Abstract
Objectives:
To compare the dynamic changes in future liver remnant (FLR) function and volume after hepatectomy and to evaluate the associations between three modalities in assessment of liver function.
Methods:
Liver function and volume were quantified pre-operatively, at post-operative day (POD) 7 and POD 28 in 10 patients with colorectal liver metastases undergoing hemihepatectomy using the indocyanine green retention (ICG) test, hepatobiliary scintigraphy (HBS) and gadoxetic acid-enhanced MRI. The 99mTc mebrofenin uptake rate in the FLR was applied as a reference of liver function. MRI-derived parameters including liver-to-muscle ratio (LMR), liver-to-spleen ratio (LSR) and hepatocellular uptake index (HUI) were used for liver function assessment. Spearman’s correlation analysis was used to evaluate the associations.
Results:
Increase in liver function ranged from 13 to 152% (median 92%) and in volume from 37 to 134% (median 79%). There was no significant discrepancy in increase between FLR function and volume during the first month following hepatectomy. LMR showed a significant correlation to ICG test (r = −0.66, p < 0.05) while LSR had an association with standardized FLR function obtained by HBS (r = −0.71, p < 0.05). During the first week after hepatectomy, pre-operative HUI and LMR showed the strongest correlation to the FLR growth in function and volume respectively (p < 0.05).
Conclusion:
The observed growth in FLR volume is closely related to the functional increase within 1 month after hepatectomy. Gadoxetic acid-enhanced MRI might substitute HBS for regional liver function assessment and provide an imaging tool for liver growth prediction.
Advances in knowledge:
Liver function growth was parallel with liver volume increase during the perioperative period. Liver function assessment with gadoxetic acid-enhanced MRI was comparable with that of HBS indicating that gadoxetic acid-enhanced MRI could substitute HBS for regional liver function evaluation.
Introduction
Safe liver resections can be performed in normal liver or with previous chemotherapy with a future liver remnant (FLR) of 25–30% and with around 40% in cirrhotic liver. 1 Current criteria for deciding cut-off levels of sufficient FLR size are based on low quality evidence (expert consensus) 2 and volume measurements are performed on CT- or MRI-based liver volumetry. However, function can be unevenly distributed in the liver in patients with chronic liver disease. 3,4 This is a potential problem in current pre-operative planning of major hepatectomies since volumetry cannot assess the heterogeneity of liver function among the liver segments. This is likely the case in, e.g. portal vein embolization or associating liver partition and portal vein ligation for staged hepatectomy, where a poor correlation between FLR function and volume has been shown. 5–8 To enable a proper management of patients with liver tumors, a comprehensive assessment of liver function with spatial information is required.
Indocyanine green (ICG) test is the only functional test which is widely used in clinical practice 9–11 and often serves as a gold-standard for quantitative global liver function evaluation pre-operatively. 12 However, it cannot be used to assess regional liver function before hepatectomy. Two techniques that can be used to evaluate liver regional function with temporal information are 99mTc mebrofenin hepatobiliary scintigraphy (HBS) and gadoxetic acid-enhanced MRI. 13 Gadoxetic acid and 99mTc mebrofenin are taken up by the hepatocytes after intravenous injection through the organic anion-transporting polypeptides transport mechanism (OATP1B1 and OATP1B3). 14 During the last decade, gadoxetic acid-enhanced MRI has been increasingly used for quantitative evaluation of liver function. 13,15 Previous studies have shown that parameters derived from gadoxetic acid-enhanced MRI have a good correlation with the retention rate of ICG at 15 min (ICG-R15), Child-Pugh score and the Model for End-Stage Liver Disease score, 12,16,17 making it a promising tool to provide more accurate pre-operative assessment for patients with liver tumors estimating both morphological, volumetric and functional capacity. 15
Compared with the ICG test and HBS, the efficacy and consistency of gadoxetic acid-enhanced MRI remains unclear. We therefore designed a prospective pilot study to explore gadoxetic acid-enhanced MRI, along with ICG-R15 and HBS to depict the dynamic changes of the liver function and volume after hepatectomy in patients with colorectal liver metastases (CRLM), in which HBS results were adopted as the reference for assessment of liver function. The main aims of this study were: (1) to depict the dynamic changes of FLR function and volume during perioperative period and the possible differential increase in liver function and volume after hepatectomy; (2) to evaluate the consistency between the three modalities in assessment of liver function; (3) in addition, the value of the three modalities in prediction of liver growth was explored, since we assumed that fast liver growth indicates a good liver function reserve with reduced risk of postoperative adverse events, such as post-hepatectomy liver failure.
Methods
Study design and subjects
This prospective, single-center study was designed to evaluate the liver function and volume in patients with CRLM using three functional modalities, ICG-R15, HBS and MRI at three time points: pre-operatively, on post-operative day (POD) 7 and on POD 28 (Figure 1). The trial registration information is available on clinicaltrials.gov through identifier NCT03140917. To make the cohort of this pilot study as homogeneous as possible, patients were regarded as eligible if they: (1) were diagnosed with CRLM with resectable lesions; (2) were planned for a right hemi-hepatectomy; (3) were treated with neoadjuvant chemotherapy; and (4) consented to participate in the study. Exclusion criteria included metastasis in the FLR, previous manipulation of the FLR such as portal vein embolization, significant comorbidity (for instance, renal dysfunction) and age less than 18 years old. Since it was a pilot study, no calculation of sample size was performed.
Figure 1.
A schematic flow chart of the study investigations. Note: HBS, hepatobiliary scintigraphy; ICG-R15, indocyanine green retention test at 15 min; KGR, kinetic liver growth; Preop., pre-operative; POD, post-operative day.
The research protocol was approved by the Regional Ethical Review Board (No. The research protocol was approved by the Regional Ethical Review Board (No. 2012/583-31/4) and the Radiation Safety Committee at Karolinska University Hospital, Stockholm, Sweden.) (blinded) and the Radiation Safety Committee at The research protocol was approved by the Regional Ethical Review Board (No. 2012/583-31/4) and the Radiation Safety Committee at Karolinska University Hospital, Stockholm, Sweden.(blinded).
Surgical procedure
Under general anesthesia, all patients underwent a right hemi-hepatectomy. After cholecystectomy had been performed, the right artery was ligated and the right portal vein was divided with an Endo GIA surgical stapler (Universal with Tri-Staple™, Covidien, Ireland). Using a cavitron ultrasonic surgical aspirator (CUSA, Valleylab Inc, Boulder, CA), the liver parenchyma was transected completely along Cantlie’s line down to the retrohepatic vena cava. The right hepatic pedicle including bile duct was isolated with an intraglissonean approach and divided using a similar stapler. The same technique of mobilization, dividing the structures in the right portal pedicle and liver transection was used irrespectively if the operation was performed open or minimally invasively.
ICG-R15 test
The ICG-R15 test was performed in the morning the day prior to surgery, on POD 7 and on POD 28. Following intravenous injection of ICG (Verdye®, Diagnostic Green GmbH, Aschheim-Dornach, Germany) with a dosage of 0.5 mg/kg elimination was measured by pulse spectrophotometry using the LiMON® system (PULSION Medical System, Munich, Germany). The results were expressed as percentage retention at 15 min.
Hepatobiliary scintigraphy
HBS was performed 1 h after ICG-R15 test and directly after the intravenous administration of 200 MBq 99mTc-labeled (2,4,6 trimethyl-3-bromo) iminodiacetic acid (99mTc-mebrofenin, Bridatec®, GE Healthcare, Milan, Italy). HBS and calculation of functional parameters were performed following the same imaging protocol as previously described. 5 In brief, a CT scan was performed for attenuation correction and anatomical correlation after planar dynamic acquisitions to obtain hepatic uptake function, and a single photon emission computed tomography (SPECT) acquisition with projections reconstructed using Hermes SUV SPECT Hybrid Recon™ FLR software (v. 1.2) (HERMES Medical Solutions AB, Stockholm, Sweden). The SPECT acquisition was centered around the peak of the hepatic time–activity curve to obtain three-dimensional assessment of liver function and to enable the calculation of functional liver volumes (Figure 2A–C). The FLR 99mTc-mebrofenin uptake rate (FLR-F) was calculated by multiplying the percentage count of the total liver count. To compensate for individual metabolic differences, FLR-F was divided by body surface area, presenting as %/min/m2.
Figure 2.
A–C. A typical case with hepatobiliary scintigraphy and SPECT/CT performed pre-operatively (A), on POD 7 (B) and POD 28 (C). D–F. The same patient’s T 1 weighted transversal MR images of the abdomen performed pre-operatively (D), on POD 7 (E) and POD 28 (F). At each image, a typical placement of four circular ROIs is showing to calculate signal intensity of liver (averaging two ROIs of left lateral section and segment IV), right spinal erector muscle (one ROI), and spleen (one ROI). POD, post-operative day; ROIs, regions of interest; SPECT, single photon emission computed tomography.
Standardized FLR-F (sFLR-F) was calculated by: sFLR-F (%) = FLR F (%/min/m2) / pre-operative total estimated liver function (%/min/m2) ×100%.
Kinetic growth rate (KGR) in function (KGR-F) was determined via:
KGR-F (%/week) = (sFLR-FPost (%) – sFLR-FPre (%)) / time elapsed (week(s)) where sFLRPost denotes sFLR-F at POD 7 or POD 28 and sFLR-FPre denotes pre-operative sFLR-F.
Gadoxetic acid-enhanced MRI
Time between MRI and HBS was 7–8 h to avoid competitive excretion. A 1.5 T MRI scanner (Aera, Siemens Medical Solutions, Germany), with a four-channel sensitivity encoding (SENSE) body coil was used. A T 1 weighted three-dimensional volume interpolated breath-hold examination sequence was applied to obtain dynamic contrast-enhanced images with the following scanning parameters: repetition time 4.1 ms; echo time 1.95 ms; flip angle 10°; field of view 81.25 mm; acquisition matrix resolution 256 × 156; slices 48; slice thickness 5 mm. Gadoxetic acid (Primovist®, Bayer Healthcare, Berlin, Germany) was injected through the anterior cubital vein at a rate of 2 ml s−1 via a power injector (concentration 0.25 mmol ml-1, 0.1 ml/kg body weight), followed by 20 ml saline infused at the same rate.
MR imaging analysis
Liver function parameters were calculated from cross-sectional MR images obtained at the bifurcation of the portal vein obtained before and 20 min after gadoxetic acid administration (hepatobiliary phase, HBP). The signal intensity (SI) was obtained after carefully avoiding large blood vessels, bile ducts and marginal artifacts, by placing four circular regions of interest (ROIs) with a diameter of 1.5 cm in left liver lobe (average of two ROIs), right spinal erector muscle (one ROI) and spleen (one ROI) (Figure 2D–F).
At MRI, three widely used parameters for quantitative liver function assessment were calculated according to the following formulas:
Liver-to-muscle ratio (LMR) 18 :
LMR = SIHBP of the liver /SIHBP of the muscle
Liver-to-spleen ratio (LSR) 18 :
LSR = SIHBP of the liver /SIHBP of the spleen
Hepatocellular uptake index (HUI) 19 :
HUI = [(SIHBP of the liver) /SIHBP of the spleen −1] * FLR volume
Liver volume calculation
Liver volume was calculated from MRI HBP images using Volume Viewer© (Voxtool 11) for AW Volume Share five running on an AW Workstation (GE Healthcare, Fairfield, CT). A ROI defining the FLR was contoured along the Cantlie line to calculate the FLR volume (FLR-V), and the standardized FLR in volume (sFLR-V) was determined by: sFLR-V(%) = FLR vol (ml) / total estimated liver volume (ml)×100%, where total estimated liver volume was calculated by 1267*body surface area-794 20 and the body surface area by Mosteller formula as previously described. 20
The KGR in liver volume (KGR-V) in POD 1–7 and POD 1–28 was calculated as the same way as that in liver function, but using the parameter of sFLR-V.
Statistical analysis
Continuous variables were presented as median and range, and compared by Mann–Whitney U test. Repeated measures analysis of variance was applied to compare the variable difference among multiple time points. Categorical variables were expressed as number (percentage). Correlation analysis was performed by using the method of Spearman. A p-value less than 0.05 was regarded as statistically significant. All statistical analysis and plotting were performed on R software (v. 4.02, Vienna, R core Team, Austria).
Results
10 patients (female: male, 3:7), aged 63 years (range 44–75), were recruited between November 2014 and March 2019. All had CRLM confirmed by post-operative histopathology. Seven patients (70%) had mild to moderate liver fibrosis in the resected part of the liver (Table 1). No patient developed post-operative hemorrhage, biliary leakage or post-hepatectomy liver failure.
Table 1.
Basic characteristic of the participants
| Variable | Value |
| Gender (F/M) | 3/7 |
| Age, years median (range) | 63 (44–75) |
| BMI (range) | 23.4 (19.6–26.0) |
| Concomitant disease | |
| Cardiovascular disease | 2 (20%) |
| Pulmonary disease | 1 (10%) |
| ASA score (1/2/3) | 7/2/1 |
| Neoadjuvant treatment | 10 (100%) |
| Cycles of chemotherapy (range) | 6 (5–6) |
| Interval between last chemotherapy and hepatectomy (weeks, range) | 4 (4–6) |
| Liver fibrosis stage a 0/1/2 | 3/5/2 |
| Liver fibrosis etiology: Chemotherapy | 10 (100%) |
| Signs of sinusoidal obstruction syndrome due to oxaliplatin chemotherapy (Yes/no) | 8/2 |
| Operation | |
| Right hemihepatectomy | 10 (100%) |
| Laparoscopic operation | 2 (20%) |
| Blood transfusion | 3 (30%) |
| Transfused Units (range) | 2 (1–4) |
| Radical resection (pR0/pR1) | 9/1 |
| Histology : CRLM | 10 (100%) |
ASA score, American Society of Anesthesiology score; BMI, body mass index; CRLM, colorectal liver metastasis.
pR0, > 1 mm from tumor to resection margin; pR1, < 1 mm from tumor to resection margin.
by the Batts-Ludwig scoring system, in which stage 0, 1 and 2 indicate no, mild and moderate fibrosis respectively (on a 5-graded scale);
Liver function and volume changes in perioperative period
Liver function evaluated by ICG test, HBS exam and gadoxetic acid-enhanced MRI, as well as the liver volume at baseline, POD7 and POD28 are presented in Table 2 and visualized in Figure 3 and Supplementary Material 1.
Table 2.
Liver function and volume changes in patients with colorectal liver metastases undergoing hepatectomy during perioperative period
| Variable | Pre-operative | POD7 | POD28 | p-value |
|---|---|---|---|---|
| ICG-R15 (%) | 7.9 (0.4–14.7) | 11.1 (1.2–23.3) | 8.3 (3.9–21.0) | 0.196 |
| Hepatobiliary scintigraphy | ||||
| FLR-F (%/min/m2 ) | 3.1 (2.3–4.7) | 5.5 (4.1–7.9) | 6.6 (5.2–7.7) | < 0.001 |
| sFLR-F (%) | 36 (25–48) | 65 (44–93) | 75 (56–94) | < 0.001 |
| Gadoxetic acid-enhanced MRI | ||||
| LMR | 2.04 (1.50–2.49) | 1.78 (1.43–2.30) | 2.04 (1.88–2.43) | 0.069 |
| LSR | 1.95 (1.26–2.67) | 1.77 (1.29–2.54) | 2.04 (1.77–2.56) | 0.025 |
| HUI | 496 (202–870) | 763 (373–1665) | 1343 (921–1525) | 0.001 |
| Liver volume | ||||
| FLR-V (ml) | 546 (377–772) | 1039 (744–1307) | 1194 (971–1404) | < 0.001 |
| sFLR-V (%) | 38 (29–53) | 69 (55–81) | 79 (66–90) | < 0.001 |
| Interval POD 1–7 | Interval POD 1–28 | |||
| Kinetic growth rate | ||||
| KGR-F (%/week) | - | 31 (5–45) | 10 (6–13) | < 0.001, b |
| KGR-V (%/week) | - | 30 (19–47) | 9 (6–13) | 0.003, b |
FLR, future liver remnant; FLR-F, future liver remnant function represented by corrected mebrofenin uptake rate; FLR-V, future liver remnant volume; HUI, hepatic uptake index; ICG-R15, indocyanine green retention test at 15 min; KGR-F, kinetic growth rate in function; KGR-V, kinetic growth rate in volume; LMR, liver-to-muscle ratio; LSR, liver-to-spleen ratio; POD, post-operative day; sFLR-F, standardized FLR-F; sFLR-V, standardized FLR-V.
Note: Data are expressed as median with range. p values are calculated by repeated measures analysis of variance.
statistically significant
compared by the Mann Whitney U test
Figure 3.
The dynamic changes of the FLR function and volume, expressed as ICG-R15, (A), sFLR-F, (B), LMR, (C),LSR, (D), HUI, (E) and sFLR-V, (F), and at three time points: pre-operative, post-operative day 7 (POD 7) and POD 28. Note: *p < 0.05, **p < 0.01, ***p < 0.001. NS, not significant. FLR, future liver remnant; HUI, hepatocellular uptake index; ICG-R15, indocyanine green retention test at 15 min; LMR, liver-to-muscle ratio; LSR, liver-to-spleen ratio; POD, post-operative day.
Both KGR-F and KGR-V were faster during POD 1–7 than that during POD 1–28 (31% /week vs 10% /week for KGR-F, 30% /week vs 9% /week for KGR-V, both p < 0.05) (Table 2), indicating a fast-to-slow process of liver function and volume growth after liver resection.
Comparison of liver function and volume during the perioperative period
Correlations between modalities for quantitative liver function evaluation
There was no significant difference in sFLR-V and sFLR-F at pre-operative (38% vs 36%, p = 0.48), at POD 7 (69% vs 65%, p = 0.32) or POD 28 (79% vs 75%, p = 0.61). No statistically significant difference between KGR-F and KGR-V at POD 7 (31% vs 30% /week, p = 0.97) or at POD 28 (10% vs 9% /week, p = 0.87) was observed (Table 2).
At pre-operative exams, LMR negatively correlated with ICG-R15 (r = −0.66, p < 0.05). Among the parameters derived from gadoxetic acid-enhanced MRI, there was a significant correlation between LMR and LSR (r = 0.66, p < 0.05), and between LSR and HUI (r = 0.83, p < 0.05). LSR showed a negative correlation with sFLR-F, with a correlation coefficient of −0.71 (p < 0.05) (Figure 4).
Figure 4.
A. Correlations between liver function parameters derived from ICG test, hepatobiliary scintigraphy exam and gadoxetic acid-enhanced MRI at preoperative exams. B. Correlation between LMR and ICG-R15. C. Correlation between LSR and sFLR-F. Note: HUI, hepatic uptake index; ICG-R15, indocyanine green retention test at 15 min; FLR, future liver remnant; FLR-F, corrected mebrofenin uptake rate in FLR (%/min/m2); LMR, liver-to-muscle ratio; LSR, liver-to-spleen ratio; sFLR-F, standardized FLR-F. *p < 0.05, **p < 0.01, ***p < 0.001. r, correlation coefficient.
Correlations between preoperative liver function parameters and liver growth after hepatectomy
During the first week after hepatectomy, LMR was positively correlated with KGR-V (correlation coefficient (r) = 0.84, p < 0.05), while ICG-R15 had a negative correlation with KGR-V (r = −0.69, p < 0.05) (Figure 5).
Figure 5.
Correlations between pre-operative liver function and volume parameters and the KGR-V during the first week after hepatectomy. Note: HUI, hepatic uptake index; ICG-R15, indocyanine green retention test at 15 min; FLR, future liver remnant; FLR-F, corrected mebrofenin uptake rate in FLR (%/min/m2); FLR-V, future liver remnant volume; KGR-V, kinetic growth rate of the future liver remnant volume; LMR, liver-to-muscle ratio; LSR, liver-to-spleen ratio; sFLR-F, standardized FLR-F; sFLR-V, standardized FLR-V.
Regarding KGR-F during the first week following liver resection, HUI and FLR-V showed a significant correlation with KGR-F, with r = 0.87 and r = −0.75 respectively, both with p < 0.05. LSR showed a trend of positive association with KGR-F, although the correlation was not significant (r = 0.6, p = 0.07) (Supplementary Material 1).
Discussion
To the best of our knowledge, this is the first study to compare the three modalities used for evaluation of liver function in the perioperative period (ICG, HBS and gadoxetic acid-enhanced MRI) in the same setting. The observed growth in FLR volume after right hemi-hepatectomy in patients with CRLM was paralleled by a comparable increase in function. Gadoxetic acid-enhanced MRI correlated strongly with HBS in the assessment of liver function. Among the pre-operative parameters, those derived from gadoxetic acid-enhanced MRI had the strongest correlation to both functional and volumetric growth during the first week after hepatectomy.
Previous studies have shown a discrepancy between liver volume growth and liver function with faster increase in function than in volume after portal vein embolization but the opposite after first stage of associating liver partition and portal vein ligation for staged hepatectomy. 5–8,10 However, the MRI parameter LMR did not change significantly after surgery in our cohort, indicating that the regenerated liver had similar functional capacity per volume as pre-operatively. If the volumetric increase had been due to swelling or to less functional parenchyma, there would have been less function per volume and a lower LMR post-operatively would have been observed. This is further supported by the consistent relation between increase in FLR function and volume. A similar finding was observed 3 months post-operatively in patients undergoing portal vein embolization prior to hepatectomy. 11
In our study, good consistency among the three modalities was observed, which may be interpreted by the fact that hepatocyte transport pathways are identical for mebrofenin and gadoxetic acid (OATP1B1 and OATP1B3) 13 and to an extent similar to ICG (OATP1B3 and sodium taurocholate cotransporting polypeptide). 14,19,21 On pre-operative imaging, LMR was significantly correlated to ICG-R15, implying that LMR may substitute ICG-R15 for liver function assessment. In addition, pre-operative MRI-based parameters (LSR) significantly correlated to a HBS-based parameter (sFLR-F) (r = −0.71), which was in line with a previous investigation that compared gadoxetic acid-enhanced MRI and HBS in patients undergoing portal vein embolization. 22 Rassam et al reported a similar result, in which a significant correlation was observed between dynamic hepatic contrast enhanced MRI and HBS, both of whole liver and of FLR, with a correlation coefficient of 0.70 and 0.89 respectively. 14
Among the pre-operative parameters, LMR had the strongest correlation to liver growth. Good post-operative liver growth, which indicates a good liver function reserve, may reduce the risk of post-hepatectomy liver failure. 23 LMR might in the future assist surgeons to reach a decision when the sFLR-V is marginal for a major liver resection. Besides, although liver growth was a surrogate variable in this study, it is an important parameter in regenerative surgery, such as portal vein embolization. 8 Numerous studies have reported encouraging results on gadoxetic acid-enhanced MRI-based prediction of post-hepatectomy liver failure. 15,24,25 In addition, gadoxetic acid-enhanced MRI supplies not only accurate anatomical information, but also reliable assessment of global and regional liver function, making it a potential “one-stop-shop” modality prior to hepatectomy. Furthermore, MRI-based liver function information can be obtained from clinical routine work-up, with no additional or delayed contrast phases/sequences needed. Another advantage is that MRI is not associated with ionizing radiation. Gadoxetic acid-enhanced MRI can also be used to diagnose and grade fibrosis, providing additional information when planning a major hepatectomy. 26,27 In this context, gadoxetic acid- enhanced MRI could outperform ICG and HBS in pre-operative liver function evaluation.
There are some limitations to be acknowledged. Firstly, although it was prospective study, the number of study subjects was small, making the statistical power weak. On the other hand, our pilot study can serve as the basis for power analysis for future research. Secondly, ICG, mebrofenin and gadoxetic acid can potentially interfere with each other. However, given the fact that the half-life time clearance of ICG, mebrofenin and gadoxetic acid are 3–5 min, 28 17 min 29 and 1.8 h 30 respectively, it can be assumed that sufficient time had passed to avoid interaction. Thirdly, as this was an observational pilot study, we selected liver growth after hepatectomy as a surrogate variable for more clinically relevant outcomes. Although a strong correlation between LMR and KGR-V was observed, the association between LMR and other clinical events, such as post-hepatectomy liver failure, still requires further research with a larger sample size cohort. Lastly, there are other quantitative liver function parameters that can be derived from gadoxetic acid-enhanced MRI, which were not included in our study, such as T1 relaxometry-based parameters (for instance T1 relaxation time or hepatic uptake rate), or dynamic contrast-enhanced MRI parameters including hepatic extraction fraction and mean transit time. 31
In conclusion, patients with CRLM experienced a similar FLR function and volume increase in the early stage after hepatectomy. Gadoxetic acid-enhanced MRI may replace HBS for regional liver function assessment in the future. Pre-operative gadoxetic acid-enhanced MRI is promising as an imaging tool for liver growth prediction.
Footnotes
Acknowledgements: The authors would like to express their appreciations to Mattias Karlsson for his assistance in hepatobiliary scintigraphy examination.
Competing interests: The authors declare that they have no conflict of interest.
Funding: Ernesto Sparrelid was supported by grants from the Bengt Ihre Foundation, the Center for Innovative Medicine at Karolinska Institutet and Region Stockholm. The funding sources were not involved in the design or conduct of the study, the writing of the report or the decision to submit the article for publication. Qiang Wang receives a scholarship from the China Scholarship Council (CSC, No. 201907930009).
Patient consent: Written informed consent was obtained from all patients before enrolling to this study.
Ethics approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This prospective study was approved by the National Ethics Review Board, Sweden (No. 2012/583-31/4).
Disclosure: Not applicable.
Contributors: Not applicable.
Contributor Information
Qiang Wang, Email: wangqiang0685@outlook.com, qiang.wang@ki.se.
Torkel B. Brismar, Email: torkel.brismar@ki.se.
Stefan Gilg, Email: stefan.gilg@ki.se.
Eduard Jonas, Email: eduard.jonas@uct.ac.za.
Henrik Nilsson, Email: henrik.nilsson@ki.se.
Antonios Tzortzakakis, Email: antonios.tzortzakakis@ki.se.
Bengt Isaksson, Email: bengt.isaksson@akademiska.se.
Rimma Axelsson, Email: rimma.axelsson@ki.se.
Ernesto Sparrelid, Email: ernesto.sparrelid@ki.se.
REFERENCES
- 1. Kishi Y, Abdalla EK, Chun YS, Zorzi D, Madoff DC, Wallace MJ, et al. Three hundred and one consecutive extended right hepatectomies: evaluation of outcome based on systematic liver volumetry. Ann Surg 2009; 250: 540–48. doi: 10.1097/SLA.0b013e3181b674df [DOI] [PubMed] [Google Scholar]
- 2. Breitenstein S, Apestegui C, Petrowsky H, Clavien PA. “State of the art” in liver resection and living donor liver transplantation: a worldwide survey of 100 liver centers. World J Surg 2009; 33: 797–803. doi: 10.1007/s00268-008-9878-0 [DOI] [PubMed] [Google Scholar]
- 3. Nilsson H, Blomqvist L, Douglas L, Nordell A, Janczewska I, Näslund E, et al. Gd-EOB-DTPA-enhanced MRI for the assessment of liver function and volume in liver cirrhosis. Br J Radiol 2013; 86(1026): 20120653. doi: 10.1259/bjr.20120653 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Nilsson H, Karlgren S, Blomqvist L, Jonas E. The inhomogeneous distribution of liver function: possible impact on the prediction of post-operative remnant liver function. HPB (Oxford) 2015; 17: 272–77. doi: 10.1111/hpb.12348 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Sparrelid E, Jonas E, Tzortzakakis A, Dahlén U, Murquist G, Brismar T, et al. Dynamic evaluation of liver volume and function in associating liver partition and portal vein ligation for staged hepatectomy. J Gastrointest Surg 2017; 21: 967–74. doi: 10.1007/s11605-017-3389-y [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Olthof PB, Tomassini F, Huespe PE, Truant S, Pruvot F-R, Troisi RI, et al. Hepatobiliary scintigraphy to evaluate liver function in associating liver partition and portal vein ligation for staged hepatectomy: liver volume overestimates liver function. Surgery 2017; 162: 775–83. doi: 10.1016/j.surg.2017.05.022 [DOI] [PubMed] [Google Scholar]
- 7. Tomassini F, D’Asseler Y, Linecker M, Giglio MC, Castro-Benitez C, Truant S, et al. Hepatobiliary scintigraphy and kinetic growth rate predict liver failure after ALPPS: a multi-institutional study. HPB (Oxford) 2020; 22: 1420–28. doi: 10.1016/j.hpb.2020.01.010 [DOI] [PubMed] [Google Scholar]
- 8. Guiu B, Quenet F, Panaro F, Piron L, Cassinotto C, Herrerro A, et al. Liver venous deprivation versus portal vein embolization before major hepatectomy: future liver remnant volumetric and functional changes. Hepatobiliary Surg Nutr 2020; 9: 564–76. doi: 10.21037/hbsn.2020.02.06 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Møller S, la Cour Sibbesen E, Madsen JL, Bendtsen F. Indocyanine green retention test in cirrhosis and portal hypertension: accuracy and relation to severity of disease. J Gastroenterol Hepatol 2019; 34: 1093–99. doi: 10.1111/jgh.14470 [DOI] [PubMed] [Google Scholar]
- 10. Vos JJ, Wietasch JKG, Absalom AR, Hendriks HGD, Scheeren TWL. Green light for liver function monitoring using indocyanine green? an overview of current clinical applications. Anaesthesia 2014; 69: 1364–76. doi: 10.1111/anae.12755 [DOI] [PubMed] [Google Scholar]
- 11. Shen Y-N, Zheng M-L, Guo C-X, Bai X-L, Pan Y, Yao W-Y, et al. The role of imaging in prediction of post-hepatectomy liver failure. Clin Imaging 2018; 52: 137–45. doi: 10.1016/j.clinimag.2018.07.019 [DOI] [PubMed] [Google Scholar]
- 12. Yoon JH, Lee JM, Kang H-J, Ahn SJ, Yang H, Kim E, et al. Quantitative assessment of liver function by using gadoxetic acid-enhanced MRI: hepatocyte uptake ratio. Radiology 2019; 290: 125–33. doi: 10.1148/radiol.2018180753 [DOI] [PubMed] [Google Scholar]
- 13. Joo I, Lee JM. Recent advances in the imaging diagnosis of hepatocellular carcinoma: value of gadoxetic acid-enhanced MRI. Liver Cancer 2016; 5: 67–87. doi: 10.1159/000367750 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Rassam F, Zhang T, Cieslak KP, Lavini C, Stoker J, Bennink RJ, et al. Comparison between dynamic gadoxetate-enhanced MRI and 99mtc-mebrofenin hepatobiliary scintigraphy with SPECT for quantitative assessment of liver function. Eur Radiol 2019; 29: 5063–72. doi: 10.1007/s00330-019-06029-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Wang Q, Wang A, Sparrelid E, Zhang J, Zhao Y, Ma K, et al. Predictive value of gadoxetic acid-enhanced MRI for posthepatectomy liver failure: a systematic review. Eur Radiol 2022; 32: 1792–1803. doi: 10.1007/s00330-021-08297-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Haimerl M, Verloh N, Fellner C, Zeman F, Teufel A, Fichtner-Feigl S, et al. MRI-based estimation of liver function: gd-EOB-DTPA-enhanced T1 relaxometry of 3T vs. the MELD score. Sci Rep 2014; 4: 5621. doi: 10.1038/srep05621 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Tamada T, Ito K, Higaki A, Yoshida K, Kanki A, Sato T, et al. Gd-EOB-DTPA-enhanced MR imaging: evaluation of hepatic enhancement effects in normal and cirrhotic livers. Eur J Radiol 2011; 80: e311–6. doi: 10.1016/j.ejrad.2011.01.020 [DOI] [PubMed] [Google Scholar]
- 18. Kamimura K, Fukukura Y, Yoneyama T, Takumi K, Tateyama A, Umanodan A, et al. Quantitative evaluation of liver function with T1 relaxation time index on gd-EOB-DTPA-enhanced MRI: comparison with signal intensity-based indices. J Magn Reson Imaging 2014; 40: 884–89. doi: 10.1002/jmri.24443 [DOI] [PubMed] [Google Scholar]
- 19. Yamada A, Hara T, Li F, Fujinaga Y, Ueda K, Kadoya M, et al. Quantitative evaluation of liver function with use of gadoxetate disodium-enhanced MR imaging. Radiology 2011; 260: 727–33. doi: 10.1148/radiol.11100586 [DOI] [PubMed] [Google Scholar]
- 20. Ribero D, Chun YS, Vauthey JN. Standardized liver volumetry for portal vein embolization. Semin Intervent Radiol 2008; 25: 104–9. doi: 10.1055/s-2008-1076681 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Ba-Ssalamah A, Bastati N, Wibmer A, Fragner R, Hodge JC, Trauner M, et al. Hepatic gadoxetic acid uptake as a measure of diffuse liver disease: where are we? J Magn Reson Imaging 2017; 45: 646–59. doi: 10.1002/jmri.25518 [DOI] [PubMed] [Google Scholar]
- 22. Donadon M, Lanza E, Branciforte B, Muglia R, Lisi C, Pedicini V, et al. Hepatic uptake index in the hepatobiliary phase of gadolinium ethoxybenzyl diethylenetriamine penta acetic acid-enhanced magnetic resonance imaging estimates functional liver reserve and predicts post-hepatectomy liver failure. Surgery 2020; 168: 419–25. doi: 10.1016/j.surg.2020.04.041 [DOI] [PubMed] [Google Scholar]
- 23. Guiu B, Quenet F, Escal L, Bibeau F, Piron L, Rouanet P, et al. Extended liver venous deprivation before major hepatectomy induces marked and very rapid increase in future liver remnant function. Eur Radiol 2017; 27: 3343–52. doi: 10.1007/s00330-017-4744-9 [DOI] [PubMed] [Google Scholar]
- 24. Cieslak KP, Runge JH, Heger M, Stoker J, Bennink RJ, van Gulik TM. New perspectives in the assessment of future remnant liver. Dig Surg 2014; 31: 255–68. doi: 10.1159/000364836 [DOI] [PubMed] [Google Scholar]
- 25. Iimuro Y. ICG clearance test and 99mtc-GSA SPECT/CT fusion images. Visc Med 2017; 33: 449–54. doi: 10.1159/000479046 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Van Beers BE, Pastor CM, Hussain HK. Primovist, eovist: what to expect? J Hepatol 2012; 57: 421–29. doi: 10.1016/j.jhep.2012.01.031 [DOI] [PubMed] [Google Scholar]
- 27. de Graaf W, Häusler S, Heger M, van Ginhoven TM, van Cappellen G, Bennink RJ, et al. Transporters involved in the hepatic uptake of (99m)tc-mebrofenin and indocyanine green. J Hepatol 2011; 54: 738–45. doi: 10.1016/j.jhep.2010.07.047 [DOI] [PubMed] [Google Scholar]
- 28. de Graaf W, van Lienden KP, van den Esschert JW, Bennink RJ, van Gulik TM. Increase in future remnant liver function after preoperative portal vein embolization. Br J Surg 2011; 98: 825–34. doi: 10.1002/bjs.7456 [DOI] [PubMed] [Google Scholar]
- 29. Wang Y, Zhang L, Ning J, Zhang X, Li X, Zhang L, et al. Preoperative remnant liver function evaluation using a routine clinical dynamic gd-EOB-DTPA-enhanced MRI protocol in patients with hepatocellular carcinoma. Ann Surg Oncol 2021; 28: 3672–82. doi: 10.1245/s10434-020-09361-1 [DOI] [PubMed] [Google Scholar]
- 30. Orimo T, Kamiyama T, Kamachi H, Shimada S, Nagatsu A, Asahi Y, et al. Predictive value of gadoxetic acid enhanced magnetic resonance imaging for posthepatectomy liver failure after a major hepatectomy. J Hepatobiliary Pancreat Sci 2020; 27: 531–40. doi: 10.1002/jhbp.769 [DOI] [PubMed] [Google Scholar]
- 31. Yang D, Li D, Li J, Yang Z, Wang Z. Systematic review: the diagnostic efficacy of gadoxetic acid-enhanced MRI for liver fibrosis staging. Eur J Radiol 2020; 125: 108857: S0720-048X(20)30046-2. doi: 10.1016/j.ejrad.2020.108857 [DOI] [PubMed] [Google Scholar]
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