Activin and activin receptor expression changes in liver regeneration in rat

BACKGROUND: This study aimed to investigate regulatory mechanisms of hepatocyte proliferation by comparing liver regeneration of the remnant lobe after 70% partial hepatectomy (PH) and portal vein branch ligation (PBL) in rat. METHODS: Expressions of activins betaA, betaC, and betaE and their receptors were investigated after PH and PBL. The proliferating cell nuclear antigen (PCNA) labeling index was used to monitor hepatocyte proliferation. RESULTS: The PCNA labeling index in the regenerative lobe of PBL rats reached a peak at 48 h, a delay of 24 h compared with the remnant lobe in PH rats. In the postoperative early stage, the expression of activin betaA, betaC, and betaE mRNAs was stronger in PBL than PH. At 72 h the expression of activin receptor type IIA mRNA reached a peak in PH but was significantly lower in PBL. CONCLUSIONS: Hepatocyte proliferation, and the regulated expression of activins and their receptors, differs during liver regeneration after PH and PBL in the rat. Thus, regulation of activin signaling through receptors is one of the factors determining liver regeneration after PH and PBL.     

The effect of denervation on liver regeneration in partially hepatectomized rats

BACKGROUND/AIM: In a partial liver transplantation, the dissected hepatic nerves are left unrepaired during active liver regeneration. In fact, the pathophysiological influence of such hepatic denervation on liver regeneration has not yet been fully clarified. The aim of the present study is to elucidate the effect of total hepatic denervation on liver regeneration. METHODS: Experiment 1: To confirm the effect of hepatic denervation, the hepatic contents of norepinephrine were measured in both denervated (n = 5) and sham (n = 5) rats. The changes in the hepatic microcirculation were also measured in both denervated (n = 5) and sham (n = 5) rats. Experiment 2: The rats (n = 80) were randomly assigned to two groups: DN group (n = 40); hepatic denervation followed by a partial hepatectomy (PH). Control group (n = 40); sham hepatic denervation followed by PH. In both groups, the animals were killed at 12, 24, 36, 48, 72, 120, and 168 h after PH, respectively. The liver to body weight ratio and the proliferating cell nuclear antigen (PCNA) labeling index were measured at each time point. RESULTS: Experiment 1: Nearly a total depletion of norepinephrine (<99%) was observed in the DN rats. In addition, the hepatic tissue blood flow significantly increased in the DN rats. Experiment 2: The liver to body weight ratio of the DN group was also significantly higher than that of the control group at 168 h (P < 0.05). The PCNA labeling index peaked between 24 and 36 h in the control group, while that in the DN group showed a delayed peak. At 72 and 120 h, the PCNA labeling index was significantly higher in the DN group than in the control group (P < 0.05). CONCLUSION: Total hepatic denervation was thus found to enhance liver regeneration after a partial hepatectomy. This phenomenon is partially triggered by the increased hepatic blood flow to the remnant liver.     

肝切除术后肝再生对大鼠结肠癌肝转移灶生长的影响

目的 探讨肝再牛进程触发大鼠结肠痛肝转移残肝内隐性转移灶进展的发生机制.方法 采用肝包膜下种植建立结肠癌肝转移大鼠模型,随机分为假手术组、37%肝切除组和70%肝切除组;采用腹膜后注射建市结肠癌腹膜后转移模型,随机分为假手术组和70%肝切除组.手术后3周处死动物,测定肝内转移瘤量、再生肝重及腹膜后瘤结节重.在含有肝切除后24 h和14 d的门静脉血清培养基中进行结肠癌细胞Lovo体外培养,5.溴脱氧尿核苷(5-BrdU)DNA掺入法检测细胞增殖反应.结果 手术切除明显促进70%肝切除组肝内残留癌牛长(P<0.05),对37%肝切除组肝内残留癌和结肠癌腹膜后转移瘤牛长无促进作用(P>0.05);肝切后24 h门静脉血清组5-BrdU DNA掺人率从第72小时开始增加,至第120小时呈持续增加趋势(P<0.05);肝切后14 d门静脉血清对结肠癌细胞生长无明显刺激作用(P>0.05).结论 结肠癌肝转移切除术后可诱发肝内微小残留灶的进展,并不通过血液循环全身性释放,对肝外转移瘤并不发挥作用.肝切除范围与诱发肿瘤生长有关,只有肝切除达到一定程度时,才足以刺激肿瘤生长.     

Lack of protection of ischaemic preconditioning in the rat model of major hepatectomy with ischaemia reperfusion injury

OBJECTIVE: To investigate the effects of ischaemic preconditioning (IP) on residual liver regeneration after major hepatectomy without portal blood bypass in rats, and to verify whether it can protect the residual liver from ischaemia reperfusion (IR) injury. METHODS: Ninety rats were randomized into three groups: Group PH, rats were subjected to 70% hepatectomy alone; Group IR, rats were subjected to 30 minutes of total hepatic ischaemia, and 70% hepatectomy was performed just before reperfusion; Group IP, rats were pretreated with IP (5/10 minutes). During the preoperative period and at 0.5, 6, 12, 24 and 48 hours after the operation, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were measured using an autoanalyser. Serum hyaluronic acid (HA) was measured by radioimmunoassay. Regenerated liver weight (RLW) of the rats was measured and the expressions of Ki-67 and cyclin D1 were determined by immunohistochemistry in remnant liver tissue. RESULTS: There were no significant differences in serum AST and ALT levels in all the groups before the operation. After partial hepatectomy, AST and ALT levels increased rapidly. From 0.5 to 24 hours after operation, serum AST and ALT levels were significantly higher in IP group rats than in PH and IR rats (p < 0.05). There were no significant differences in serum HA levels in all the groups before the operation. After partial hepatectomy, HA levels increased rapidly, reaching peak values at 12 hours. In the early stage (during 12 hours) after the operation, HA level was significantly higher in IP rats than in PH and IR rats (p < 0.05). The RLW of the rats rapidly increased after partial hepatectomy, and significantly decreased in IP rats compared with PH and IR rats (p < 0.05). Cyclin D1 and Ki-67 expression in all groups before the operation were low and were not significantly different. After partial hepatectomy, they rapidly increased. The expression of Ki-67 and cyclin D1 reached a peak at 24 hours after the operation in PH rats, and they were significantly higher compared with IR and IP rats (p < 0.05). In groups IR and IP, the expression of cyclin D1 and Ki-67 reached peak values at 48 hours. A significant decrease (p < 0.05) was observed after 24 and 48 hours of reperfusion in group IP compared with groups PH and IR. CONCLUSION: IP impairs residual liver regeneration after major hepatectomy without portal blood bypass in rats, and protection from IR injury disappears. IP-induced hyperperfusion may be the cause of reduced liver regeneration.     

Improvement of morphological changes after 70% hepatectomy with portocaval shunt: preclinical study in porcine model

BACKGROUND: After extensive hepatectomy, excessive portal venous flow (PVF) and elevated portal venous pressure (PVP) may lead to postoperative liver damage. We have evaluated the use of portocaval shunt (PCS) to control PVF and PVP following partial hepatectomy (PH) to reduce the postoperative liver damage. METHOD: Twenty-four pigs were divided into two Groups: Group C (n = 10) underwent 70% PH alone and Group S (n = 14) underwent 70% PH with PCS. The changes in PVF, PVP, serum liver function tests, and histology were evaluated. RESULTS: PVP and PVF per unit of remnant liver weight and serum total bilirubin levels in Group S were significantly lower than those in Group C postoperatively (P < 0.05). Histology showed that there were significant differences in hepatocyte ballooning, necrosis, and neutrophil aggregation between the two groups (P < 0.05). In particular, hepatic necrosis was observed in zone 3 of Group C as centrilobular necrosis. These results suggest that hepatic and sinusoidal damage after 70% PH were more severe in Group C than in Group S, with the latter group maintaining an almost normal ultrastructural appearance. Hepatocyte apoptotic index differed significantly between the two groups (P < 0.0001). CONCLUSION: After 70% PH, extensive centrolobular necrosis and neutrophil aggregation were present and may have caused liver damage, manifested as hyperbilirubinemia and coagulopathy. The delayed liver regeneration with PCS may reduce the postoperative liver damages rather than the rapid liver hypertrophy. The diversion of PVF with PCS to maintain adequate PVP is a very effective procedure for avoiding the postoperative liver failure after extensive hepatectomy.     

Liver blood flow after partial hepatectomy in the pig

The role of liver blood flow in liver regeneration remains controversial. This study in 17 pigs documents the total hepatic blood flow, and portal and arterial components measured with an electromagnetic flowmeter, the portal pressure, and the cardiac output for 6 days after partial hepatectomy (PH) or sham operation. There was a twofold increase in total flow immediately after PH which rose to three- to fourfold by the second postoperative day. Thereafter values decreased but remained elevated above preoperative values; no similar increase was noted in sham animals. The increase in flow was both absolute as well as relative to the proportion of liver remnant remaining. The portal component increased from 74 +/- 3% preoperatively to 84 +/- 3% (P less than 0.05) on the second postoperative day, and portal pressure was apparently increased. These changes in flow precede the previously documented maximum regeneration response between Days 3 and 4. The factors resulting in the increased flow may be responsible in part, for regeneration.     

Beneficial effects of arterialization of the portal vein on extended hepatectomy

BACKGROUND: Extended hepatectomy may result in postoperative liver failure. The aim of this study was to evaluate the effects of arterialization of the portal vein on oxygen supply, hepatic energy metabolism and liver regeneration after extended hepatectomy. METHODS: Portal haemodynamics were evaluated 0 or 10 days after arterialization of the portal vein in three experimental groups: 85 per cent partial hepatectomy, 85 per cent partial hepatectomy 10 days after arterialization of the portal vein and 85 per cent partial hepatectomy 10 days after ligation of the hepatic artery. Survival rates, weight of the regenerating liver, levels of adenine nucleotides and hepatic energy charge were assessed. RESULTS: Arterialization of the portal vein caused a significant increase in partial pressure of oxygen and oxygen saturation. Portal blood flow 10 days after arterialization was significantly increased. Survival rate and weight of the regenerating liver in the group with arterialization of the portal vein were significantly higher than those in the other two groups. The group with arterialization of the portal vein showed the highest levels of adenosine 5'-triphosphate. CONCLUSION: The increase in portal blood flow and oxygen supply produced by arterialization of the portal vein has beneficial effects on hepatic energy metabolism and liver regeneration, and leads to improved survival after experimental extended hepatectomy.     

肠道缺乏胆汁酸对大鼠肝再生的影响

目的 探索肠道缺乏胆汁酸对肝再生的影响.方法 通过喂养大鼠0.2%胆酸(胆酸负荷组)、2%考来烯胺(胆酸缺乏组)建立干扰肠道胆汁酸代谢的动物模型,以喂养标准饲料作为对照组,所有大鼠均行70%肝部分切除术(PH).比较PH后0、1、2、3、7 d三组大鼠的肝脏再生情况,并检测法尼酯衍生物X受体FXR及其靶基因胆汁酸合成限速酶CYP7a1的mRNA表达.结果 胆酸缺乏组的肝再生率在PH后3、7 d显著低于胆酸负荷组和对照组(P＜0.05),1 d时PCNA和Ki-67标记指数(22.21%±2.31%、17.25%±6.50%)显著低于胆酸负荷组(44.4%±4.92%、30.83%±3.91%)和对照组(38.74%±6.42%、27.04%±7.22%),且标记指数高峰延迟.在PH后,胆酸缺乏组FXR mRNA表达显著低于其他两组,而FXR的靶基因CYP7al的mRNA则随时间升高,明显高于其他两组.结论 肠道缺乏胆汁酸可延迟肝脏再生,并伴随FXR mRNA表达下降.     

Platelets Promote Liver Regeneration under Conditions of Kupffer Cell Depletion after Hepatectomy in Mice

BACKGROUND: Platelets have been proven to promote liver regeneration after hepatectomy. Kupffer cells produce inflammatory cytokines and also promote liver regeneration. In the present study, we examined whether platelets promote liver regeneration after hepatectomy under conditions of Kupffer cell depletion. METHODS: Seventy percent hepatectomy was carried out in mice, which were subsequently divided into four groups: (1) a normal group without any treatment, (2) a Kupffer cell depleted (KD) group, (3) a thrombocytotic group, and (4) a combined thrombocytotic and Kupffer cell depleted (TKD) group. Growth kinetics in the liver regeneration, growth factors, inflammatory cytokines, and signal transduction relating to hepatocyte proliferation were analyzed. RESULTS: In the KD group, liver regeneration was significantly delayed compared to the normal group 48 h after hepatectomy. On the other hand, liver regeneration of the TKD group increased significantly compared to KD group, to a level that was the same as that recorded in the normal group. In the thrombocytotic group, liver regeneration increased significantly compared to the normal group. Tumor necrosis factor alpha (TNF-alpha) expression was lower in the KD and TKD groups than in the normal group after hepatectomy, but, in the TKD group, hepatocyte growth factor and Akt phosphorylation were higher than in the normal and KD groups. CONCLUSIONS: After hepatectomy, liver regeneration in the Kupffer cell depleted group was delayed because of lower TNF-alpha expression. Platelets promote liver regeneration even under condition of Kupffer cell depletion by stimulating hepatocyte growth factor and insulin-like growth factor-1 expression, and they activate Akt.     

Increased intraabdominal pressure impairs liver regeneration after partial hepatectomy in rats

BACKGROUND: There are many experimental studies showing that increased intraabdominal pressure (IAP) reduces liver blood flow, leading to ischemia and portal venous congestion. But, there is no study evaluating the effect of increased IAP on liver regeneration. It is well known that acute liver ischemia and portal venous congestion impair liver regeneration. We, therefore, aimed to determine the effect of increased IAP on liver regeneration in this study. METHODS: Sprague-Dawley rats underwent partial hepatectomy with or without IAP of 12-14 mm Hg for 24 h or sham operation. Rats were randomly divided into six groups: two sham-operated groups, two hepatectomy groups, and two hepatectomy with increased IAP groups. Mitotic index, proliferating cell nuclear antigen (PCNA)-labeling index, and liver regeneration rate as liver regeneration parameters were studied on day 1 or on day 4 after operation. Additionally, serum aspartate transaminase (AST) level and histopathological changes in intestinal mucosa were studied. RESULTS: Hepatectomy with/without increased IAP groups had significantly higher serum AST levels than the sham-operated group on day 1. Serum AST level was found to be significantly higher in the hepatectomy with increased IAP group than in the other groups on day 4. Intestinal mucosal injury was found in the hepatectomy with increased IAP groups on days 1 and 4. Mitotic index and PCNA-labeling index were markedly higher in all hepatectomy with/without increased IAP groups than in the sham-operated groups. However, together with liver regeneration rate, both indices were significantly less in the hepatectomy with increased IAP groups than in the hepatectomy groups both on day 1 and on day 4. CONCLUSION: Maintenance of IAP between 12 and 14 mm Hg for 24 h impaired liver regeneration after partial hepatectomy in rats.     

VEGF is important for early liver regeneration after partial hepatectomy

BACKGROUND: The aim of the study was to determine the role of Vascular Endothelial Growth Factor (VEGF) on the microvasculature and on angiogenetic gene expression after partial hepatectomy (PH) in the rat model. METHODS: To determine the effect of exogenous and endogenous VEGF after PH, rats were subjected to 70% PH and treated either with VEGF, anti-VEGF or NaCl. Postoperatively (3-168 h), vessel density (VD), vessel diameter (VDi), and intersinusoidal space, liver body weight ratio (LBR), hepatic proliferation and biochemical markers were assessed. To further elucidate the underlying molecular mechanisms hepatic gene expression was determined by customized cDNA arrays and quantitative RT-PCR. RESULTS: In the VEGF group, VD, VDi, and LBR were significantly increased compared with anti-VEGF or controls. Blockage of endogenous VEGF led to a marked increase of biochemical markers. Anti-VEGF almost completely suppressed and VEGF markedly enhanced hepatic proliferation in the first 24 h after surgery. This was associated with a modulation of cell cycle control genes (PC4, Gadd45a, Tis21/BTG2), v-jun, and CD14 by VEGF. CONCLUSIONS: VEGF plays an important role in liver regeneration and this may be due in part through its effects on neovascularization. Whether it may, when given therapeutically, represent a strategy to optimize liver regeneration in problematic patients needs to be clarified.     

大鼠肝卵圆细胞中matrilin-2的表达及其意义

目的探讨大鼠肝脏再生过程中肝卵圆细胞matrilin-2的表达及其意义。方法利用大鼠部分肝切除(PH)或2-乙酰氨基芴灌胃+/部分肝切除(2-AAF/PH)建立大鼠肝脏再生模型,并设正常对照组。应用免疫组织化学和RT-PCR方法研究肝脏组织中matrilin-2表达情况。结果免疫组化发现正常对照组及PH组肝脏组织中只有极少量的matrilin-2表达位于胆管血管周围及肝窦状隙内,而在2-AAF/PH模型中可见matrilin-2表达位于门静脉周围的肝窦状隙内,RT-PCR发现2-AAF/PH组肝卵圆细胞中matrilin-2mRNA高表达,而PH组及正常对照组成熟肝细胞中无matrilin-2mRNA表达。结论matrilin-2是肝卵圆细胞在肝脏再生过程中产生的重要的细胞外基质蛋白,与肝卵圆细胞的增殖分化过程有密切关系。     

Liver‐specific Sirtuin6 ablation impairs liver regeneration after 2/3 partial hepatectomy

Sirtuin 6 (Sirt6) is an NAD+‐dependent deacetylase that regulates central metabolic functions such as glucose homeostasis, fat metabolism, and cell apoptosis. However, the tissue‐specific function of Sirt6 in liver regeneration remains unknown. Here, we show that liver‐specific Sirt6 knockout (Sirt6LKO) impaired liver reconstitution after 2/3 partial hepatectomy, which was attributed to an alteration of cell cycle progression. Sirt6 LKO delayed hepatocyte transition into S phase during liver regeneration, as shown by the analysis of cell cycle‐related proteins and the immuno staining of Ki‐67 and 5‐bromo‐2‐deoxyuridine (BrdU). The delayed cell cycle in Sirt6 LKO mice was attributed to the disruption of m‐TOR and Akt activity, which is an important pro‐proliferation pathway in liver regeneration. Sirt6 LKO also reduced carbon tetrachloride (CCl₄)‐induced liver damage. Our results suggest that Sirt6 LKO impaired liver regeneration via delayed cell cycle and impaired m‐TOR and Akt activity.     

间断低氧预适应对大鼠肝切除术后残余肝脏再生的影响

目的 研究间断低氧预适应对大鼠肝切除术后残余肝脏再生的影响。方法 54只SD大鼠用SPSS软件随机分为3组：假手术组（SO组）、肝部分切除组（PH组）和间断低氧预适应组（IHP组）。PH组切除大鼠的左叶和中叶肝脏,约占70％。IHP组大鼠每日在低氧环境下暴露1h,连续进行1周后行肝切除术。于术后第1、3、5天每组随机选取6只SD大鼠处死进行检测。称取肝脏重量,计算肝脏再生度和再生指数。取下腔静脉血用全自动生化分析仪检测血清谷丙转氨酶（ALT）和谷草转氨酶（AST）水平。采用免疫组化方法检测残余肝组织增生细胞核抗原（PCNA）阳性率。结果 IHP组术后第1天和第3天残余肝脏的再生度和再生指数明显高于PH组（P＜0.05）,而术后第5天两组差异无统计学意义。虽然IHP组和PH组大鼠术后血清ALT和AST水平开始下降,但二者均明显高于SO组,且术后第1天IHP组明显低于PH组（P＜0.05）。术后各个时间点IHP组残余肝脏的PCNA阳性细胞比例明显高于SO组和PH组（P＜0.05）。结论 间断低氧预适应能够在一定程度上防止肝切除术后残余肝组织中肝细胞破坏,并且能促进肝脏的早期再生。但其机制需进一步研究。     

Effects of portal vein arterialization on liver regeneration after partial hepatectomy in the rat

Although portal venous supply is considered essential to preserve hepatic integrity, in this study, effects of portal arterialization on liver regeneration were evaluated in a rat model of partial hepatectomy (PH). Ninety-six Lewis rats were randomly assigned to four groups of 24 rats each: PH only (group 1), PH with either venous or arterialized portal supply (groups 2 and 3, respectively), and PH without portal supply (group 4). Liver regeneration rate (LRR), 5-bromo-2-deoxyuridine (BrdU) labeling index, and liver biological characteristics were assessed on days 1, 2, 3, and 7. Compared with group 1, all tested rats had a marked body weight loss after surgery, and only rats in group 4 showed no signs of recovery on day 7. With maintained portal inflow (groups 1, 2, and 3), LRRs increased steadily to day-7 values of 89.2% [plusmn] 11.8%, 81.4% [plusmn] 8%, and 77.4% [plusmn] 9.4%, respectively (P = not significant), and 24-hour peak values of BrdU labeling index were 159 [plusmn] 26, 157 [plusmn] 42, and 149 [plusmn] 48, respectively (P = not significant). Conversely, rats deprived of portal supply (group 4) showed profound inhibition of these two parameters (14 [plusmn] 13; P [lt ] .01;32.1% [plusmn] 7.7%; P [lt ] .001, respectively). These results indicate that proper portal blood supply is essential to initiate and maintain liver regeneration after PH. With an equivalent portal inflow rate of either venous or arterial source, the hepatic regeneration response can be sustained. (Liver Transpl 2002;8:146-152.)     

Measurement of the portal blood flow in man by continuous local thermodilution method: II. Portal hemodynamics before and after hepatectomy

We found that measurements of portal blood flow by continuous thermodilution were highly reproducible even after hepatectomy. Our subjects numbered 59 in all: In these patients having diseases of the liver and biliary tract, we studied portal hemodynamics during percutaneous transhepatic portography. Of these, 37 underwent hepatectomy. We chose 19 subjects from this group, and measured again both portal venous flow and portal venous pressure many times, continuing for 14 more days. In all 19 patients checked after hepatectomy, portal hemodynamics became hypodynamic, and this change was greater when the amount of liver resected was large. In 18 of these patients, hemodynamics started to improve after the 7th postoperative day. Changes in hemodynamics were not significantly different in patients with or without cirrhosis. In one patient who died of hepatic failure, the portal hypodynamic state did not improve. With this exception, in patients with major resections, portal venous flow per liver volume had increased after surgery and continued to increase. This was not true for patients with minor resections. Portal hemodynamics are important in the functioning and regeneration of the remaining liver, and it is necessary to understand and medically correct portal hemodynamics before and after hepatectomy.     

门静脉动脉化对大鼠肝脏再生的影响

目的探讨门静脉动脉化重建肝血流后对肝脏再生的影响。方法建立门静脉动脉化重建肝脏血流加半肝切除(43%)的大鼠实验模型,分别在术后3 d和10 d取出肝脏烘干称重、光镜下计数进入有丝分裂期的肝细胞和分离肝细胞进行流式细胞仪分析,以观察肝脏再生的情况。结果实验组术后3 d和10 d测定的肝脏干重分别为(67.56±3.70)%(、78.76±5.68)%,与对照组(71.66±3.24)%(、82.38±4.86)%相比无显著性差异(P>0.05);进入有丝分裂期的肝细胞计数(708.4±68.21、239.6±24.50)与对照组(724.8±69.99、216.2±23.81)相比无显著性差异(P>0.05);流式细胞仪测得的进入G2和M期的肝细胞的DNA含量[(25.72±4.78)%、(15.60±2.52)%]与对照组[(28.78±3.37)%、(13.34±2.88)%]相比无显著性差异(P>0.05)。结论行门静脉动脉化重建肝血流不影响肝脏的再生。     

Loss of p27(Kip1) accelerates DNA replication after partial hepatectomy in mice

BACKGROUND: Liver regeneration after partial hepatectomy (PH) is accomplished by a synchronous replication of hepatocytes. Both positive and negative regulators of cyclin-dependent protein kinase (Cdk) have been implicated in hepatocyte proliferation, but their specific roles in vivo remain to be clarified. To investigate the specific role of p27(Kip1), a member of the Cip/Kip family of Cdk inhibitors, in cell-cycle regulation during liver regeneration, p27-knockout mice were studied after PH. MATERIALS AND METHODS: Under ether anesthesia, mice were subjected to 70% PH. Animals were sacrificed at intervals after the surgery, and the remnant liver was harvested and analyzed. RESULTS: In p27-deficient mice, the timing of DNA synthesis was significantly accelerated with a perturbation in the ordered distribution of proliferating cells in the hepatic lobule. p27 deficiency, however, did not affect the whole population of cycling cells, the number of apoptotic cells, or liver injury and mortality after PH. CONCLUSION: These data provide in vivo evidence that p27 functions as a brake in the "start" of the hepatocyte cell cycle, thereby coordinating temporally and spatially the onset of DNA synthesis of hepatocytes within the hepatic lobules.