Posthepatectomy Liver Dysfunction Research Articles

Coagulation factor XIII is a critical driver of liver regeneration after partial hepatectomy

BackgroundActivation of coagulation and fibrin deposition in the regenerating liver appears to promote adequate liver regeneration in mice. In humans, perioperative hepatic fibrin deposition is reduced in patients who develop liver dysfunction after partial hepatectomy (PHx), but the mechanism underlying reduced fibrin deposition in these patients is unclear. Methods and ResultsHepatic deposition of cross-linked (ie, stabilized) fibrin was evident in livers of mice after two-thirds PHx. Interestingly, hepatic fibrin cross-linking was dramatically reduced in mice after 90% PHx, an experimental setting of failed liver regeneration, despite similar activation of coagulation after two-thirds or 90% PHx. Likewise, intraoperative activation of coagulation was not reduced in patients who developed liver dysfunction after PHx. Preoperative fibrinogen plasma concentration was not connected to liver dysfunction after PHx in patients. Rather, preoperative and postoperative plasma activity of the transglutaminase coagulation factor (F)XIII, which cross-links fibrin, was lower in patients who developed liver dysfunction than in those who did not. PHx-induced hepatic fibrin cross-linking and hepatic platelet accumulation were significantly reduced in mice lacking the catalytic subunit of FXIII (FXIII−/− mice) after two-thirds PHx. This was coupled with a reduction in both hepatocyte proliferation and liver–to–body weight ratio as well as an apparent reduction in survival after two-thirds PHx in FXIII−/− mice. ConclusionThe results indicate that FXIII is a critical driver of liver regeneration after PHx and suggest that perioperative plasma FXIII activity may predict posthepatectomy liver dysfunction. The results may inform strategies to stabilize proregenerative fibrin during liver resection.

Increasing Living Liver Donor Pools: Liver Paired Exchange Versus ABO-incompatible Living Donor Liver Transplantation.

Increasing Living Liver Donor Pools: Liver Paired Exchange Versus ABO-incompatible Living Donor Liver Transplantation.

Outcomes of Hepatic Resection for Hepatocellular Carcinoma Associated with Portal Vein Invasion

To evaluate our experience of liver resection for hepatocellular carcinoma (HCC) patients associated with macroscopic portal vein invasion (PVI). Consecutive HCC patients who underwent liver resection for HCC between November 2009 & June 2019 were included. To overcome selection bias between patients with and without macroscopic PVI, we performed 1:1 match using propensity score matching (PSM). Macroscopic PVI was detected in 37 patients (12.8%). We divided our patients into two groups according to the presence of macroscopic PVI. After PSM, 36 patients of PVI group were matched with 36 patients from Non-PVI group. After PSM, both groups were well balanced regarding tumor site, number, liver resection extent and type. Longer operation time and more blood loss were noted in PVI group. Higher incidence of post-operative morbidities occurred in PVI group especially, post-hepatectomy liver dysfunction. The 1-, 2-, and 3-y overall survival rates for Non-PVI group were 85.3%, 64.6%, and 64.6% & 69.8%, 42%, and 0% for PVI group, respectively (P=0.009). There were no significant differences regarding the recurrence rate, site, and its management. The 1-, 2-, and 3-y disease-free survival (DFS) rates for Non-PVI group were 81.7%, 72.3%, and 21.7% & 67.7%, 42.3%, and 0% for PVI group, respectively (P=0.172). Surgical management of advanced HCCs with macroscopic PVI is feasible, and associated with comparable DFS but poorer overall survival, compared to patients without PVI.

Ceramides and sphingosine-1-phosphate mediate the distinct effects of M1/M2-macrophage infusion on liver recovery after hepatectomy

Post-hepatectomy liver dysfunction is a life-threatening morbidity that lacks efficient therapy. Bioactive lipids involved in macrophage polarization crucially regulate tissue injury and regeneration. Herein, we investigate the key bioactive lipids that mediate the cytotherapeutic potential of polarized-macrophage for post-hepatectomy liver dysfunction. Untargeted lipidomics identified elevation of ceramide (CER) metabolites as signature lipid species relevant to M1/M2 polarization in mouse bone-marrow-derived-macrophages (BMDMs). M1 BMDMs expressed a CER-generation-metabolic pattern, leading to elevation of CER; M2 BMDMs expressed a CER-breakdown-metabolic pattern, resulting in upregulation of sphingosine-1-phosphate (S1P). After infusing M1- or M2-polarized BMDMs into the mouse liver after hepatectomy, we found that M1-BMDM infusion increased M1 polarization and CER accumulation, resulting in exaggeration of hepatocyte apoptosis and liver dysfunction. Conversely, M2-BMDM infusion enhanced M2 polarization and S1P generation, leading to alleviation of liver dysfunction with improved hepatocyte proliferation. Treatment of exogenous CER and S1P or inhibition CER and S1P synthesis by siRNA targeting relevant enzymes further revealed that CER induced apoptosis while S1P promoted proliferation in post-hepatectomy primary hepatocytes. In conclusion, CER and S1P are uncovered as critical lipid mediators for M1- and M2-polarized BMDMs to promote injury and regeneration in the liver after hepatectomy, respectively. Notably, the upregulation of hepatic S1P induced by M2-BMDM infusion may have therapeutic potential for post-hepatectomy liver dysfunction.

Predictive Factors for Early Mortality after Hepatic Resection for Hepatitis C Virus Related Hepatocellular Carcinoma: A Single Center Experience

Abstract Background: Hepatocellular Carcinoma (HCC) is the most common malignancy affecting the liver. It accounts for almost ninety percentage of primary malignancies affecting the liver. HCC develops on a carcinogenic background of liver cirrhosis. Aim of Study: To evaluate our center experience of liver resection for Hepatitis C Virus (HCV) related Hepatocellular Carcinoma (HCC) to determine the predictive factors of early post-operative mortality. Patients and Methods: We reviewed the data for all consecutive patients who underwent liver resection for HCV related HCC during the period between January 2010 and June 2018. Results: Two hundred fourteenconsecutive patients were included in the study. The median age was 59 years (18-78), and median MELD score was 7 (6-16). The median operation time was 170 minutes (70-380) and median blood loss was 680ml (100-5000). The median hospital stay was 5 days (2-60). Post-operative morbidities occurred in 120 patients (56%). Early post-operative mortality occurred in 19 patients (8.9%), all of them developed variable degrees of post-hepatectomy liver dys-function. The median follow-up duration was 22 months (5-110). Recurrence occurred in 130 patients (60.7%). The 1-, 3-, and 5-years disease-free survival rates were 69.2%, 35.4%, and 17.6%, respectively. Late mortality occurred in 59 patients (27.6%). The 1-, 3-, and 5-years overall survival rates were 78.2%, 59.1%, and 50%, respectively. Predictive factors for early mortalityincluded pre-operative albumin, Child-Pugh score, MELD score, blood loss, severe post-operative morbidities, renal complications, and post-hepatectomy liver dysfunction. Conclusion: Proper selection of liver resection candidates based on pre-operative laboratory findings, together with meticulous surgical techniques to minimize blood loss can help to avoid early post-operative mortality.

Surgical Portosystemic Shunts: History, Evolution, and Current Applications

AbstractMechanical obstruction, thrombus, intrinsic liver disease causing fibrosis or cirrhosis, or an outflow obstruction at the level of the sinusoids or hepatic venous obstruction can cause an increase in pressure or resistance, or both, leading to portal hypertension (PH). Portosystemic shunts (PSS) are usually performed to relieve the congestion that inevitably occurs in the setting of PH. Since their introduction, surgical PSS were often the treatment of choice to prevent recurrent bleeding in patients with clinically significant PH. Development of novel pharmacological therapies, continuous improvement of endoscopic approaches, the introduction of transjugular intrahepatic portosystemic shunt, and advancements in transplantation has provided an evolution in the approach for PH and has precipitated the steady decrease in the proportion of patients needing surgical shunts. Despite this, PSS remain important tools in the surgeon's armamentarium, as they are often employed in the pediatric population with extrahepatic portal vein obstruction and are frequently being used for portal inflow modulation to achieve better portal hemodynamics in resections and transplantation. This has become of great relevance to decrease the risk of small-for-size syndrome and portal hyperperfusion in liver transplantation, and to decrease the risk of posthepatectomy liver dysfunction after major resections in hepatobiliary surgery.

Initially unresectable hepatocellular carcinoma treated by combination therapy of tyrosine kinase inhibitor and anti-PD-1 antibody followed by resection.

e16690 Background: Combination of tyrosine kinase inhibitor (TKI) and anti-PD-1 antibody showed a high tumor response for advanced hepatocellular carcinoma (HCC). We are aiming to study the effect of combination therapy followed by resection in pts with initially unresectable HCC. Methods: 60 consecutive pts with unresectable or advanced HCC were treated with combination therapy as first-line treatment, including 2 in BCLC-A (China Liver Cancer stage [CNLC]-Ib), and 13 in BCLC-B (CNLC-IIa and IIb), 26 in BCLC-C (vascular invasion, CNLC-IIIa) and 19 in BCLC-C (extrahepatic metastasis, CNLC-IIIb). Tumor response and resectability were evaluated by imaging every 2 months (± 1 week). The criteria of resectability included: (1) R0 resection can be achieved; (2) remnant liver volume ≥ 40%; (3) Child-Pugh score is 5; (4) no contra-indications for hepatectomy. Results: Conversion to resectable HCC was identified in 11 (18.3%) pts after combination therapy. Of them, 2 pts are still under treatment for immune-related adverse events, and 9 underwent hepatectomy as of January 2020. Of the 9 pts, the initial tumor was unresectable because of macro-vascular invasion (n = 6, 1 Vp3, 3 Vp4, 1 hepatic vein, 1 inferior vena cava), extrahepatic metastasis (n = 1, right adrenal gland), tumor nodules ≥ 4 (n = 1) and recurrent HCC within 2 months after first resection (n = 1). The TKIs used were lenvatinib (n = 6) and apatinib (n = 3); anti-PD-1 antibodies used were pembrolizumab (n = 4), sintilimab (n = 3), camrelizumab (n = 1) and nivolumab (n = 1). The median interval between start of combination therapy and resection was 99 days (range, 73–251). The median post-operative hospital stay was 14 days (range, 11–68). The prevalence of post-hepatectomy liver dysfunction (the criteria by ISGLS) is 5 (55.6%) pts, and the post-operative complications (by Clavien–Dindo classification) occurred in 4 (44.4%) pts, including grade I in 1, grade IIIa in 2, and grade V in 1 (died from immune-related adverse events). Tumor response (RECIST v1.1) evaluated before surgery were PR (n = 5), SD (n = 3), and PD (n = 1). Pathological CR (pCR) was found in 5 (55.6%) cases. After a median follow up of 72 days (range, 11–184), tumor recurrence were diagnosed in 1 patient, and mortality without tumor recurrence in 1 patient, the other 7 cases remained tumor-free. Conclusions: This is to date the largest cohort of pts underwent R0 resection after combination therapy for initially un-resectable HCC. The combination of a TKI and anti-PD-1 antibody is feasible as a conversion therapy.

Development and Validation of a Nomogram to Preoperatively Estimate Post-hepatectomy Liver Dysfunction Risk and Long-term Survival in Patients With Hepatocellular Carcinoma.

To develop a nomogram to estimate the risk of SPLD (International Study Group of Liver Surgery definition grade B or C) and long-term survival in patients with HCC before hepatectomy. SPLD is the leading cause of post-hepatectomy mortality. The decision to refer an HCC patient for hepatectomy is mainly based on the survival benefit and SPLD risk. Prediction of SPLD risk before hepatectomy is of great significance. A total of 2071 consecutive patients undergoing hepatectomy for HCC were recruited and randomly divided into the development cohort (n = 1036) and internal validation cohort (n = 1035). Five hundred ninety patients from another center were enrolled as the external validation cohort. A nomogram was developed based on independent preoperative predictors of SPLD determined in multivariable logistic regression analysis. The SPLD incidences in the development, internal, and external validation cohorts were 10.1%, 9.5%, and 8.6%, respectively. Multivariable analysis identified total bilirubin, albumin, gamma-glutamyl transpeptidase, prothrombin time, clinically significant portal hypertension, and major resection as independent predictors for SPLD. Incorporating these variables, the nomogram showed good concordance statistics of 0.883, 0.851, and 0.856, respectively in predicting SPLD in the 3 cohorts. Its predictive performance in SPLD, 90-day mortality, and overall survival (OS) outperformed Child-Pugh, model for end-stage liver disease, albumin-bilirubin, and European Association for the Study of the Liver recommended algorithm. With a nomogram score of 137, patients were stratified into low and high risk of SPLD. High-risk patients also had decreased OS. The nomogram showed good performance in predicting both SPLD and OS. It could help surgeons select suitable HCC patients for hepatectomy.

Functional remnant liver volume to spleen volume ratio is a useful predictive factor for posthepatectomy liver dysfunction

Objective Toidentify factors contributing to posthepatectomy liver dysfunction (PHLD), focusing on the Functional remnant liver volume to spleen volume ratio (FreLSVR). Methods The clinical data of 74 patients undergoing precise liver resection from January 2016 to October 2017 were retrospectively analyzed. IQQA liver system was used to reconstruct the liver and spleen 3D image by using patients′ preoperative abdominal CT image data. Tumor volume, 3D estimated functional residual liver volume, spleen volume and FreLSVR were measured and calculated. Preoperative and postoperative liver function test, blood coagulation function test, operation time, intraoperative blood loss, and the volume of daily postoperative abdominal drainage were recorded. Correlations between multiple parameters and PHLD were analyzed. Results PHLD occurred in 16 (21.6%). Single factor analysis revealed that the standardized residual liver volume ratio (P 2.56 group (53 cases), the highest postoperative INR value (1.46±0.19 to 1.29±0.29, t=-2.405, P<0.05) was higher that of FreLSVR≤2.56 group, and the amount of average daily abdominal drainage in one and two weeks after operation was higher, (188.0(79.2~375.1)ml to 96.0(46.5~179.3)ml, P<0.05) and (207.2(125.6~827.1)ml to 71.8(14.0~179.8) ml, P<0.05), respectively. Conclusion FreLSVR has significant correlation with postoperative hepatic dysfunction, and provides guidance for the safety of liver resection in the future. Key words: Posthepatectomy liver failure; Spleen volume; Remnant liver volume; Hepatectomy

Predictive Factors of Liver Dysfunction After Right Hemihepatectomy for Adult Living Donor Liver Transplantation

BackgroundLiving liver donors represent a special group of patients. They are healthy individuals who are exposed to a major surgery, in which the dominant liver proportion is extracted as a graft. Of all potential donor-related morbidities, posthepatectomy liver dysfunction (PHLD) is the most significant as it may be directly related to donor mortality. We aimed to review our data of adult living donor liver transplantation (LDLT) utilizing the right hemiliver grafts to determine the incidence and potential predictors for the development of PHLD, defined according to the International Study Group of Liver Surgery. MethodsWe reviewed the data of all adult living donors who underwent right hemihepatectomy during the period between May 2004 and 2016. ResultsDuring the study period, 434 cases underwent right hemihepatectomy for adult LDLT. We divided our cases into 2 groups according to the occurrence of PHLD. A significant lower residual liver volume and percentage were noted in PHLD group. Longer intensive care unit stay and hospital stay, and more postoperative morbidities, were observed in PHLD group. PHLD occurred in 50 cases (11.5%), and most of them were grade A (47 cases [10.8%]). Two cases (0.5%) had grade B requiring diuretic therapy, and 1 case (0.2%) had grade C requiring ultrasound guided tube drainage and surgical exploration finally. ConclusionsWe should not underestimate the risks of liver donation surgery, especially when utilizing the right hemiliver graft. Donor safety should be ensured by accurate preoperative volumetric assessment of the remnant liver and remnant liver volume limitations must be strictly followed.

Predicting the trajectory of post-hepatectomy liver dysfunction (PHLD)

Objective: PHLD is an expected outcome with more extensive liver resections, and it remains a major cause of morbidity. Early recognition of severe cases may be beneficial. The International Study Group of Liver Surgery (ISGLS) consensus criteria for post-hepatectomy liver failure serve to identify individuals with significant liver dysfunction. However, because the diagnostic criteria comprise liver dysfunction persisting more than 4 days after hepatectomy, the ISGLS definition is of limited use to a clinician. Our objective was to identify factors that inform the clinician whether PHLD is likely to be accompanied by an adverse clinical course. Methods: Liver resections between 2006 and 2014 were retrospectively reviewed. Patients with bilirubin ≥40 μmol/L and/or prothrombin time ≥1.5 at any time after surgery were identified. Factors associated with severe complications, ICU admission and death were identified. Results: During the study period, 1010 liver resections were performed and 110 patients (10.9%) had PHLD. Of those, 76 (69%) met the ISGLS criteria for liver failure. Clavien-Dindo complication grades ≥4 (ICU admission or mortality) occurred in 25 patients (22.7%). Factors associated with those adverse outcomes included patient age (P=0.015), duration of surgery (P=0.030), estimated blood loss (P=0.010), and the need for intraoperative blood transfusions (P < 0.001). The extent of liver resection and presence of cirrhosis did not predict clinical trajectory. Conclusion: Intraoperative events leading to prolonged surgery and excessive blood loss had the greatest influence on the clinical trajectory of PHLD.

Bioartificial liver attenuates intestinal mucosa injury and gut barrier dysfunction after major hepatectomy: Study in a porcine model

The aim of this study was to evaluate whether bioartificial liver support can attenuate gut mucosa injury in a porcine model of posthepatectomy liver dysfunction. Posthepatectomy liver failure was induced in pigs combining major (70%) liver resection and ischemia/reperfusion injury. An ischemic period of 150minutes was followed by reperfusion for 24hours. Animals were divided randomly into 2 groups: a control group (n=6) that received standard critical care and a bioartificial liver support group (Hepat, n=6) that were subjected to extracorporeal liver support for 6 hours during reperfusion. Intestinal mucosal injury, bacterial translocation, and endotoxin translocation were evaluated in all animals. Intestinal mucosa was also evaluated with markers of oxidative injury and immunohistochemical staining for caspase3. When compared with median values, the control group, animals in the Hepat group had a lesser intestinal mucosal injury score (4.0 [range:2.0-5.0] vs 1.0 [range:1.0-2.0]; P<.01), decreased bacterial translocation in the portal and the systemic circulation at 24hours of reperfusion (P<.05), and decreased portal and systemic endotoxin levels at 24hours (P<.05). At 24hours after reperfusion, mucosal protein carbonyls and malondialdehyde levels were decreased in Hepat animals (0.57nmol/mg [range:0.32-0.70] vs 0.33nmol/mg [range:0.03-0.53] and 3.85nmol/mg [range:3.01-6.43] vs 3.27nmol/mg [range:1.46-3.55], respectively; P<.05). There was no difference in tissue caspase staining. Bioartificial liver support seems to attenuate intestinal mucosal injury and gut barrier dysfunction after major hepatectomy.

Risk factors for post-hepatectomy liver dysfunction in primary liver cancer patients with concurrent hepatic schistosomiasis and chronic hepatitis

ObjectiveThe purpose of this study was to analyze risk factors for development of post-hepatectomy liver dysfunction in primary liver cancer (PLC) patients with concurrent hepatic schistosomiasis and chronic hepatitis. MethodsA retrospective analysis of 73 PLC patients with concurrent hepatic schistosomiasis and chronic hepatitis, of which 16 patients developed liver dysfunction (persistent ascites or pleural effusion or occurrence of liver-related potentially fatal complications) following hepatectomy, was performed. After clinical characteristics were recorded, preoperative liver function parameters and surgery-related parameters in these patients were assessed. Seventeen potential risk factors for post-hepatectomy liver dysfunction were identified. The association between these potential risk factors and post-hepatectomy liver dysfunction then was analyzed. ResultsUnivariate analysis showed that liver cirrhosis, intraoperative blood loss, and preoperative total bilirubin were associated with the development of post-hepatectomy liver dysfunction. Multivariate logistic regression analysis of these three factors revealed that intraoperative blood loss ≥600 mL and cirrhosis were two independent risk factors for post-hepatectomy liver dysfunction in PLC patients with concurrent hepatic schistosomiasis and chronic hepatitis. ConclusionKeeping intraoperative blood loss below 600 mL can help avoid the development of post-hepatectomy liver dysfunction in liver cancer patients with concurrent hepatic schistosomiasis and chronic hepatitis. For patients with concomitant liver cirrhosis, every effort should be made to minimize potential liver function impairment induced by other adverse factors.

Antioxidant Treatment Attenuates Intestinal Mucosal Damage and Gut Barrier Dysfunction After Major Hepatectomy. Study in a Porcine Model

BackgroundThis study aims to evaluate whether injury of gut mucosa in a porcine model of post-hepatectomy liver dysfunction can be prevented using antioxidant treatment with desferrioxamine. MethodsPost-hepatectomy liver failure was induced in pigs combining major (70%) liver resection and ischemia/reperfusion injury. An ischemic period of 150 minutes, was followed by reperfusion for 24 h. Animals were randomly divided into a control group (n = 6) and a desferrioxamine group (DFX, n = 6). DFX animals were treated with continuous IV infusion of desferrioxamine 100 mg/kg. Intestinal mucosal injury (IMI), bacterial and endotoxin translocation (BT) were evaluated in all animals. Intestinal mucosa was also evaluated for oxidative markers. ResultsDFX animals had significantly lower IMI score (3.3±1.2 vs. 1.8 ± 0.9, p < 0.05), decreased BT in the portal circulation at 0 and 12 h of reperfusion (p = 0.007 and p = 0.008, respectively), decreased portal endotoxin levels at 6 (p = 0.006) and 24 h (p = 0.004), decreased systemic endotoxin levels (p = 0.01) at 24 h compared to controls. Also, 24 h post-reperfusion mucosal malondialdehyde and protein carbonyls were decreased in DFX animals compared to controls (4.1±1.2 vs. 2.5 ± 1.2, p = 0.05 and 0.5±0.1 vs. 0.4 ± 0.1, p = 0.04 respectively). ConclusionDesferrioxamine seems to attenuate mucosal injury from post-hepatectomy liver dysfunction possibly through blockage of iron-catalyzed oxidative reactions.

Perioperative use of the LiMON method of indocyanine green elimination measurement for the prediction and early detection of post-hepatectomy liver failure

Introduction A non-invasive liver function monitoring system, the LiMON ®, has been developed that measures indocyanine green (ICG) elimination by pulse spectrophotometry. The aim was to assess the relationship between pre and post-operative ICG plasma disappearance rate (ICG PDR %/min) values and the onset of post-hepatectomy liver dysfunction. Methods 37 patients scheduled for major liver resections were selected. None had chronic liver disease. IGC PDR was measured preoperatively and on days 1, five and 10 postoperatively. On the same day, serum liver function tests were measured. Results The median preoperative and post-operative day 1 ICG PDR for the patients who developed liver dysfunction was significantly lower compared to those who did not ( p = 0.044, p = 0.014). Significant correlation was found between ICG PDR measurement taken on postoperative day 1 and bilirubin level on day 1 ( p = 0.002), 5 ( p =<0.001) and 10 ( p = 0.001). The same was true for ICG PDR on post-operative day 1 and albumin level on day 5 and 10 ( p = 0.003, p < 0.001). Discussion LiMON ICG PDR measured by pulse spectophotometry is a quick, non-invasive and reliable liver function test in patients undergoing liver resection that aids in the prediction and early detection of post-hepatectomy liver dysfunction.

Effect of Short‐term Administration of Prostaglandin E1 on Viability after Ischemia/Reperfusion Injury with Extended Hepatectomy in Cirrhotic Rat Liver

The cytoprotective effect of prostaglandin E(1) (PGE(1)) has been demonstrated experimentally and clinically against hepatic ischemia and reperfusion injury and against the effects of partial hepatectomy in both individual and combined models of noncirrhotic livers. Cirrhotic livers are more vulnerable to ischemia/reperfusion injury during hepatectomy than are noncirrhotic livers, and postoperative malfunctioning complicates life with multiple organ failure. Cirrhotic livers with tumors have mostly been treated conservatively because extended hepatectomy with induced ischemia during surgery is impossible. The purpose of our study was to document postoperative surgical adaptation in inoperable cases with improved survival after extended hepatectomy in a rat model of cirrhosis treated by PGE(1). Cirrhosis was induced by intraperitoneal injections of 1% dimethylnitrosamine. The liver was subjected to 15 minutes of total ischemia by occluding the hepatoduodenal ligament. Hepatectomy was performed during ischemia. Pretreatment with PGE(1) (0.4 microg/kg/min) (or without it in the controls) was given for 15 minutes by intravenous infusion prior to inducing ischemia and during reperfusion. Portal venous flow (PVF) and liver tissue blood flow (LTBF) were measured during reperfusion. At the end of 60 minutes of reperfusion, venous blood was collected for liver function tests. The animals were followed up regarding survival for 48 hours. The PVF and LTBF were significantly improved in the PGE(1) group. The blood chemical analysis indicated that PGE(1) significantly suppressed posthepatectomy liver dysfunction. Most importantly, PGE(1) treatment markedly improved the survival rate, from 42% in the controls to 75% in the test animals at 24 hours after hepatectomy and from 17% in the controls to 58% in the test animals at 48 hours. We concluded that short-term administration of PGE(1) makes extensive hepatectomy possible under ischemic conditions in cirrhotic livers.

Liver regeneration after major hepatectomy for biliary cancer

The aim of this study was to evaluate serial changes in liver volume after major hepatectomy for biliary cancer and to elucidate clinical factors influencing liver regeneration. Serial changes in liver volume were determined, using computed tomography, in 81 patients with biliary cancer who underwent right hepatic lobectomy or more extensive liver resection with or without portal vein resection and/or pancreatoduodenectomy. Possible factors influencing liver regeneration were evaluated by univariate and multivariate analyses. The remnant mean(s.d.) liver volume was 41(8) per cent straight after hepatectomy. This increased rapidly to 59(9) per cent within 2 weeks, then increased more slowly, finally reaching a plateau at 74(12) per cent about 1 year after hepatectomy. The regeneration rate within the first 2 weeks was 16(8) cm3/day and was not related to the extent of posthepatectomy liver dysfunction. On multivariate analysis, the extent of liver resection (P < 0.001), body surface area (P = 0.02), combined portal vein resection (P = 0.024) and preoperative portal vein embolization (P = 0.047) were significantly associated with the liver regeneration rate within the first 2 weeks. In addition, body surface area (P < 0.001) and liver function expressed as plasma clearance rate of indocyanine green (P = 0.01) were significant determinants of final liver volume 1 year after hepatectomy. The liver regenerates rapidly in the first 2 weeks after major hepatectomy for biliary cancer. This early regeneration is influenced by four clinical factors. Thereafter, liver regeneration progresses slowly and stops when the liver is three-quarters of its original volume, approximately 6 months to 1 year after hepatectomy.

Activated protein C prevents multiple organ injury following extensive hepatectomy in cirrhotic rats

Background/Aims: Extended hepatectomy for cirrhotic liver in patients with hepatocellular carcinoma often triggers posthepatectomy liver failure. It has been shown that the microcirculatory disturbance caused by microthrombus formation and sinusoidal endothelial cellular injury is one of the causes of posthepatectomy liver dysfunction. We therefore investigated the effect of activated protein C (APC), a potent antithrombotic serine protease with anti-in-flammatory effects, on posthepatectomy liver dysfunction and multiple organ injury in cirrhotic rats. Methods/Results: Dimethylnitrosamine-induced cirrhotic rats underwent 70% hepatectomy and received lipopolysaccharide (200 μg/kg) 48 h later to prepare a lethal posthepatectomy acute liver failure model. APC (1500 U/kg), given intravenously 15 min before and 1 h after endotoxin challenge, attenuated liver dysfunction and decreased serum tumor necrosis factor-α concentration. APC significantly improved the survival rate of rats at 12 h after endotoxin challenge. Histological examination revealed that APC treatment inhibited not only intrasinusoidal fibrin deposition and massive hepatocellular necrosis but also pulmonary injury and glomerular fibrin deposition. Immunohistochemically, expression of intercellular adhesion molecule-1 on sinusoidal cells and renal glomeruli was decreased in the APC-treated animals. Conclusions: APC administration prevented acute liver dysfunction and attenuated multiple organ injury following extended hepatectomy in cirrhotic rats, possibly via anticoagulant and anti-inflammatory effects.

Pretreatment with Soluble Thrombomodulin Prevents Intrasinusoidal Coagulation and Liver Dysfunction following Extensive Hepatectomy in Cirrhotic Rats

The major cause of posthepatectomy liver dysfunction is supposed to be microcirculatory disturbance caused by imbalance of intrasinusoidal coagulation equilibrium. Thrombomodulin (TM) is a potent anticoagulant expressed on the endothelial cell surface that regulates the coagulation system by binding thrombin and accelerating the thrombin-catalyzed activation of protein C. Therefore, we examined the effect of soluble TM purified from human urine (UTM) on intrasinusoidal coagulation in cirrhotic rats. Dimethylnitrosamine-induced cirrhotic rats underwent 70% hepatectomy and received endotoxin 48 h after. UTM or vehicle alone was intravenously administered to each rat 30 min before endotoxin injection. UTM treatment attenuated the increases in cytosolic enzymes and serum hyaluronic acid level. The UTM supply improved the survival rate of the rats at 12 h after endotoxin challenge. Histologically, intrasinusoidal fibrin depositions and massive hepatocellular necrosis observed in control rats were scarcely found in UTM-treated rats. Immunohistochemical examination revealed that marked TM stains in sinusoidal endothelial cells were well preserved in UTM-treated rats. In conclusion, UTM administration prevented intrasinusoidal fibrin depositions and attenuated posthepatectomy liver dysfunction in cirrhotic rats.

Portal branch ligation with a continuous hepatocyte growth factor supply makes extensive hepatectomy possible in cirrhotic rats.

In a cirrhotic liver, the regenerative ability and specific functions are so impaired that excessive resection easily complicates postoperative liver dysfunction, which frequently leads to life-threatening multiple-organ failure. Hepatocyte growth factor (HGF), first identified as the most potent stimulator of DNA synthesis in primary hepatocytes, not only stimulates liver regeneration, but also accelerates hepatic function, improves fibrosis, and protects liver cells against injury. Therefore, we investigated the efficacy of preoperative portal branch ligation (PBL) (which can induce compensatory hypertrophy of the unaffected lobes) combined with a continuous HGF supply in the performance of extensive hepatectomy in cirrhotic rats. Cirrhosis was induced by intraperitoneal injections of dimethylnitrosamine (DMN) three times per week for 3 weeks. Five days after the last injection, when 70% hepatectomy is lethal, the rats underwent portal ligation of the left lateral and median branches (corresponding to approximately 70% of the total volume of the liver). Simultaneously, they were continuously treated with either recombinant human HGF (rhHGF) or vehicle from an intraperitoneally implanted osmotic pump. Four days after the portal ligation, the occluded lobes were resected. The HGF treatment rapidly increased both the wet weight of the unoccluded lobes and the hepatocellular DNA synthesis. The blood chemical analysis indicated that HGF significantly suppressed the posthepatectomy liver dysfunction. Most importantly, the HGF treatment markedly improved the survival rate of the rats at 48 hours after the major hepatectomy. In conclusion, PBL combined with a continuous HGF supply makes extensive hepatectomy possible in cirrhotic rats, mainly by promoting the hypertrophy of the unaffected lobes.