Bile salts predict liver regeneration in rabbit model of portal vein embolization.

BACKGROUND: Portal vein embolization (PVE) is employed to increase future remnant liver (FRL) volume through induction of hepatocellular regeneration in the nonembolized liver lobe. The regenerative response is commonly determined by CT volumetry after PVE. The aim of the study was to examine plasma bile salts and triglycerides in the prediction of the regenerative response following PVE. METHODS: PVE of the cranial liver lobe was performed in 15 rabbits, divided into three groups: NaCl (control), gelatin sponge (short-term occlusion), and polyvinyl alcohol particles with coils (PVAc, long-term occlusion). In all rabbits CT volumetry and blood sampling were performed prior to PVE and on days 3 and 7. Plasma bile salts and triglycerides were correlated with volume increase of the nonembolized liver lobe. RESULTS: After 3 and 7 d, respectively, FRL volume was increased in both embolized groups, with the largest hypertrophy response observed in the PVAc group. Plasma bile salt levels were increased after PVE, especially in the PVAc group at day 3 (P < 0.01 compared to gelatin sponge). Plasma bile salts at day 3 predicted FRL volume increase at day 7 showing a positive correlation of 0.811 (P < 0.001). Levels of triglycerides were not significantly altered in either of the PVE procedures. CONCLUSIONS: Plasma bile salt levels early after PVE strongly correlated with the regenerative response in a rabbit model of PVE, showing more pronounced elevation with larger volume increase of the nonembolized lobe. Therefore, plasma bile salts, but not triglycerides, can be used in the prediction of the regenerative response after PVE.

Diagnostic accuracy of MRI in differentiating hepatocellular adenoma from focal nodular hyperplasia: prospective study of the additional value of gadoxetate disodium.

OBJECTIVE: The purpose of this article is to prospectively determine the sensitivity of hepatobiliary phase gadoxetate disodium-enhanced MRI combined with standard MRI in differentiating focal nodular hyperplasia (FNH) from hepatocellular adenoma (HCA). SUBJECTS AND METHODS: Patients suspected of having FNH or HCA larger than 2 cm underwent gadoxetate disodium-enhanced MRI. Standard MRI was evaluated separately from the additional hepatobiliary phase by two blinded radiologists. For the largest lesion in each patient, findings were compared with histologic diagnosis. Sensitivity, positive predictive value (PPV), and distinctive features were analyzed using McNemar and analysis of variance tests. RESULTS: Fifty-two patients completed the study. Histologic diagnosis revealed 24 HCAs and 28 FNHs. Characterization on standard MRI was inconclusive in 40% (21/52) and conclusive in 60% (31/52) of lesions. The sensitivity of standard MRI for HCA was 50% (12/24) with a PPV of 100% (12/12). The sensitivity for FNH was 68% (19/28) with a PPV of 95% (18/19). After review of hepatobiliary phase, the sensitivity for HCA improved to 96% (23/24) with a PPV of 96% (23/24). The sensitivity for FNH improved to 96% (27/28) with a PPV of 96% (27/28). Features with significant predictive value for diagnosis in HCA included bleeding (p < 0.001), fat (p = 0.010), and glycogen (p = 0.024). The presence of a central scar was predictive for FNH (p < 0.001). CONCLUSION: This study shows high sensitivity of gadoxetate disodium-enhanced MRI when standard series are combined with the hepatobiliary phase for differentiation of FNH and HCA in lesions larger than 2 cm.

Short-term effects of combined hepatic vein embolization and portal vein embolization for the induction of liver regeneration in a rabbit model.

PURPOSE: Alternative methods to optimize the hypertrophy response after portal vein embolization (PVE) are desired. This study assessed the effect of hepatic vein embolization (HVE) in addition to PVE on liver hypertrophy response in a standardized rabbit model. MATERIALS AND METHODS: Thirty rabbits were allocated to groups according to intervention: PVE alone, HVE alone, and a combination of HVE and PVE. The liver regeneration response of the nonembolized, caudal liver was assessed by computed tomographic volumetry, liver-to-body weight index, and the amount of proliferating hepatocytes. RESULTS: The caudal liver volume (CLV) increased significantly more in the PVE and combined PVE/HVE group than in the HVE group at 3 and 7 days after the procedure (P < .01). There were no significant differences in CLV increase or degree of hypertrophy between the PVE and combined embolization groups. The caudal liver-to-body weight index was significantly higher in the PVE and combined embolization groups than in the HVE group on day 7 (P < .01). The index was also significantly higher in the combined PVE/HVE group compared with the PVE group (P = .008). The caudal liver tissue of the PVE and combined groups contained a significantly higher number of proliferating hepatocytes compared with the HVE group on day 7 (P < .01). CONCLUSIONS: Although histologic and additional regenerative changes are seen, HVE in addition to PVE has no additional short-term effect on hypertrophy response. The combination of HVE and PVE may therefore have little use in a clinical setting.

Liver regeneration after portal vein embolization using absorbable and permanent embolization materials in a rabbit model.

OBJECTIVE: To compare the safety and hypertrophy response after portal vein embolization (PVE) using 2 absorbable and 3 permanent embolization materials. BACKGROUND: Portal vein embolization is used to increase future remnant liver volume preoperatively. Application of temporary, absorbable embolization materials could be advantageous in some situations, provided sufficient hypertrophy is achieved from the nonembolized lobe. METHODS: Six groups of rabbits (n = 5) underwent PVE of 80% of the total liver volume using saline (sham), gelatin sponge, fibrin glue, polyvinyl alcohol particles with coils, n-butyl cyanoacrylate, or polidocanol. The rabbits were killed after 7 days. Portography, computed tomographic volumetry, Doppler ultrasonography, laboratory liver function and damage parameters (nonembolized) liver-to-body weight ratio, immunohistochemistry, and cytokine and growth factor tissue levels were assessed to examine the differences in the liver regeneration response. RESULTS: Polidocanol was discontinued because of toxic reactions in 3 rabbits. Gelatin sponge was the only material that was absorbed after 7 days and resulted in less hypertrophy of the nonembolized lobe than the other 3 materials. There were no significant differences in hypertrophy response between the other 3 embolization groups. Volumetric data obtained from computed tomography were supported by liver-to-body weight ratio and the amount of proliferating hepatocytes. The volume gain of the nonembolized lobe was proportional to the volume loss of the embolized liver lobes. The number of Kupffer cells in the embolized liver lobe was significantly higher in the fibrin glue, polyvinyl alcohol particles with coils, and n-butyl cyanoacrylate groups than in the sham and gelatin sponge groups. However, the levels of interleukin-6, tumor necrosis factor-α, hepatocyte growth factor, and transforming growth factor-ß1 were significantly lower. CONCLUSIONS: Temporary occlusion using gelatin sponge for PVE resulted in significantly less hypertrophy response than the use of permanent embolization materials. Except for polidocanol, none of the embolization materials exhibited evident hepatotoxicity.

Portal vein embolization induces more liver regeneration than portal vein ligation in a standardized rabbit model.

BACKGROUND: Portal vein ligation (PVL) and portal vein embolization (PVE) are used to induce hypertrophy of the future remnant liver before major liver resection. The aim of our study was to compare the hypertrophy response of the liver after PVL versus PVE in a rabbit model. METHODS: Twenty rabbits were divided into an embolization group (n = 10) and a ligation group (n = 10). Both groups were divided in 2 subgroups of 5 rabbits that were humanely killed after days 7 and 14. The portal vein branches to the 3 cranial liver lobes (80% of the liver) were occluded. Regeneration of the caudal liver lobe was measured using volumetry based on computed tomography on days 3, 7, 10, and 14. Immunohistochemistry for Ki-67 and RAM11 was performed to quantify proliferating cells and macrophages. In addition, tissue tumor necrosis factor-α and interleukin-6 were assessed. RESULTS: The caudal liver volume increased over time in both groups (P < .001), but this increase was greater after PVE than after PVL (P = .001) with a mean degree of hypertrophy of 15% ± 4% and 20% ± 2%, respectively. When comparing the groups on the separate time points, a difference was found on days 10 and 14 (P = .008 and P = .016, respectively). These data were confirmed by Ki-67 staining, which showed a greater number of proliferating hepatocytes on day 7 after embolization (P = .016). Cytokine analysis of liver tissue did not show significant differences between the ligation and embolization groups on days 7 and 14. CONCLUSION: PVE is superior to PVL in terms of the extent of the hypertrophy response in this rabbit model.

Differentiation of hepatocellular adenoma and focal nodular hyperplasia using 18F-fluorocholine PET/CT.

The aim of this pilot study was to evaluate the use of PET/CT with (18)F-fluorocholine in the differentiation of hepatocellular adenoma (HCA) from focal nodular hyperplasia (FNH). Patients with liver lesions larger than 2 cm suspicious for HCA or FNH were prospectively included. All patients underwent PET/CT with (18)F-fluorocholine and histopathological diagnosis was obtained by either liver biopsy or surgery. The ratios between the maximum standardized uptake value (SUV) of the lesion and the mean SUV of normal liver parenchyma were calculated and a receiver operating characteristic (ROC) curve analysis was performed. Ten patients with FNH and 11 with HCA were included. The mean SUV ratio was 1.68±0.29 (±SD) for FNH and 0.88±0.18 for HCA (p<0.001). An SUV ratio cut-off value between 1.12 and 1.22 differentiated patients with FNH from those with HCA with 100% sensitivity and 100% specificity. This pilot study showed that PET/CT with (18)F-fluorocholine can differentiate HCA from FNH.

A rabbit model for selective portal vein embolization.

BACKGROUND: Portal vein embolization (PVE) is a technique to increase future remnant liver volume. A standardized animal model, resembling the clinical PVE procedure, is needed to clarify some of the unresolved issues surrounding PVE. For this purpose we developed a new rabbit model for PVE. MATERIALS AND METHODS: Twenty female New Zealand white rabbits were allocated to two protocols, each containing two subgroups. Eighty percent of the liver portal venous system was embolized with polyvinyl-alcohol particles and coils (protocol 1: 300-500 µm particles and one coil; protocol 2: 90-180 µm combined 300-500 µm particles and three coils). In all rabbits CT-volumetry, ICG clearance test, blood sampling, and portography were performed prior to PVE and at d 7 and 14. Additional blood sampling and CT volumetry was done on d 3 and 7. RESULTS: PVE was technically feasible in the rabbit. CT-volumetry demonstrated a strong correlation with actual liver weight and volume measured at sacrifice. The hypertrophy response was highest at d 7 in both protocols, which was consistent with the amount of proliferating hepatocytes. Protocol 2 showed less revascularization of the portal venous system and demonstrated the highest hypertrophy response. Comparable to the clinical situation, only a small, transient increase in transaminases was observed. There were no changes in liver function parameters after PVE. Histopathologic findings in the rabbit livers were comparable to those found in human livers. CONCLUSIONS: We successfully devised a rabbit model for PVE, which resembles the human clinical situation.

James Cantlie's early messages for hepatic surgeons: how the concept of pre-operative portal vein occlusion was defined.

In 1897, James Cantlie from Scotland published his findings of an autopsy on a patient in which the right side of the liver was atrophied whereas the left side of the liver showed a marked hypertrophy. He noted the hepatic vessels to the atrophied side to be obliterated. From this observation, he drew two important conclusions. First, that the transition of the atrophied part to the hypertrophied part defined the anatomical mid-line of the liver, according to the portal division of blood supply to the liver. This line we now know as Cantlie's line which he described connecting the fundus of the gallbladder with the centre of the inferior vena cava. Second, he foresaw that the potential of one half of the liver to hypertrophy when the other half is deprived of its blood supply, could be used to the advantage of hepatic resection. It would take another 85 years, however, before the first clinical, pre-operative portal vein embolization was carried out in Japan in 1982.

Imaging modalities for focal nodular hyperplasia and hepatocellular adenoma.

BACKGROUND/AIMS: There are several imaging modalities available for the detection of focal liver lesions. Differentiation between focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) is important because of the consequences for management. However, differentiation based on imaging alone still shows limitations. METHODS: We reviewed the literature for typical features of FNH and HCA on radiologic and nuclear imaging with emphasis on differentiation of both lesions. RESULTS: Seven articles describe the performance of an imaging modality for the differentiation between FNH and HCA. Limitations of these studies are the small sample size and/or the lack of comparison with the 'gold standard', i.e. histological diagnosis. No studies are available that compare the accuracy of several imaging modalities in the differentiation of FNH and HCA. Conventional ultrasound (US) is not useful in the differentiation because of the non-specific features. On contrast-enhanced US, the arterial filling direction of FNH is centrifugal and centripetal in case of HCA. The parenchymal enhancement of FNH is sustained in the portal venous and delayed phases, but shows rapid washout in case of HCA. Multiphase CT scan can differentiate FNH from HCA when there is a central scar. FNH may have a slightly higher relative enhancement in the arterial phase. On MRI with hepatocyte-specific contrast agents, HCA does not show contrast uptake in the hepatobiliary phase in contrast to FNH. CONCLUSION: We conclude that there is limited evidence of the diagnostic performance of currently used imaging modalities for the differentiation of FNH and HCA. We therefore propose a prospective study (DiFA trial) to determine the accuracy of several radiologic and nuclear imaging studies in differentiating FNH and HCA.

Volumetric and functional recovery of the remnant liver after major liver resection with prior portal vein embolization : recovery after PVE and liver resection.

INTRODUCTION: Portal vein embolization is an accepted method to increase the future remnant liver preoperatively. The aim of this study was to assess the effect of preoperative portal vein embolization on liver volume and function 3 months after major liver resection. MATERIALS AND METHODS: This is a retrospective case-control study. Data were collected of patients who underwent portal vein embolization prior to (extended) right hemihepatectomy and of control patients who underwent the same type of resection without prior portal vein embolization. Liver volumes were measured by computed tomography volumetry before portal vein embolization, before liver resection, and 3 months after liver resection. Liver function was assessed by hepatobiliary scintigraphy before and 3 months after liver resection. RESULTS: Ten patients were included in the embolization group and 13 in the control group. Groups were comparable for gender, age, and number of patients with a compromised liver. The mean future remnant liver volume was 33.0 +/- 8.0% prior to portal vein embolization in the embolization group and 45.6 +/- 9.1% in the control group (p < 0.01). Prior to surgery, there were no significant differences in future remnant liver volume and function between the groups. Three months postoperatively, the mean remnant liver volume was 81.9 +/- 8.9% of the initial total liver volume in the embolization group and 79.4 +/- 11.0% in the control group (p > 0.05). Remnant liver function increased up to 88.1 +/- 17.4% and 83.3 +/- 14% respectively of the original total liver function (p > 0.05). CONCLUSION: Preoperative portal vein embolization does not negatively influence postoperative liver regeneration assessed 3 months after major liver resection.

Induction of tumor growth after preoperative portal vein embolization: is it a real problem?

Although preoperative portal vein embolization (PVE) is an effective means to increase future remnant liver (FRL) volume, little has been published on possible adverse effects. This review discusses the clinical and experimental evidence regarding the effect of PVE on tumor growth in both embolized and nonembolized liver lobes, as well as potential strategies to control tumor progression after PVE. A literature review was performed using MEDLINE with keywords related to experimental and clinical studies concerning PVE, portal vein ligation (PVL), and tumor growth. Cross-references and references from reviews were also checked. Clinical and experimental data suggest that tumor progression can occur after preoperative PVE in embolized and nonembolized liver segments. Clinical evidence indicating possible tumor progression in patients with colorectal metastases or with primary liver tumors is based on studies with small sample size. Although multiple studies demonstrated tumor progression, evidence concerning a direct increase in tumor growth rate as a result of PVE is circumstantial. Three possible mechanisms influencing tumor growth after PVE can be recognized, namely changes in cytokines or growth factors, alteration in hepatic blood supply and an enhanced cellular host response promoting local tumor growth after PVE. Post-PVE chemotherapy and sequential transcatheter arterial chemoembolization (TACE) before PVE have been proposed to reduce tumor mass after PVE. We conclude that tumor progression can occur after PVE in patients with colorectal metastases as well as in patients with primary liver tumors. However, further research is needed in order to rate this risk of tumor progression after PVE.

Controversies in the use of portal vein embolization.

BACKGROUND/AIMS: Portal vein embolization (PVE) has reached worldwide acceptance to increase future remnant liver (FRL) volume before undertaking major liver resection. The aim of this overview is to point out and discuss current controversies in the application of PVE. METHODS: Review of literature pertaining to techniques of PVE, complications, tumor proliferation, timing of resection, and hypertrophy response after PVE. RESULTS: Procedure-related complications after PVE include hematoma, hemobilia, overflow of embolization material, and thrombosis of portal vein branch(es) of the non-embolized lobe. Persistence of the embolized, atrophic lobe is usually not harmful. Embolization of the portal branches to segment 4 in addition to embolization of the right portal trunk is controversial and is advised only in selected cases. It remains undecided whether embolization of the portal venous system is more effective in inducing hypertrophy of the FRL than ligation of the portal vein. Accelerated tumor growth after PVE is a major concern and requires consideration of post-PVE chemotherapy. A waiting time of 3 weeks between PVE and liver resection is advised. Post-hepatectomy regeneration is not hampered after preoperative PVE. CONCLUSION: PVE is a useful preoperative intervention to increase volume and function of the FRL. Further progress awaits clarification of the mechanisms of the hypertrophy response induced by PVE in conjunction with new embolization materials and protective chemotherapy.