. We investigated the effects of OzoneOP on liver regeneration after 70% partial hepatectomy (PHx) in rats. Methods: Rats were divided into three groups: PHx, I/R + PHx, and OzoneOP + I/R + PHx groups. Ozone (intraperitoneal, 1.2 mg/kg) was given to rats subjected to I/R and 70% hepatectomy daily five times before operation. At 24 hr and 48 hr after resection, samples were collected for the measurement of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6). Moreover, liver regeneration rate, proliferating cell nuclear antigen (PCNA) labeling index, mitotic index, and histopathological examination were evaluated. Results: OzoneOP reduced liver injury determined by liver histology and serum transaminases. There was a rise in serum TNF-α and IL-6 levels in the I/R + PHx group whereas OzoneOP significantly decreased the rise in the level of TNF-α but not IL-6 on the 24 hr and 48 hr of reperfusion. Moreover, liver regeneration in OzoneOP + PHx group, as assessed by the regenerated liver weight, mitotic, and PCNA-labeling index, was significantly improved when compared to I/R + PHx group. Conclusion: These results suggest that OzoneOP ameliorates the hepatic injury associated with I/R and has a stimulatory effect on liver cell regeneration that may make it valuable as a hepatoprotective modality.     

The promotion of liver regeneration in mice after a partial hepatectomy as a result of the modulation of macrophage activation by dexmedetomidine

BackgroundThis study investigates the effect of dexmedetomidine (DEX), a highly selective agonist of alpha 2-adrenergic receptors (α2-ARs), on the regulation of hepatic macrophage activation in liver regeneration.MethodsA two-thirds partial hepatectomy (PHx) mouse model was performed. DEX (25 μg/kg) or a vehicle control (saline) was injected i.p. at 30 min before and every 12 h after PHx. The expression of α2B-ARs in the liver was detected using immunofluorescence staining. The effects of DEX on liver regeneration were assessed by Ki67 staining. The gene expression of inflammatory cytokines in isolated hepatic macrophages was quantified 36 h after the PHx.Resultsα2B-ARs colocalized with hepatic macrophages after the PHx. The number of Ki67-positive hepatocytes in the mice treated with DEX was markedly increased (p < 0.05). The increases in Ki67-positive hepatocytes after treatment with DEX were inhibited in the macrophage-depleted mice. DEX treatment inhibited the expression of major pro-inflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor and elevated the expression of anti-inflammatory cytokines IL-4, IL-10, and transforming growth factor-β1 in hepatic macrophages 36 h after the PHx (p < 0.05).ConclusionsThe α2B-AR subtype is expressed in hepatic macrophages after a PHx. DEX modulates hepatic macrophage activation toward an anti-inflammatory phenotype via α2B-AR, which promotes the process of liver regeneration.     

Incidence of microalbuminuria in children with pyelonephritic scarring

There is experimental evidence that loss of renal parenchyma results in hyperfiltration in the remnant glomeruli followed by development of glomerulosclerosis. Microalbuminuria, i.e., a urinary albumin excretion rate of 20 – 200 μg/min, is considered to be an early predictor of diabetic glomerulosclerosis. Hypothetically, increased urinary albumin excretion in patients with pyelonephritic scarring may also indicate glomerulosclerosis, with risk for future deterioration of renal function. This study was performed to determine the incidence of increased albumin excretion in children with mild to moderate pyelonephritic scarring, and to relate the information to glomerular filtration rate (GFR; clearance of inulin) and effective renal plasma flow (clearance of para-aminohippuric acid), as well as to the degree of scarring. The functional investigations were performed under water diuresis. Fifty-seven children, aged 1.7 – 17.9 years, with pyelonephritic renal scarring were included in the study. Nine young healthy adults were used as controls. The GFR was significantly lower in the children with pyelonephritic scarring than in the controls (median 93 ml/min per 1.73 m², range 48 – 133 vs. 111 ml/min per 1.73 m², range 89 – 121, P<0.05), and the urine albumin excretion was significantly higher (median 20 μg/min per 100 ml GFR, range 0.8 – 170 vs. 9.2 μg/min per 100 ml GFR, range 3.3 – 21, P<0.05). An inverse correlation was found between urine albumin excretion and GFR. Increased urine albumin excretion was found in 70% of the children with a GFR below 90 ml/min per 1.73 m² compared with 41% of the children with a GFR above this level. Increased urine albumin excretion (>20 μg/min per 100 ml GFR) was found in 51% of the children with pyelonephritic scarring, while only 14% had increased age-adjusted serum creatinine concentrations. The high incidence of microalbuminuria in children with pyelonephritic scarring indicates long-term follow-up until the ultimate outcome has been better defined. Received January 17, 1995; received in revised form and accepted April 2, 1996     

Geranylgeranylacetone suppresses inflammatory responses and improves survival after massive hepatectomy in rats

Overproduction of heat shock protein 70 (HSP70) in the liver protects hepatocytes under various pathologic conditions. In this study we examined the effects of a nontoxic HSP70 inducer, geranylgeranylacetone (GGA), on acute hepatic failure after 95% hepatectomy in rats. When GGA (100 mg/kg) or vehicle was intragastrically administered to rats 4 hours before 95% hepatectomy, all 25 rats pretreated with vehicle died within 60 hours after the operation, whereas 10 of 25 rats pretreated with GGA survived. During the 24-hour postoperative period, GGA significantly suppressed the release of aspartate or alanine aminotransferase and elevation of the serum interleukin-6 level, and completely inhibited an increase in the serum level of tumor necrosis factor-alpha. Histologic examinations showed that GGA prevented hemorrhagic necrosis, which was observed in vehicle-treated livers more than 12 hours after the operation. During the 24-hour postoperative period, HSP70 induction was absent in remnant livers of vehicletreated rats. In contrast, GGA stimulated the HSP70 mRNA expression and HSP70 accumulation within 4 hours, and viable hepatocytes contained abundant HSP70 in their nuclei. Our results suggest that GGA may prevent acute liver failure after massive hepatectomy, at least in part, by enhancing HSP70 induction in the remnant liver. Presented at the Forty-Second Annual Meeting of The Society for Surgery of the Alimentary Tract, Atlanta, Georgia, May 20–23, 2001 (oral presentation). Supported by a Grant-in-Aid for Scientific Research (No. 12557105) from the Japanese Ministry of Education, Science and Culture (K.R.).     

Effects of pneumoperitoneum on cardiac autonomic nervous activity evaluated by heart rate variability analysis during sevoflurane, isoflurane, or propofol anesthesia

Background: The effects of pneumoperitoneum on the activity of the cardiac autonomic nervous system have not been completely understood. Methods: In this study, 45 unpremedicated adult patients who underwent laparoscopic cholecystectomy were anesthetized with either 3.5% sevoflurane, 2% isoflurane, or 8 mg/kg/h propofol (15 patients in each group). The status of cardiac autonomic nervous activity was evaluated by heart rate variability analysis three times: once when the patient was awake, once after induction of general anesthesia, and once after insufflation for pneumoperitoneum. Intra-abdominal pressure was maintained automatically at 10 mmHg by a carbon dioxide (CO₂) insufflator. For each measurement, electrocardiogram was recorded for 256 s and played back offline to detect R-R intervals. Power spectral analysis of heart rate variability was applied, and the low-frequency (LF, 0.04–0.15 Hz) and high-frequency (HF, 0.15–0.40 Hz) bands of the spectral density of the heart rate variability were obtained from a power spectra of R-R intervals using the fast-Fourier transform algorithm. The HF/LF ratio also was analyzed. Results: Measurements of heart rate variability in the three groups showed similar change. Although the power of HF, which represents parasympathetic nervous activity, did not change, the power of LF, which represents both sympathetic and parasympathetic nervous activity, decreased during the anesthetized stage and increased during the insufflated stage. The HF/LF ratio, which represents the balance of parasympathetic and sympathetic activity, increased after induction of general anesthesia, and decreased after insufflation. Conclusions: Our results suggest that pneumoperitoneum increases sympathetic cardiac activity. The choice of general anesthetic did not seem to have a major influence on the change in the cardiac autonomic nervous system after induction of pneumoperitoneum for laparoscopic cholecystectomy. Received: 22 January 1999/Accepted: 22 March 1999     

Mechanism of liver regeneration after liver resection and portal vein embolization (ligation) is different?

Whether or not liver regeneration after portal branch embolization (PE) (ligation, PVL) in the non-embolized (ligated) lobe is by the same mechanism as regeneration in the remnant lobe after liver resection has been reviewed. Portal vein branch embolization and heat shock protein are then discussed. Tumor growth accelerated in the remnant liver after hepatectomy. In contrast, PE or PVL resulted in marked contralateral hepatic hypertrophy and significant reduction of tumor growth in the non-embolized (non-ligated) lobes. Follistatin administration significantly increased liver regeneration after hepatectomy in rats. In contrast, regeneration of non-ligated lobes after PVL was not accelerated by exogenous follistatin. Tumor growth also was not accelerated. The liver regeneration rate peaked at 48–72 h in the nonligated lobe after PVL, a delay of 24 h compared with the remnant liver after hepatectomy. In the postoperative early stage, the expression of activin βA, βC, and βE mRNAs was stronger in PVL than in hepatectomy. At 72 h the expression of activin receptor type IIA mRNA reached a peak in hepatectomy, but was significantly lower in PVL. Thus, regulation of activin signaling through receptors is one of the factors determining liver regeneration after hepatectomy and PVL. These serial experimental results imply that the mechanism of liver regeneration after portal branch ligation (embolization) is different from that after hepatectomy. Heat shock protein was induced in the liver experimentally by intermittent ischemic preconditioning and could play some beneficial role in the recovery of liver function after hepatectomy, even in cirrhotic patients. When heat shock protein following right portal vein embolization in both the embolized and non-embolized hepatic lobes was investigated in clinical cases, a two to fourfold increase in HSP70 was induced in the non-embolized lobe compared with the embolized lobe. Oral administration of geranylgeranylacetone (a non-toxic HSP inducer) suppressed inflammatory responses and improved survival after 95% hepatectomy by induction of HSP70 in rats.     

Regeneration After Two-Stage Hepatectomy vs Repeat Resection for Colorectal Metastasis Recurrence

Background Two-stage hepatectomy aims to minimize liver failure risk by performing a second resection after regeneration, assuming that remnant liver hypertrophy after the second resection is similar to that seen in repeat hepatectomy, yet the impact of a two-stage strategy on liver volume and function remains to be demonstrated. Patients and Methods Twenty patients undergoing two-stage hepatectomy for multiple colorectal cancer metastases and 21 patients with more than two sections of liver parenchyma totally removed by repeat liver resections for recurrence were enrolled. Liver volumes after final hepatectomy and postoperative liver function were compared. Results Median total liver volumes before initial hepatectomy and after final hepatectomy of multiple resections were 942 and 863 ml in patients with repeat hepatectomy, whereas volumes at corresponding time points were 957 and 777 ml in patients with two-stage hepatectomy. The ratio of total liver volume after both hepatectomies to preoperative volume in the two-stage group (81.7%) was lower than that in the repeat resection group (92.0%, P = 0.027). Greater aspartate aminotransferase and prothrombin time and lower platelet count 1 month postoperatively and lower albumin at 6 months were evident after two-stage hepatectomy compared with repeat hepatectomy. Conclusions Two-stage hepatectomy is characterized by diminished hepatic regenerative capacity and postoperative liver function.     

Carnitine Contents in Remnant Liver, Kidney, and Skeletal Muscle after Partial Hepatectomy in Rats: Randomized Trial

p < 0.01). The increase of total carnitine content was more obvious than that of the free form. In contrast, the decreasing concentrations of total carnitine and free carnitine in the kidney were significant ( p < 0.01). In skeletal muscle the total carnitine content decreased to a small extent, and it was observed only at 6 hours after partial hepatectomy ( p < 0.05). It is suggested that remnant liver promoted the generation of carnitine, whereas kidney and skeletal muscle released their stored carnitine at an early stage after partial hepatectomy. As a result, the influx of the carnitine into hepatocytes increased at the regenerative stage. The carnitine content of remnant liver is sufficient during the early posthepatectomy stage.