Assessment of liver graft function and regeneration by galactosyl-human serum albumin (99mTc-GSA) liver scintigraphy in adult living-donor liver transplantation

Abstract: Background: In adult living‐donor liver transplantation (LDLT), the assessment of the graft functional reserve is very important. We evaluated the graft functional reserve by technetium‐99m‐diethylenetriaminepenta‐acetic acid‐galactosyl‐human serum albumin (^99mTc‐GSA) liver scintigraphy. Patients and method: From May 2003 to September 2006, ^99mTc‐GSA studies were performed in 27 adult recipients on two, four wk after LDLT, the receptor index [ratio of liver to heart‐plus‐liver radioactivity at 15 minutes (LHL15)] (LHL15) was calculated. Recipients were divided into two groups according to LHL15 on two wk after LDLT (group H; >0.935, group L; <0.935). Liver functional tests and recipients’ background parameters were evaluated between the two groups. Result: Group L accompanied higher preoperative model for end‐stage liver disease (MELD) score (p = 0.038), lower graft‐recipient weight ratio (GRWR) (p = 0.032) and older donor age (p = 0.003) compared with group H. There was no significant difference in the graft regeneration rate between two groups. The three‐yr cumulative survival rate was 76.1% in group L and 88.9% in group H. Conclusion: In LDLT, LHL15 has the potential to assess the graft function and predict the recipients’ outcome. Graft function after LDLT may be related closely to the pretransplant MELD score, GRWR, and donor age.     

Insulin requirements for hepatic regeneration following hepatectomy.

On the basis of changes in the adenine nucleotide the mitochondrial metabolism of the remnant liver, insulin requirements for hepatic regeneration were studied in diabetic rats treated with varying amounts of alloxan. Mildly diabetic rats with less than 30% inhibition in maximal portal insulin response to oral glucose load, showed a parabolic glucose tolerance pattern and could tolerate partial hepatectomy. Whereas, severely diabetic rats with more than 45% inhibition showed a linear glucose tolerance pattern and died within 24 hours after partial hepatectomy. In the former rats, the energy charge (ATP + 1/2ADP/ATP + ADP + AMP) levels of the remnant liver decrease slightly at an early period after partial hepatectomy but could be restored rapidly to normal levels with a concomitant rise of oxidative phosphorylation in remnant liver mitochondria. In contrast, the energy charge levels in the latter groups fell more markedly and could not be restored, because of insufficient enhancement of mitochondrial oxidative phosphorylation. It is suggested that an enhancement in mitochondrial phosphorylative activity of the remnant liver following partial hepatectomy is inhibited in proportion to the severity of impaired insulin secretion, resulting in a decrease of the potential functional capacity of liver.     

动态SPECT 99mTc半乳糖人血清清蛋白显像技术评估硬化肝脏的储备功能

目的 探讨动态SPECT99mTc半乳糖人血清清蛋白(GSA)显像技术对硬化肝脏储备功能评估的有效性.方法 对2010年1月至2011年12月55例肝硬化患者进行研究,其中男性43例,女性12例;年龄35 ～ 69岁,平均年龄(51±9)岁.利用SPECT/CT一体机顺次进行CT扫描和99mTc-GSA动态SPECT扫描,计算全肝和半肝肝实质形态学体积(MLV)、功能学体积(FLV)及肝细胞摄取速率常数(GSA-K).分析GSA-K与常规生化指标、Child-Pugh评分、吲哚菁绿血浆清除率(ICG-K)等的关系.进一步将患者分为门静脉左支闭塞或狭窄组(组1,5例)、门静脉右支闭塞或狭窄组(组2,13例)和门静脉未受累组(组3,37例),比较各组MLV和FLV.结果 患者全肝、左半肝、右半肝的FLV分别为(594±152) ml、(244±119) ml、(356±171)ml.GSA-K值与总胆红素、凝血酶原时间、Child-Pugh评分及ICG-K值有相关关系(r=-0.730～-0.298,P＜0.05).组1的受累侧半肝与对侧半肝的FLV比值及MLV比值分别为0.09±0.06、0.30±0.14,组2为0.57 ±0.43、1.08±0.63,组3为0.71±0.30、0.71 ±0.48.方差分析比较各组间MLV比值与FLV比值的差异有统计学意义(F =22.8,P=0.000);LSD法两两比较发现,组1和组3之间(P=0.000)、组2和组3之间有明显差异(P =0.000).结论 动态SPECT99mTc-GSA显像技术不仅可以有效地评估硬化肝脏的全肝功能,更能准确地反映区域肝脏功能的变化.     

Functional assessment of liver regeneration after major hepatectomy

BackgroundLiver regeneration is crucial to restore the functional liver mass after liver resection. The aim of this study was to evaluate the early postoperative changes in remnant liver function, volume and liver stiffness after major liver resection and their correlation with postoperative outcomes.MethodsPatients undergoing major liver resection (≥3 segments) between February and November 2018 underwent both functional assessment using technetium-99m mebrofenin hepatobiliary scintigraphy (HBS) and CT-volumetry of the (future) remnant liver on preoperative day 1, the 5^th postoperative day, and 4–6 weeks after resection. At the same time points, patients underwent transient elastography (TE) for the assessment of liver stiffness. Severe postoperative complications (Clavien-Dindo ≥ 3A) and mortality were correlated with the functional and volumetric increases of the remnant liver. Liver failure was graded according to the International Study Group of Liver Surgery (ISGLS) criteria.ResultsA total of 18 patients were included of whom 10 (56%) had severe complications and one patient (5%) developed liver failure. Function and volume of the remnant liver had increased by the 5^th postoperative day from 6.9 (5.4–10.9) to 9.6 (6.7–13.8) %/min/m², P=0.004 and from 795.5 (538.3–1,037.5) to 1,080.0 (854.0–1,283.3) mL, P<0.001, respectively. After 4–6 weeks, remnant liver volume had further increased [from 1,080.0 (854.0–1,283.3) to 1,222.0 (1,016.0–1,380.5) mL, P=0.035], however, liver function did not show any significant, further increase [from 9.6 (6.7–13.8) to 10.9 (8.8–13.6) %/min/m², P=0.177]. Liver elasticity of the future remnant liver (FRL) increased [from 10.8 (5.7–18.7) to 17.5 (12.4–22.6) kPa, P=0.018] and gradually recovered after 4–6 weeks to a median of 10.9 (5.7–18.8) kPa (T3 vs. T4, P=0.079). Patients who had severe postoperative complications did not show a significant increase in liver function on the 5^th postoperative day (P=0.203), despite increase of volume (P<0.01).ConclusionsFunctional regeneration of the remnant liver predominantly occurs during the first 5 days after resection. In case of severe complications, functional regeneration is delayed, in contrast to volume increase.     

Endothelial-directed hepatic regeneration after partial hepatectomy

OBJECTIVE: To determine the role of the microvascular endothelium in the regulation of regenerating liver mass after partial hepatectomy. SUMMARY BACKGROUND DATA: Angiogenesis is critical for both pathologic and physiologic processes. The ability of certain tissues, such as the liver, kidney, and spleen, to regenerate after injury is poorly understood. The liver will regenerate to its normal mass within 8 days of surgical excision. Because the authors have previously shown that the endothelial cell regulates tumor mass, we hypothesized that normal adult organ mass is also controlled by the endothelial cell. METHODS: Two-thirds partial hepatectomy was performed in 7- to 8-week-old C57 BL/6 mice, followed by systemic treatment with either the angiogenesis stimulator basic fibroblast growth factor (bFGF) (1 microg/g/d intraperitoneal) or the angiogenesis inhibitor TNP-470 (30 mg/kg/qod subcutaneous). Groups of three mice were then euthanized on postoperative days 2, 4, 6, and 8, and the livers were weighed and analyzed by immunohistochemistry. RESULTS: bFGF accelerated hepatic regeneration by 42%, 19%, 16%, and 16% on postoperative days 2, 4, 6, and 8, respectively. TNP-470 inhibited hepatic regeneration by 46%, 74%, 67%, and 64% on postoperative days 2, 4, 6, and 8, respectively. Immunohistochemistry revealed that bFGF and TNP-470 primarily affected the endothelial compartment. Specifically, bFGF increased endothelial proliferation and decreased endothelial apoptosis. TNP-470, in contrast, inhibited endothelial cell proliferation. The cessation of the regenerative process correlated with a decrease in endothelial proliferation and an increase in endothelial apoptosis. CONCLUSIONS: The systemic administration of angiogenesis agents modulates the regeneration of hepatic mass primarily by affecting endothelial cell proliferation or apoptosis. Endothelial cell apoptosis is associated with the cessation of the regenerative process in control mice. These results suggest that the endothelial cell is one of the key mediators of regenerating adult tissue mass in this partial hepatectomy model.     

Biliary obstruction from hepatic regeneration following extended right hepatectomy for tumor.

Two patients, aged 2 and 6 months, underwent extended right hepatectomy for hepatoblastoma. Tumor resection was complete in both and postoperative chemotherapy was begun. One patient became markedly jaundiced 4 months postoperatively. Imaging evaluation showed marked nodular liver enlargement and intrahepatic ductal dilatation. At laparotomy an obstructed distal common duct was draped over a huge regenerating liver nodule. A high Roux-En-Y choledochojejunostomy was followed by a decrease in bilirubin to normal within 4 days. Chemotherapy was restarted and the patient remains anicteric and healthy. No evidence of tumor recurrence was found. A second patient became jaundiced 2 weeks after resection. Imaging evaluation suggested tumor recurrence. At laparotomy biopsy failed to confirm recurrent tumor but the area of the porta was not explored. Jaundice persisted and the patient died of liver failure thought secondary to tumor recurrence 4 months postoperation. Postmortem examination showed a completely obstructed common duct draped over a liver nodule and no evidence of tumor. These two patients illustrate the heretofore unrecorded entity of biliary obstruction from regenerating liver following resection for tumor. The sudden appearance of jaundice following a successful liver resection for tumor should raise the suspicion of benign repairable biliary obstruction rather than unresectable tumor recurrence. The definitive evaluation is reexploration rather than various imaging modalities, which may not only be misleading, but may delay life-saving intervention.     

Effects of hepatic blood inflow occlusion on liver regeneration following partial hepatectomy in an experimental model of cirrhosis

BACKGROUND: Hepatic blood inflow occlusion during hepatectomy may influence postoperative liver regeneration. The aim of this study was to investigate the influence of hepatic blood inflow occlusion on liver regeneration following partial hepatectomy in thioacetamide-induced cirrhotic rats. METHODS: Forty-three cirrhotic Wistar-Furth rats were randomly assigned to three groups. Rats in group 1 underwent 64 per cent hepatectomy alone, those in group 2 were subjected to 15 min hepatic blood inflow occlusion followed by 64 per cent hepatectomy, and animals in group 3 were subjected to 30 min inflow occlusion followed by 64 per cent hepatectomy. Liver function, 5-bromo-2'-deoxyuridine (BrdU) labelling index and percentage of initial liver weight on days 1, 2 and 7 posthepatectomy were assessed. RESULTS: Rats in groups 1 and 2 had a significantly higher serum albumin level and a markedly lower alanine aminotransferase level than animals in group 3 on day 1 posthepatectomy (P < 0.05). There was no significant difference in the serum level of total bilirubin of the three groups on days 1, 2 and 7. The BrdU labelling index was significantly higher in groups 1 and 2 than in group 3 animals on day 1 posthepatectomy (P < 0.01 and P < 0.05 respectively). Percentages of initial liver weight were similar in groups 1, 2 and 3 on days 1, 2 and 7 after hepatectomy. CONCLUSION: Hepatic blood inflow occlusion for up to 30 min suppressed DNA synthesis and hepatocyte proliferation at an early posthepatectomy stage and consequently delayed recovery of liver function in cirrhotic rats. However, it did not affect restoration of liver mass or survival after 64 per cent hepatectomy.     

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.     

肝再生增强因子促进肝再生的细胞信号途径研究

目的探讨肝再生增强因子（ALR）促进肝部分切除（PH）后再生的机制。方法采用肝再生率评价ALR对PH后肝再生的作用；MTT检测ALR协同肝再生大鼠血清对肝细胞增殖和ALR对TGF-β1抑制肝细胞增殖的作用；免疫组化观察再生肝中ALR的表达；免疫细胞化学和Western blot检测经ALR刺激后肝细胞中ALR表达变化。结果ALR明显促进PH后的肝再生，可协同肝再生大鼠血清促进肝细胞增殖；ALR能拮抗TGF-β1对肝细胞增殖的抑制；ALR主要表达于正常肝细胞浆内；PH后2～3d肝细胞ALR减少甚至消失，第6天随着肝再生的完成，ALR含量又恢复正常；ALR刺激后肝细胞内源性ALR表达增高。结论ALR能以自主分泌方式从肝细胞中释放，与间质细胞产生的肝再生调控因子相互作用，如抑制TGF-β1生物活性，间接促进PH后的肝再生过程。     

Factors influencing liver regeneration following living-donor liver transplantation of the right hepatic lobe

BACKGROUND: As a result of the shortage of cadaveric livers for adults, many institutes perform living-donor liver transplantation (LDLT) using right-lobe grafts. It is important to learn whether regeneration of the graft is compromised by division of middle hepatic vein (MHV) tributaries. Accordingly, we studied the effect on graft regeneration of transection of the MHV tributaries and other factors, including graft versus body weight ratio (GRBW). METHODS: Of 100 adult recipients having undergone right-lobe LDLT, 30 6-month survivors were studied. Liver regeneration was assessed by volumetry based on the computed tomography (CT). A regeneration index was defined as the ratio of the graft volume 6 months after LDLT to the preoperative value. The dominance of the MHV tributaries over the right hepatic vein in venous drainage of the anterior segment was evaluated by preoperative CT using a 5-point scale. RESULTS: The regeneration index of the posterior segment was significantly greater than that of the anterior segment (Wilcoxon signed rank test, P=0.01). The relatively poor regeneration of the anterior segment compared with the whole graft was associated with preoperatively dominant MHV tributaries (Spearman rank correlation: R=-0.44, P=0.01). The only significant determinant of the whole-graft regeneration, however, was GRBW (stepwise regression: Y=-0.80X+0.2, R(2)=0.70, P<0.0001). CONCLUSIONS: Despite deprivation of MHV tributaries, a graft will regenerate to meet the metabolic demand, and a smaller graft for the recipient is capable of regenerating to a greater extent.     

Nonsuperiority of technetium-99m-galactosyl human serum albumin scintigraphy over conventional volumetry for assessing the future liver remnant in patients undergoing hepatectomy after portal vein embolization

BackgroundTechnetium-99m-galactosyl human serum albumin scintigraphy is preferred for assessing the liver functional reserve in patients undergoing hepatectomy, but its superiority over computed tomography volumetry after portal vein embolization and subsequent hepatectomy remains elusive. We aimed to compare technetium-99m-galactosyl human serum albumin scintigraphy with conventional computed tomography volumetry for predicting posthepatectomy liver failure in patients after portal vein embolization.MethodsThis retrospective study analyzed 152 consecutive patients who underwent hepatobiliary cancer resection after portal vein embolization between 2006 and 2021. Posthepatectomy liver failure was graded according to the International Study Group of Liver Surgery criteria. The predictive abilities for posthepatectomy liver failure were compared between the future remnant uptake (%) by technetium-99m-galactosyl human serum albumin scintigraphy and the future remnant volume (%) by computed tomography volumetry.ResultsFuture remnant uptake (%) was significantly greater than future remnant volume (%) after portal vein embolization (47.9% vs 40.8%; P < .001), while the values were comparable before portal vein embolization (32.7% vs 31.2%; P = .116). Receiver operating characteristic curve analysis revealed that post–portal vein embolization future remnant volume (%) had a significantly higher area under the curve than post–portal vein embolization future remnant uptake (%) (0.709 vs 0.630; P = .046) for predicting posthepatectomy liver failure. Multivariable analysis revealed that post–portal vein embolization future remnant volume (%) independently predicted posthepatectomy liver failure, but future remnant uptake (%) did not. Although the incidence of posthepatectomy liver failure grade ≥B was 17.8% when indocyanine green–clearance of the future liver remnant based on both future remnant volume (%) and future remnant uptake (%) was ≥0.05, it was higher in other combinations: 55.6% for indocyanine green clearance of the remnant volume ≥0.05/indocyanine green clearance of the remnant uptake ≤0.05; 50.0% for indocyanine green clearance of the remnant volume ≤0.05/indocyanine green clearance of the remnant uptake ≥0.05; and 50% for indocyanine green clearance of the remnant volume ≤0.05/indocyanine green clearance of the remnant uptake ≤0.05.ConclusionsTechnetium-99m-galactosyl human serum albumin scintigraphy is not superior to computed tomography volumetry for assessing the future liver remnant in patients undergoing major hepatectomy after portal vein embolization.     

胆汁酸在梗阻性黄疸小鼠肝部分切除术后肝再生中作用的研究

目的：探讨胆汁酸（CA）在梗阻性黄疸（OJ）小鼠肝部分切除术后肝再生中的作用及机制。 方法：180只健康雄性小鼠随机均分为6组,分别行假手术（对照组）、胆总管结扎（OJ组）、胆总管结扎并于7 d加行外引流（ED组）、胆总管结扎+0.2%CA灌胃并7 d后加行外引流（ED+0.2%CA组）、胆总管结扎+1%CA灌胃并于7 d后加行外引流（ED+1%CA组）、胆总管结扎并于7 d后加行内引流（ID组）,各组分别于实验第14天行70%肝切除,且各外引流组改行内引流。检测各组肝切除术后不同时间点肝再生率与肝组织增殖细胞核抗原Ki-67表达、叉状头盒M1b基因（Foxm1b）mRNA相对表达、成纤维细胞生长因子受体4（FGFR4）蛋白表达,并观察部分组肝细胞原位凋亡情况。 结果：除对照组外,肝再生率、肝组织Ki-67阳性表达率、Foxm1b mRNA及FGFR4蛋白表达在其余各组均由高到低依次为：ID组>ED+0.2%CA组>ED组>OJ组>ED+1%CA组,组间差异均有统计学意义（均P<0.05）;ID组与对照组间各指标差异均无统计学意义（均P>0.05）;肝细胞凋亡率由高到低依次为：ED+1%C组>ED组>ED+0.2%CA组>对照组,组间差异均有统计学意义（均P<0.05）。 结论：内引流通过减少内源性CA的丢失有利于肝切除后肝再生;外源性低浓度CA可以恢复外引流引起的肝再生障碍,可能与其上调Foxm1b与FGFR4的表达从而促进肝再生有关。     

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.     

Clinical significance of 99mTc-DTPA-galactosyl human serum albumin liver scintigraphy in follow-up patients with biliary atresia

Purpose

Technetium 99m DTPA-galactosyl human serum albumin (GSA) liver scintigraphy was performed in follow-up patients with biliary atresia, and its clinical significance was investigated.

Methods

Between 1994 and 2001, GSA liver scintigraphy was performed 153 times in 57 follow-up patients. HH15, LHL15, and H/L15 (HH15/LHL15) were obtained. Patients were divided into 3 groups according to the clinical status (good, n = 17; fair, n = 24; poor, n = 16). The correlation between these parameters and liver function tests was examined. Twenty-six patients of the 57 underwent 3 serial GSA scintigraphies and also were divided into 3 groups (good, n = 13; fair, n = 8; poor, n = 5). (3rd/1st)H/L15 (3rd H/L15/1st H/L15) was obtained and compared.

Results

H/L15 had a correlation with serum albumin and serum cholinesterase. H/L15 was statistically different among 3 groups (good, 0.97 ± 0.15; fair, 0.94 ± 0.09; poor, 1.12 ± 0.21; P < .05). Although most patients in the good (10 patients; 76.9%) and fair (7 patients; 87.5%) groups showed (3rd/1st)H/L15 of less than 1.1, 3 patients (60%) in the poor group showed (3rd/1st)H/L15 of more than 1.1. (3rd/1st)H/L15 in the poor group was significantly higher than those in good and fair groups (P < .05).

Conclusions

Technetium 99m-GSA liver scintigraphy is useful to assess the functional hepatic reserve in follow-up patients with biliary atresia. Serial assessment with GSA scintigraphy can provide the trend of the patient’s liver condition and can estimate the prognosis of the liver.