Hepatic Extraction Fraction Research Articles

Non-contrast based approach for liver function quantification using Bayesian-based intravoxel incoherent motion diffusion weighted imaging: A pilot study.

Liver cirrhosis disrupts liver function and tissue perfusion, detectable by magnetic resonance imaging (MRI). Assessing liver function at the voxel level with 13-b value intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) could aid in radiation therapy liver-sparing treatment for patients with early impairment. This study aimed to evaluate the feasibility of IVIM-DWI for liver function assessment and correlate it with other multiparametric (mp) MRI methods at the voxel level. This study investigates the variability of apparent diffusion coefficient (ADC) derived from 13-b value IVIM-DWI and B1-corrected dual flip angle (DFA) T1 mapping. Experiments were conducted in-vitro with QIBA and NIST phantoms and in 10 healthy volunteers for IVIM-DWI. Additionally, 12 patients underwent an mp-MRI examination. The imaging protocol included a 13-b value IVIM-DWI sequence for generating IVIM parametric maps. B1-corrected DFA T1 pulse sequence was used for generating T1 maps, and Gadoxatate low temporal resolution dynamic contrast-enhanced (LTR-DCE) MRI was used for generating the Hepatic extraction fraction (HEF) map. The Mann-Whitney U test was employed to compare IVIM-DWI parameters (Pure Diffusion, Dslow ; Pseudo diffusion, Dfast ; and Perfusion Fraction, Fp ) between the healthy volunteer and patient groups. Furthermore, in the patient group, statistical correlations were assessed at a voxel level between LTR-DCE MRI-derived HEF, T1 post-Gadoxetate administration, ΔT1%, and various IVIM parameters using Pearson correlation. For-vitro measurements, the maximum coefficient of variation of the ADC and T1 parameters was 12.4% and 16.1%, respectively. The results also showed that Fp and Dfast were able to distinguish between healthy liver function and mild liver function impairment at the global level, with p=0.002 for Fp and p<0.001 for Dfast . Within the patient group, these parameters also exhibited a moderate correlation with HEF at the voxel level. Overall, the study highlighted the potential of Dfast and Fp for detecting liver function impairment at both global and pixel levels.

Towards a model of biliary atresia - Pilot feasibility study in newborn piglets

Biliary atresia (BA) is a rare congenital liver disease with unknown etiology, and it is the most common indication for liver transplantation in children. As BA infants suffer from intestinal malabsorption and neurodevelopmental deficits, it is necessary to identify optimal medical and nutritional strategies using appropriate neonatal animal models. We aim to determine the feasibility of using newborn piglets with surgically induced cholestasis (bile duct ligation (BDL)) to mimic clinical features of BA. Six piglets were subjected to abdominal surgery on day 4 after birth. The bile ducts were ligated, and the piglet were followed for up to 12 days. On day 12 the piglets were subjected to a hepatobiliary scintigraphy using the tracer radiolabeled Technetium(99m-tc)-mebrofenin, and blood samples were collected for biochemical profiling. Of the six piglets, hepatobiliary scintigraphy verified that two piglets (BDL) had no excretion of bile into the duodenum, i.e. full cholestasis with a hepatic extraction fraction of 84–87% and clearance time of 230–318 min. One piglet (SHAM) had bile excretion to the duodenum. In accordance with this, the BDL piglets had steatorrhea, and increased levels of bilirubin and gammaglutamyl transferase (GGT). The last three piglets were euthanized due to bile leakage or poor growth. Surgically induced cholestasis in young piglets, may offer an animal model that displays clinical characteristics of biliary atresia, including malabsorption, hyperbilirubinaemia, increased GGT and reduced hepatic excretory function. Following refinement, this animal model may be used to optimize feeding strategies to secure optimal nutrition and neurodevelopment for neonatal cholestasis/BA patients.

Determination of hepatic extraction fraction with gadoxetate low-temporal resolution DCE-MRI-based deconvolution analysis: validation with ALBI score and Child-Pugh class.

In this study, we aimed to investigate the feasibility of gadoxetate low-temporal resolution (LTR) DCE-MRI for voxel-based hepatic extraction fraction (HEF) quantification for liver sparing radiotherapy using a deconvolution analysis (DA) method. The accuracy and consistency of the deconvolution implementation in estimating liver function was first assessed using simulation data. Then, the method was applied to DCE-MRI data collected retrospectively from 64 patients (25 normal liver function and 39 cirrhotic patients) to generate HEF maps. The normal liver function patient data were used to measure the variability of liver function quantification. Next, a correlation between HEF and ALBI score (a new model for assessing the severity of liver dysfunction) was assessed using Pearson's correlation. Differences in HEF between Child-Pugh score classifications were assessed for significance using the Kruskal-Wallis test for all patient groups and Mann-Whitney U-test for inter-groups. A statistical significance was considered at a P-value <0.05 in all tests. The results showed that the implemented method accurately reproduced simulated liver function; root-mean-square error between estimated and simulated liver response functions was 0.003, and the coefficient-of-variance of HEF was <20%. HEF correlation with ALBI score was r = -0.517, P < 0.0001, and HEF was significantly decreased in the cirrhotic patients compared to normal patients (P < 0.0001). Also, HEF in Child-Pugh B/C was significantly lower than in Child-Pugh A (P = 0.024). The study demonstrated the feasibility of gadoxetate LTR-DCE MRI for voxel-based liver function quantification using DA. HEF could distinguish between different grades of liver function impairment and could potentially be used for functional guidance in radiotherapy.

Quantitative evaluation of liver function with gadoxetic acid enhanced MRI: Comparison among signal intensity-, T1-relaxometry-, and dynamic-hepatocyte-specific-contrast-enhanced MRI- derived parameters

Aims Three types of gadoxetic acid enhanced MRI parameters have been proposed to quantify liver function. However, until now there is no consensus on which one that has the greatest potential for use in clinical practice. This study was conducted to compare the efficacy of three types of gadoxetic acid enhanced MR parameters for quantitative assessment of liver function. Methods Imaging data of 10 patients with chronic liver disease and 20 healthy volunteers were analyzed. Parameters based on signal intensity(SI), T1 changes or dynamic-hepatocyte-specific-contrast-enhancement MR were calculated. Their mutual correlations, discriminatory capacity between cirrhotic and healthy liver and correlations with Child-Pugh score and Model for end-stage liver-disease (MELD) were estimated. Results The strongest correlations were observed between relative enhancement of the liver and T1 time at 20 min after contrast agent injection, and between liver-spleen contrast ratio at 20 min after contrast agent injection and hepatic uptake rate (|r|> 0.90, p < .05, both). All parameters but input-relative blood flow (p = 0.17) were significantly different between patient and control group (p < .05), with AUROCs of liver-to-muscle ratio (LMR), increase of LMR and hepatic extraction fraction greater than 0.90 (p < .05). Liver-to-spleen ratio, LMR and hepatic uptake index presented a strong correlation with Child-Pugh score and MELD (|r|> 0.8, p < .05). Conclusion Simple SI-based parameters were as good as more complex parameters in evaluating liver function at gadoxetic acid enhanced MR. In clinical routine LMR seems to be the easiest-to-use parameter for quantitative evaluation of liver function.

In-vitro and in-vivo functional observation studies to establish therapeutic potential of alpha-ketoglutarate against methotrexate induced liver injury

BackgroundMethotrexate (MTX) is widely used in chemotherapy but its associated hepatotoxicity is a major complication, limiting its use. This study evaluates possible therapeutic effect of oral alpha-ketoglutarate (AKG) supplementation against MTX-induced hepatotoxicity. MethodsHepG2 cells were used to evaluate in-vitro cyto-protection conferred by AKG against MTX induced cytotoxicity. For in-vivo animal study, rats were divided into three groups. Group-I served as control. Group-II animals were administered single intraperitoneal injection of MTX (20 mg/kg/body weight), while Group-III received MTX as in group-II followed by oral AKG (2 gm/kg body weight) for 5 days. 99mTc-Mebrofenin hepatobiliary study was performed under a gamma camera to determine real time functional status of rats’ livers. Multiple parameters concerning hepatic mebrofenin uptake and excretion, including Tpeak and T1/2 peak in control and treated animals were determined. Biochemical analysis of the liver homogenate in terms of hepatic enzyme activities in serum, antioxidant status, tissue factor activity, tissue collagen content and histological analysis of the liver tissue were also done. ResultsAKG supplementation significantly reversed MTX induced derangement in activities of serum liver enzymes [ALT and ALP (p = 0.003); AST (p = 0.005)], antioxidant status [LPO and GSH (p = 0.005); CAT (p = 0.004)], tissue factor activity (p = 0.005) and tissue collagen content (p = 0.005). Functional imaging confirmed that hepatic retention and fractional biliary excretion were significantly abnormal in MTX treated group (Tpeak: 234 s ± 40 s; T1/2 peak: 846sec ± 32sec) as compared to AKG supplemented group (Tpeak: 144 s ± 35sec; T1/2peak: 468sec ± 27sec). Hepatic extraction fraction (HEF) was 92.2 ± 1.8%, 48.7 ± 2.6% and 69.8 ± 4.3% in control, MTX and AKG supplemented rats respectively. Conclusion99mTc-mebrofenin imaging strongly suggests therapeutic action of AKG in protecting liver damage by MTX in rats. Functional imaging parameters correlated well with biochemical and histopathological findings.

Alpha-ketoglutarate mediated hepatoprotection against alcohol induced toxicity: in vivo functional observation studies in Sprague Dawley rats using gamma scintigraphy

Alcohol is the most abused psychoactive substance and known hepatotoxicant. Present study elucidates possible therapeutic effect of oral alpha-ketoglutarate (AKG) supplementation against alcohol induced hepatic dysfunction, using biochemical, histopathological and most importantly, in vivo functional imaging approaches. Animals were divided into three groups of 6 animals each. Group-I (control): Normal saline; Group-II: 20% (v/v) solution of ethanol (5 ml/day) intragastrically using oral gavage for 2 months. Group-III: ethanol treatment as in group-II along with AKG supplementation (2g/kg/bw; intragastrically using oral gavage for 2 months). In vivo hepatobiliary scintigraphy was performed in all animals using 99mTc-mebrofenin (99mTc-MEB) as radiotracer to determine changes in (a) Hepatic extraction fraction (HEF), for quantification of radiotracer uptake, (b) Time to reach maximum hepatic uptake (Tpeak), and (c) Time for hepatic uptake to reduce by 50% (T1/2peak). Biochemical (alanine aminotransferase, aspartate aminotransferase, reduced glutathione, superoxide dismutase, catalase, and lipid peroxidation) and histological parameters were also studied. Hepatic uptake and excretion kinetics using 99mTc-MEB scintigraphy showed prompt 99mTc-MEB clearance from liver in control group (HEF: 91.26 ± 2.32; Tpeak: 143 ± 23 sec; T1/2peak: 434 ± 41 sec), while it was significantly abnormal in ethanol group and showed less efficient radiotracer accumulation (HEF: 62.72 ± 5.6; Tpeak: 201 ± 33 sec; T1/2peak: 542 ± 52 sec). Supplementation of AKG along with ethanol significantly improved liver function (HEF: 76.42 ± 5.3; Tpeak: 155 ± 34 sec; T1/2peak: 455 ± 22 sec). Biochemical and histopathology parameters were correlative to findings of functional imaging study. Results strongly indicate hepatoprotective potential of AKG against alcohol-induced hepatic injury. Study further proposes the use of in vivo hepatobiliary scintigraphy for high throughput screening of other hepatoprotectants.

Lipoic Acid Prevents High-Fat Diet-Induced Hepatic Steatosis in Goto Kakizaki Rats by Reducing Oxidative Stress Through Nrf2 Activation.

Prevention of hepatic fat accumulation may be an important approach for liver diseases due to the increased relevance of hepatic steatosis in this field. This study was conducted to investigate the effects of the antioxidant α-lipoic acid (α-LA) on hepatic steatosis, hepatocellular function, and oxidative stress in a model of type 2 diabetes fed with a high fat diet (HFD). Goto-Kakizaki rats were randomly divided into four groups. The first group received only a standard rat diet (control GK) including groups 2 (HFD), 3 (vehicle group), and 4 (α-LA group), which were given HFD, ad libitum during three months. Wistar rats are the non-diabetic control group. Carbohydrate and lipid metabolism, liver function, plasma and liver tissue malondialdehyde (MDA), liver GSH, tumor necrosis factor-α (TNF-α) and nuclear factor E2 (erythroid-derived 2)-related factor-2 (Nrf2) levels were assessed in the different groups. Liver function was assessed using quantitative hepatobiliary scintigraphy, serum aspartate, and alanine aminotransferases (AST, ALT), alkaline phosphatase, gamma-glutamyltranspeptidase, and bilirubin levels. Histopathologically steatosis and fibrosis were evaluated. Type 2 diabetic animals fed with HFD showed a marked hepatic steatosis and a diminished hepatic extraction fraction and both were fully prevented with α-LA. Plasma and liver tissue MDA and hepatic TNF-α levels were significantly higher in the HFD group when compared with the control group and significantly lower in the α-LA group. Systemic and hepatic cholesterol, triglycerides, and serum uric acid levels were higher in hyperlipidemic GK rats and fully prevented with α-LA. In addition, nuclear Nrf2 activity was significantly diminished in GK rats and significantly augmented after α-LA treatment. In conclusion, α-LA strikingly ameliorates steatosis in this animal model of diabetes fed with HFD by decrementing the inflammatory marker TNF-α and reducing oxidative stress. α-LA might be considered a useful therapeutic tool to prevent hepatic steatosis by incrementing antioxidant defense systems through Nrf2 and consequently decreasing oxidative stress and inflammation in type 2 diabetes.

The utility of genomics and functional imaging to predict irinotecan pharmacokinetics and pharmacodynamics: The PREDICT IR study.

2564 Background: BSA-based dosing of Irinotecan (IR), does not account for its pharmacokinetic (PK) and pharmacodynamic (PD) variability. Given IR’s unique metabolism, functional hepatic nuclear imaging (HNI) with probes for hepatic transporters correlated with its PK. This study further evaluated the utility of HNI combined with extensive excretory/metabolic/PD pharmacogenomics (PG) to predict IR PK and PD in patients (pts) treated with FOLFIRI to enable dose individualization. Methods: Eligible pts had advanced colorectal cancer, suitable for 1st/2nd-line FOLFIRI± Bevacizumab. Pts had blood analyzed by Affymetrix DMET™ Plus Array and additional SNPs were genotyped. For HNI, pts were given IV 250MBq 99mTc-IDA and imaging data analyzed for hepatic extraction/excretion parameters (clearance [CL], 1hour retention [1hRET], deconvulutional CL [DeCL], hepatic extraction fraction [HEF]). Pts treated with chemotherapy, q2-weekly, and restaged after 4 cycles. Blood taken for IR and metabolite (SN38, SN38G) analysis on day 1 cycle 1, PK parameters derived by non-compartmental analysis. Statistical correlations were evaluated between (i) IDA HNI and (2) PGs, with IR PK, toxicity, objective response (ORR) and progression-free survival (PFS). Results: 32 pts analysed, 31 pts completed 4 cycles. (1) PK correlates: (a) HNI CL and 1hRET with SN38 Metabolic CL, (P = 0.04) and (b) HNI DeCL with IR AUC(0-∞) (P = 0.04). (2) Grade 3+ diarrhea (N = 4, 13%) predicted by SN38 AUC(0-∞) and Metabolic CL (P = 0.04), and gene variants for SCL22A2 and -28A3, ABCC2, UGT2B17, CYP2C18 and DPYD (P &lt; 0.05). (3) Grade 3+ neutropenia (N = 9, 28%) predicted by SN38 PK exposure (P &lt; 0.02), HNI CL and 1hRET (P &lt; 0.0001) and variants for SLC7A7-, SLC22A2-, CHST1-, UGT1A1-, -2B7, ABCB1. (4) ORR (N = 6, 20%) predicted by Methylene tetrahydrofolate reductase (MTHFR) 677C &gt; T (P = 0.002), SN38 exposure (P &lt; 0.003), and variants in metabolic/transporter genes (P &lt; 0.05). (5) PFS by SN38 PK exposure, MTHFR 677C &gt; T, HNI CL, HNI HEF and variants in PK genes (P &lt; 0.05). Conclusions: Hepatic functional imaging with extensive pharmacogenomics correlate with Irinotecan PK and PD enabling the development of nomograms to individualize dosing. Clinical trial information: ACTRN12610000898055.

Hepatic gadoxetic acid uptake as a measure of diffuse liver disease: Where are we?

3 J. Magn. Reson. Imaging 2017;45:646-659.

Pre-treatment estimation of future remnant liver function using gadoxetic acid MRI in patients with HCC

This study aimed to determine whether the predicted remnant liver function on dynamic hepatocyte-specific contrast media-enhanced magnetic resonance (DHCE-MR) imaging correlates with the results of the indocyanin green retention test (ICG R15) after hepatic resection or radiofrequency ablation (RFA). This prospective multicenter study was approved by the Institutional Review Boards of each hospital. Informed consents were obtained from all. DHCE-MRI and ICG R15 were performed in 57 patients scheduled to undergo hepatectomy or RFA for hepatocellular carcinoma, once before treatment and repeated on post-treatment day 3. In nine donors and three recipients, DHCE-MRI and ICG R15 were performed only preoperatively. The predicted remnant liver function (HEFml) was estimated using the hepatic extraction fraction (HEF) multiplied by the remnant liver volume, and compared with post-treatment ICG R15. Intra-individual heterogeneity of HEF was assessed using pooled coefficients of variation (CV) among hepatic segments. Finally, development of post-treatment hepatic failure was assessed according to the 50-50 criteria on post-treatment day 5. Predicted remnant HEFml showed a negative correlation with post-treatment ICG R15 (r=-0.45, p=0.001), whereas liver volume did not (p>0.05). There were significant correlations between pre-treatment HEFml and pre-treatment ICG R15 (r=-0.33, p=0.006) and between post-treatment HEFml and post-treatment ICG R15 (r=-0.54, p<0.001). Pooled CV among segmental HEFs was 12.6%. No patients showed post-treatment liver failure on post-treatment day 5. DHCE-MRI using Gd-EOB-DTPA was able to provide both global and segmental liver function information, and post-treatment remnant liver function predicted on pre-treatment DHCE-MRI showed a significant negative correlation with post-treatment ICG R15. Post-treatment liver function could be predicted at pre-treatment DHCE-MRI. Liver function was heterogeneous among the liver segments. Liver anatomy, disease extent, and underlying liver function can be assessed in one DHCE-MRI examination. ClinicalTrials.gov number, NCT01490203.

Результаты резекционных вмешательств на печени на фоне хронической диффузной гепатопатии

Relevance Improvement of the technical aspects of performing liver resections allowed to neutralize the risk of many specific postresection complications. However, among the last until now, post-resection hepatic failure (PHF) remains a difficult problem, which on the background of diffuse changes in the liver, significantly complicates the postoperative period. The purpose of the study To evaluate an influence of concomitant chronic diffuse liver disease on the results of resections performed for benign and malignant focal lesions of the liver. Materials and methods To assess the impact of chronic diffuse liver process in the frequency of complications of liver resections analyzed a control group of patients (81 patients), operated in the department of surgery of the liver and biliary tract and in the department of surgery of portal hypertension and pancreatoduodenal zone during the period from 1998 to 2009. Patients were divided into a group with concomitant diffuse liver disease (chronic viral hepatitis and steatosis) - 53 patients (65.4%) and a group of 28 patients without concomitant liver pathology. Results and their discussion Study the frequency of PHF showed that the development of severe complications in the early postoperative period is clearly correlated with the presence of diffuse liver disease. Thus, in patients without chronic liver diseasePHF occurred in 2 cases against the background of extensive liver resections, which amounted to 7.1% (2/28). In patients with hepatic pathology, the incidence of PHF of varying severity amounted to 18.9% (10/53). The overall incidence of PHF in the study group was 14.8% (12/81). On the background of extensive liver resections PHF complicated the postoperative period, more than twice as often in the presence of chronic liver disease, 28.6% versus 13.3% (8/28 vs. 2/13). At segmental resections PHF occurred only in patients with chronic pathologies in the liver and was 8.0%. The presence of concomitant chronic diffuse liver disease causes a significant decrease in functional status of hepatocytes, which represents a decline of hepatic extraction fraction at 17,1% (67,5 ± 2,3% against 81,4 ± 1,9%) and an increase in half-life of the radiopharmaceutical drop to 26 5% (37,2 ± 1,7 min vs. 29,4 ± 1,2 m) (P <0,001) relative to the group without parenchymatous processes. Conclusion Performing of resection interventions in focal liver disease with chronic diffuse pathology of a liver increases the risk of PHF, which is associated with reduced functional reserve of hepatocytes and slowing compensatory regeneration process.

Cyclosporin A, but not tacrolimus, negatively affects the hepatic extraction fraction of hepatobiliary scintigraphy in liver transplant recipients.

BackgroundHepatobiliary scintigraphy using 99mTc-mebrofenin has been used as an investigation to study liver function after liver transplantation (LTx). Hepatic extraction fraction (HEF) is a measurement of the hepatic extraction efficiency and hepatic extraction rate. With the purpose of evaluating a possible diverging effect of cyclosporin A (CSA) and tacrolimus (TAC) on the HEF, we compared the HEF with biochemical and histological parameters in LTx patients receiving either CSA or TAC.MethodsThirty-nine adult patients who underwent LTx due to hepatitis C virus (HCV) cirrhosis were evaluated. All patients underwent a 3-month and 1-year follow-up that included hepatobiliary scintigraphy and biochemistry tests. Liver biopsy was performed at 1 year. These clinical parameters were compared between the two groups, TAC (n = 15) and CSA (n = 24).ResultsThe average HEF was significantly lower in the CSA group compared to the TAC group both at 3 months and 1 year after LTx. The liver biochemistry tests, average donor and recipient age, average cold ischemia time (CIT), and a clearance were comparable in the two groups. The TAC group had more inflammation than the CSA group. Moreover, three patients who converted from CSA to TAC increased their HEF values.ConclusionsCSA-treated patients presented a lower HEF value on hepatobiliary scintigraphy in spite of comparable liver function by traditional measurements indicating a decrease on HEF values by CSA.

Advanced fibrosis: Correlation between pharmacokinetic parameters at dynamic gadoxetate-enhanced MR imaging and hepatocyte organic anion transporter expression in rat liver.

To compare the value of enhancement and pharmacokinetic parameters measured at dynamic gadoxetate-enhanced magnetic resonance (MR) imaging in determining hepatic organic anion transporter expression in control rats and rats with advanced liver fibrosis. Institutional animal review board approval was received before the study began. Advanced liver fibrosis was created in rats by means of carbon tetrachloride injections over an 8-week period. In 17 rats with liver fibrosis and eight control rats, dynamic gadoxetate-enhanced MR images of the liver were obtained during 1 hour after injection of 0.025 mmol gadoxetate per kilogram of body weight. Enhancement parameters (maximum enhancement [Emax], time to peak [Tmax], and elimination half-life) were measured on enhancement-versus-time curves, and pharmacokinetic parameters (hepatic extraction fraction [HEF] and mean residence time [MRT]) were obtained by means of deconvolution analysis of the concentration-versus-time curves in the liver and the portal vein. The parameters were correlated at simple and multiple regression analysis with the expression of the hepatic anion uptake transporter organic anion-transporting polypeptide 1A1 (Oatp1a1), the hepatobiliary transporter multidrug resistance-associated protein 2 (Mrp2), and the backflux transporter Mrp4, as determined with reverse transcription polymerase chain reaction. In rats with advanced liver fibrosis, the Emax, Tmax, HEF, and MRT decreased significantly relative to those in control rats, whereas the elimination half-life increased significantly. The enhancement and pharmacokinetic parameters correlated significantly with the expression of the transporters at simple regression analysis. At multiple regression analysis, HEF was the only parameter that was significantly associated with the expression of Oatp1a1 and Mrp2 (P < .001, r = 0.74 and P < .001, r = 0.70, respectively). The pharmacokinetic parameter HEF at dynamic gadoxetate-enhanced MR imaging is independently correlated with hepatic organic anion transporter expression.

Cyclosporin A Negatively Effects the Hepatic Extraction Fraction of Hepatobiliary Scintigraphy in Liver Transplant Recipients.

Aim of the study Hepatobiliary scintigraphy can detect post-liver transplantation (LTx) structural complications and provide information of graft function. Hepatic extraction fraction (HEF) is a measurement of the hepatic extraction efficiency and hepatic extraction rate. In this study, we compared the HEF with biochemical and histological parameters between the LTx patients receiving cyclosporin A (CSA) or tacrolimus (TAC). Methods Thirty-nine adult patients who underwent LTx due to HCV cirrhosis between March 2007 and May 2011 were evaluated. All patients underwent a three-month follow-up that included hepatobiliary scintigraphy and blood biochemistry tests (s-bilirubin, ALT, AST, ALP, and gamma-GT). The same tests were repeated at the one-year follow-up; in addition s-creatinine, Iohexol clearance and a liver biopsy were performed. These clinical parameters were compared between the two groups, TAC (n=15), and CSA (n=24). Results The average HEF was significantly lower in the CSA group compared to the TAC group both at 3-month and 1-year after transplantation (p<0.001). The liver biochemistry tests, average donor and recipient age, average cold ischemia time, and Iohexol clearance were comparable between the two groups. Histology showed that the TAC group had more inflammation than the CSA group. Moreover, three patients who converted from CSA to TAC for liver unrelated side effects between 3.7 and 6.3 months postoperatively all increased their HEF values (27 to 90%, 42 to 100%, and 13 to 26%). Conclusion CSA treated patients presented a lower HEF value on hepatobiliary scintigraphy in spite of comparable liver function by traditional measurements indicating a false decrease on HEF values by CSA. Our finding has significant clinical implications as it indicates that the assessment of the liver graft function may be misled due to the falsely low HEF values in CSA treated patients with otherwise good liver function.

Functional hepatocellular regeneration in elderly patients undergoing hepatectomy

More than 50% of liver tumours occur in patients aged 65 years or more. Assessment of functional liver regeneration capacity is crucial to minimize postoperative liver failure. We aimed to study functional hepatocellular regeneration, through scintigraphic quantification of Mebrofenin hepatic extraction fraction (HEF), after partial hepatectomy, comparing elderly patients with younger ones. One hundred and two patients undergoing partial hepatectomy for primary or secondary hepatic lesions were prospectively included and divided in two groups: Group A - 58 patients aged <65 years (33 men, 53.9 ± 8.7 years), Group B - 44 patients aged ≥65 years (32 men, 71 ± 5 years). Groups were comparable in several aspects except for the presence of cirrhosis (more common in Group B, all patients Child-Pugh score A) and the initial diagnosis (Group B - primary lesions, Group A - metastases). The scintigraphic evaluation of Mebrofenin-HEF was performed before surgery, on the 5th and 30th day post-hepatectomy. Mortality and morbidity were 3.4 and 12.1%, respectively, in Group A and 2.3 and 11.4% in Group B (n.s.). HEF values (%), T1/2 (min) and Tmax (min) showed no significant differences between the two groups: Group A (preoperative: HEF = 99.2 ± 1.5%, T1/2 = 36.7 ± 21.3, Tmax = 15 ± 6. Day 5: HEF = 96.3 ± 10.8%, T1/2 = 76.4 ± 75.9; Tmax = 13.3 ± 4.9. Day 30: HEF = 98.4 ± 5.5%, T1/2 = 38.6 ± 7.7, Tmax = 12.8 ± 3.6) and Group B (preoperative: HEF = 95.3 ± 13%, T1/2 = 38.1 ± 24.1; Tmax = 15.9 ± 9.4. Day 5: HEF = 98.4 ± 2.6%, T1/2 = 106.6 ± 131.7; Tmax = 15.1 ± 6.2. Day 30: HEF = 99 ± 2.1%, T1/2 = 40.5 ± 27; Tmax = 15.5 ± 6.7). Our results suggest that functional hepatocellular regeneration is early, fast and similar between elderly and younger patients. Thus, age alone, does not appear to represent an absolute contraindication to hepatectomy.

Dynamic gadoxetate‐enhanced MRI for the assessment of total and segmental liver function and volume in primary sclerosing cholangitis

To evaluate dynamic hepatocyte-specific contrast-enhanced MRI (DHCE-MRI) for the assessment of global and segmental liver volume and function in patients with primary sclerosing cholangitis (PSC), and to explore the heterogeneous distribution of liver function in this patient group. Twelve patients with primary sclerosing cholangitis (PSC) and 20 healthy volunteers were examined using DHCE-MRI with Gd-EOB-DTPA. Segmental and total liver volume were calculated, and functional parameters (hepatic extraction fraction [HEF], input relative blood-flow [irBF], and mean transit time [MTT]) were calculated in each liver voxel using deconvolutional analysis. In each study subject, and incongruence score (IS) was constructed to describe the mismatch between segmental function and volume. Among patients, the liver function parameters were correlated to bile duct obstruction and to established scoring models for liver disease. Liver function was significantly more heterogeneously distributed in the patient group (IS 1.0 versus 0.4). There were significant correlations between biliary obstruction and segmental functional parameters (HEF rho -0.24; irBF rho -0.45), and the Mayo risk score correlated significantly with the total liver extraction capacity of Gd-EOB-DTPA (rho -0.85). The study demonstrates a new method to quantify total and segmental liver function using DHCE-MRI in patients with PSC.

Spatially resolved assessment of hepatic function using 99mTc‐IDA SPECT

99mTc-iminodiacetic acid (IDA) hepatobiliary imaging is usually quantified for hepatic function on the entire liver or regions of interest (ROIs) in the liver. The authors presented a method to estimate the hepatic extraction fraction (HEF) voxel-by-voxel from single-photon emission computed tomography (SPECT)∕CT with a 99mTc-labeled IDA agent of mebrofenin and evaluated the spatially resolved HEF measurements with an independent physiological measurement. Fourteen patients with intrahepatic cancers were treated with radiation therapy (RT) and imaged by 99mTc-mebrofenin SPECT before and 1 month after RT. The dynamic SPECT volumes were with a resolution of 3.9 × 3.9 × 2.5 mm(3). Throughout the whole liver with approximate 50 000 voxels, voxelwise HEF quantifications were estimated and compared between using arterial input function (AIF) from the heart and using vascular input function (VIF) from the spleen. The correlation between mean of the HEFs over the nontumor liver tissue and the overall liver function measured by Indocyanine green clearance half-time (T1∕2) was assessed. Variation of the voxelwise estimation was evaluated in ROIs drawn in relatively homogeneous regions of the livers. The authors also examined effects of the time range parameter on the voxelwise HEF quantification. Mean of the HEFs over the liver estimated using AIF significantly correlated with the physiological measurement T1∕2 (r = 0.52, p = 0.0004), and the correlation was greatly improved by using VIF (r = 0.79, p < 0.0001). The parameter of time range for the retention phase did not lead to a significant difference in the means of the HEFs in the ROIs. Using VIF and a retention phase time range of 7-30 min, the relative variation of the voxelwise HEF in the ROIs was 10% ± 6% of respective mean HEF. The voxelwise HEF derived from 99mTc-IDA SPECT by the deconvolution analysis is feasible to assess the spatial distribution of hepatic function in the liver.

Predictive Models for Regional Hepatic Function Based on 99mTc-IDA SPECT and Local Radiation Dose for Physiologic Adaptive Radiation Therapy

High-dose radiation therapy (RT) for intrahepatic cancer is limited by the development of liver injury. This study investigated whether regional hepatic function assessed before and during the course of RT using 99mTc-labeled iminodiacetic acid (IDA) single photon emission computed tomography (SPECT) could predict regional liver function reserve after RT. Fourteen patients treated with RT for intrahepatic cancers underwent dynamic 99mTc-IDA SPECT scans before RT, during, and 1 month after completion of RT. Indocyanine green (ICG) tests, a measure of overall liver function, were performed within 1 day of each scan. Three-dimensional volumetric hepatic extraction fraction (HEF) images of the liver were estimated by deconvolution analysis. After coregistration of the CT/SPECT and the treatment planning CT, HEF dose-response functions during and after RT were generated. The volumetric mean of the HEFs in the whole liver was correlated with ICG clearance time. Three models, dose, priori, and adaptive models, were developed using multivariate linear regression to assess whether the regional HEFs measured before and during RT helped predict regional hepatic function after RT. The mean of the volumetric liver HEFs was significantly correlated with ICG clearance half-life time (r=-0.80, P<.0001), for all time points. Linear correlations between local doses and regional HEFs 1 month after RT were significant in 12 patients. In the priori model, regional HEF after RT was predicted by the planned dose and regional HEF assessed before RT (R=0.71, P<.0001). In the adaptive model, regional HEF after RT was predicted by regional HEF reassessed during RT and the remaining planned local dose (R=0.83, P<.0001). 99mTc-IDA SPECT obtained during RT could be used to assess regional hepatic function and helped predict post-RT regional liver function reserve. This could support individualized adaptive radiation treatment strategies to maximize tumor control and minimize the risk of liver damage.

Hepatectomy and liver regeneration: from experimental research to clinical application

The mechanisms and kinetics of hepatic growth have continuously been investigated. This study concerns liver regeneration in animal and patients who underwent partial hepatectomy evaluated by the hepatic extraction fraction (HEF) calculated through radioisotopic methods. Thirty normal Wistar rats were submitted to an 85% hepatectomy, and 95 patients with primary and secondary liver tumours were included. In animal study, the liver regeneration kinetics was assessed by HEF using 99mTc-mebrofenin, the ratio liver/bodyweight and by using bromodeoxyuridine deoxyribonucleic acid incorporation. In patient study, the liver regeneration was evaluated by calculation of HEF before surgery, 5 and 30 days after hepatectomy. In animal, we verified a positive correlation between HEF kinetics and liver/bodyweight ratio or hepatocyte proliferation evaluated by bromodeoxyuridine deoxyribonucleic acid staining after 85% hepatectomy. In the clinical arm, no statistical differences of the HEF before hepatectomy, 5 and 30 days after hepatectomy, were observed. Our results support the view that human liver regeneration commences early, is fast, non-anatomical and functionally complete 5 days after hepatectomy. The fast functional liver regeneration may have a high clinical impact particularly concerning the post-operative oncological therapeutic approaches.

Gd-EOB-DTPA-enhanced MRI for the assessment of liver function and volume in liver cirrhosis

The aims of this study were to use dynamic hepatocyte-specific contrast-enhanced MRI to evaluate liver volume and function in liver cirrhosis, correlate the results with standard scoring models and explore the inhomogeneous distribution of liver function in cirrhotic livers. 10 patients with liver cirrhosis and 20 healthy volunteers, serving as controls, were included. Hepatic extraction fraction (HEF), input relative blood flow and mean transit time were calculated on a voxel-by-voxel basis using deconvolutional analysis. Segmental and total liver volumes as well as segmental and total hepatic extraction capacity, expressed in HEFml, were calculated. An incongruence score (IS) was constructed to reflect the uneven distribution of liver function. The Mann-Whitney U-test was used for group comparison of the quantitative liver function parameters, liver volumes and ISs. Correlations between liver function parameters and clinical scores were assessed using Spearman rank correlation. Patients had larger parenchymal liver volume, lower hepatocyte function and more inhomogeneous distribution of function compared with healthy controls. The study demonstrates the non-homogeneous nature of liver cirrhosis and underlines the necessity of a liver function test able to compensate for the heterogeneous distribution of liver function in patients with diseased liver parenchyma. The study describes a new way to quantitatively assess the hepatic uptake of gadoxetate or gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid in the liver as a whole as well as on a segmental level.