Development and validation of a predictor of insufficient enhancement during the hepatobiliary phase of Gd-EOB-DTPA-enhanced magnetic resonance imaging

Abstract

Background

Insufficient enhancement of liver parenchyma negatively affects diagnostic accuracy of Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI). Currently, there is no reliable method for predicting insufficient enhancement during the hepatobiliary phase (HBP) in Gd-EOB-DTPA-enhanced MRI.

Purpose

To develop a predictor for insufficient enhancement of liver parenchyma during HBP in Gd-EOB-DTPA-enhanced MRI.

Material and Methods

In order to formulate a HBP enhancement test (HBP-ET), clinical factors associated with relative enhancement ratio (RER) of liver parenchyma were retrospectively determined from the datasets of 156 patients (Development group) who underwent Gd-EOB-DTPA-enhanced MRI between November 2012 and May 2015. The independent clinical factors were identified by Pearson’s correlation and multiple stepwise regression analysis; the performance of HBP-ET was compared to Child-Pugh score (CPS), Model for End-stage Liver Disease score (MELD), and total bilirubin (TBIL) using receiver operating characteristic (ROC) curve analysis. The datasets of 52 patients (Validation group), which were examined between June 2015 and Oct 2015, were applied to validate the HBP-ET.

Results

Six biochemical parameters independently influenced RER and were used to develop HBP-ET. The mean HBP-ET score of patients with insufficient enhancement was significantly higher than that of patients with sufficient enhancement (P < 0.001) in both the Development and Validation groups. HBP-ET (area under the curve [AUC] = 0.895) had better performance in predicting insufficient enhancement than CPS (AUC = 0.707), MELD (AUC = 0.798), and TBIL (AUC = 0.729).

Conclusion

The HBP-ET is more accurate than routine indicators in predicting insufficient enhancement during HBP, which is valuable to aid clinical decisions.

Keywords

Liver function test gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)magnetic resonance imaging (MRI)liver disease

Introduction

Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) is a liver-specific contrast agent for magnetic resonance imaging (MRI) (1). Approximately 50% of Gd-EOB-DTPA is excreted via the kidneys and the remaining 50% via the hepatobiliary system. Several studies show that Gd-EOB-DTPA is more sensitive for early detection of small focal lesions in the liver than conventional extracellular gadolinium-based contrast agents because of its specific hepatocyte uptake (2 –6). However, the enhancement of liver parenchyma during hepatobiliary phase (HBP) with Gd-EOB-DTPA is dependent on the liver function (7 –10). As a result, insufficient enhancement during HBP has been shown to compromise diagnostic accuracy in patients with impaired liver function (11 –13).

Various measures, such as extending the delay time of HBP, or changing acquisition parameters of the MRI sequence, can be taken to improve liver parenchymal enhancement during HBP if it can be predicted beforehand that the performance of Gd-EOB-DTPA-enhanced MRI will be poor (14 –17). Therefore, it is clinically important to be able to predict degree of liver parenchymal enhancement prior to conducting a Gd-EOB-DTPA-enhanced MRI.

The purpose of this study was to investigate clinical features that can influence liver enhancement during HBP in Gd-EOB-DTPA-enhanced MRI, in the interest of developing a simple and valuable predictive tool of the HBP enhancement test (HBP-ET), and then further assess the performance of HBP-ET as a predictor of the insufficient enhancement during HBP in Gd-EOB-DTPA-enhanced MRI.

Material and Methods

Patients

The Ethics Committee of our hospital approved this retrospective study. From November 2012 to October 2015, 297 patients underwent Gd-EOB-DTPA-enhanced MRI examination. Among them, 89 patients were excluded from this study. Seven patients were excluded due to poor renal function (estimated glomerular filtration rate [GFR] <30 mL/min/1.73 m²) and 26 were exclude after undergoing surgical intervention. Eight patients were excluded due to severe breathing artifacts and 18 had inaccurate delay time of HBP. In addition, nine patients were excluded due to extensive tumor growth interfering with regions of interest (ROI) on the exam and 21 patients had incomplete laboratory information.

A total of 208 patients were enrolled in this study. Twenty-nine patients with normal liver function were identified by blood tests and routine imaging studies (computed tomography [CT], MRI, or ultrasonography). The remaining 179 patients were diagnosed with underlying chronic liver disease of varied etiology, including hepatitis B (n = 139), hepatitis C (n = 26), concomitant hepatitis B and C (n = 7), clonorchis sinensis (n = 5), and alcohol-induced hepatitis (n = 2). All patients were untreated before undergoing the Gd-EOB-DTPA-enhanced MRI. Patients were divided into two groups: the Development group and the Validation group.

The Development group consisted of 156 patients (127 men, 29 women; aged 54.77 ± 13.99 years; age range, 17–79 years) who underwent Gd-EOB-DTPA-enhanced abdominal MRI between November 2012 and May 2015. This group included 18 patients with normal liver function and 138 with chronic liver disease. The RER and related clinical factors of each patient were used to screen for factors associated with enhanced degree of liver parenchyma during HBP and to formulate a scoring tool to predict the insufficient enhancement during HBP.

The Validation group consisted of the remaining 52 patients (41 men, 11 women; aged 54.69 ± 12.21 years; age range, 27–81 years) who underwent Gd-EOB-DTPA-enhanced abdominal MRI between June 2015 and October 2015. This group contained 11 patients with normal liver function and 41 with chronic liver disease. The RER and related clinical factors of these patients were used to validate the repeatability of HBP-ET.

Gd-EOB-DTPA-enhanced MRI

All MRI examinations were performed on a clinical 1.5 T MRI system (Achieva, Philips Medical Systems, Best, The Netherlands). A combination of body and spine coil elements was used for signal acquisition, with patients holding their breath in the supine position. A three-dimensional (3D), T1-weighted (T1W) and fat-suppressed sequence (3D THRIVE [3D-T1 High-Res Isotropic Vol Excitation]) was performed both before (pre-contrast) and after (post-contrast) the injection of Gd-EOB-DTPA. The post-contrast images were obtained 20 min after contrast media administration. The parameters of the 3D THRIVE sequence were: repetition time (TR), 3.36 ms; echo time (TE), 1.62 ms; flip angle (FA), 10°; matrix size, 240 × 240; field of view (FOV), 350 × 284 mm²; slice thickness, 5 mm; acquisition time, 16 s.

A dose of 0.1 mL/kg (0.025 mmol/kg) Gd-EOB-DTPA (Primovist®, Bayer China, Shanghai, PR China) was administered in a bolus at a flow rate of 1.0 mL/s with subsequent flushing with 30 mL of saline.

MRI data analysis

Four ellipsoidal ROIs sized 1.6–2.7 cm² (mean, 1.9 ± 0.7 cm²) were placed in the right lobe (anterior and posterior segments) and left lobe (medial and lateral segments) on the largest transversal slice of liver (Fig. 1a and b). Each ROI was drawn as large as possible, with care to avoid the blood vessels, focal liver lesions, and artifacts. ROIs were copied from the pre-contrast to the post-contrast images to ensure identical size and location in all sequences.

Fig. 1.

Definition of ROIs (anterior and posterior segments in the right lobe, and medial and lateral segments in the left lobe) for measurement of signal intensities of liver parenchyma in pre-contrast (a) and post-contrast (b) images.

Two radiologists, with 11 and 9 years of experience in abdominal imaging, respectively, independently measured and assessed the level of hepatic enhancement during HBP according to criteria cited from Tamada et al. (18). They were both blinded to the clinical history, laboratory tests, and final diagnosis of the patients. The signal intensity (SI) of the liver parenchyma was measured relative to the portal vein as liver-to-portal vein contrast (LPVC) and relative to the kidney as liver-to-kidney contrast (LKC) by consensus using the following 5-point grading scale: 1, hyperintense; 2, slightly hyperintense; 3, isointense; 4, slightly hypointense; and 5, hypointense. An LPVC or LKC score ≥3 indicated insufficient enhancement.

The average signal intensities of four ROIs in both pre-contrast and post-contrast images were used for data analysis. The RER of the liver parenchyma was defined as: (SI_post – SI_pre)/SI_pre (19).

Medical history and laboratory parameters

The age and weight of each patient was recorded. The medical history of each patient and various blood serum biochemical parameters of liver function were acquired within one week before or after the MRI examination. These parameters included: alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), albumin, total bilirubin (TBIL), platelet count (PLT), prothrombin time, thrombin time, activated partial thromboplastin time (APTT), and creatinine.

Predictor development

In the Development group, correlations were assessed between the clinical factors age, weight, or biochemical parameters and the RER of the liver parenchyma using Pearson’s correlation analysis. Independent variables were then subjected to a multiple stepwise regression analysis to identify overall correlation with the RER. Subsequently, the identified independent factors were scored in a semi-quantitative manner to establish HBP-ET, which was used to predict enhancement during HBP.

Predictor evaluation and validation

Spearman’s correlation analysis was used to evaluate the association between the HBP-ET score and RER. Student’s t-tests were used for comparisons of the scores and RE between subgroup A (Sufficient enhancement) and subgroup B (Insufficient enhancement) in both the Development and Validation groups. The performance of the HBP-ET score for assessing the insufficient enhancement during HBP was evaluated using receiver operating characteristic (ROC) curve analysis.

Comparison of ROC curve analysis was used to compare the performance among HBP-ET, CPS, MELD, and TBIL value in predicting the insufficient enhancement of liver parenchyma during HBP. The validation dataset was used to confirm the repeatability of results.

Statistical analysis

Concordance rates using kappa statistics between two radiologists were calculated. A kappa value of 0.20 or less indicated poor agreement; 0.21– 0.40, fair agreement; 0.41–0.60, moderate agreement; 0.61–0.80, good agreement; and 0.81–1.00, excellent agreement. Spearman’s correlation analysis, multiple stepwise regression analysis, t-tests, and chi-squared tests (McNemar’s) were performed using SPSS 14.0 (SPSS Inc., Chicago, IL, USA). ROC analysis was performed using MedCalc 11.4 (MedCalc Software, Ostend, Belgium). Statistical significance was accepted at P < 0.05 for all tests.

Results

The assessment the degree of the enhancement during HBP

Concordance rate was excellent on assessment of insufficient enhancement during HBP (kappa value = 0.856). The mean RER of insufficient subgroup was statistically lower than that of sufficient subgroup in the Development and Validation groups (Table 1).

Table 1.

Results of two-sample t-tests of mean RER between the Development and Validation groups differing in enhanced degree during HBP.

	Enhanced degree	n	Mean ± SD	t	P
Development	Sufficient enhancement	106	1.416 ± 0.391	9.309	<0.001
	Insufficient enhancement	50	0.753 ± 0.463
Validation	Sufficient enhancement	34	1.457 ± 0.399	3.481	<0.001
	Insufficient enhancement	18	1.003 ± 0.530

Establishment of HBP-ET

According to Pearson’s correlation analysis, the ALT, TBIL, prothrombin time, AST, GGT, ALP, and thrombin time correlated negatively with RER, while PLT and albumin correlated positively with RER (Table 2).

Table 2.

Clinical factors and their correlations with the RER of liver parenchyma in the Development group (n = 156).

	Mean ± SD*	r†	P
Demographic
Weight (kg)	70.55 ± 7.34	−0.123	0.126
Age (years)	54.77 ± 13.99	−0.054	0.501
Clinical signs
ALT (U/L)	50.34 ± 55.88	−0.747	<0.001
TBIL (µmol/L)	29.95 ± 38.29	−0.715	<0.001
Prothrombin time (s)	13.95 ± 3.42	−0.678	<0.001
AST (U/L)	50.24 ± 42.99	−0.671	<0.001
GGT (U/L)	103.98 ± 124.66	−0.455	<0.001
ALP (U/L)	107.88 ± 66.60	−0.390	<0.001
Thrombin time (s)	20.49 ± 2.98	−0.185	0.02
APTT (s)	30.27 ± 8.81	−0.120	0.134
Creatinine (µmol/L)	86.04 ± 61.56	0.008	0.378
TP (g/L)	70.55 ± 6.55	0.109	0.175
PLT (10⁹/L)	140.68 ± 67.67	0.493	<0.001
Albumin (g/L)	34.13 ± 10.01	0.610	<0.001

Standard deviation.

†

Pearson’s correlation coefficient.

The multiple stepwise regression analysis revealed that poor RER in patients of insufficient liver parenchymal enhancement during HBP could be predicted independently by the following abnormalities: elevated ALT, TBIL, GGT, or prothrombin time, or low levels of albumin or PLT (Table 3).

Table 3.

Multiple stepwise regression analysis of potential independent variables with RER as a dependent variable.

	Beta	P
ALT	−0.362	<0.001
TBIL	−0.177	0.007
PLT	0.181	<0.001
GGT	−0.160	<0.001
Albumin	0.147	0.006
Prothrombin time	−0.137	0.024

R = 0.861; adjusted R²= 0.731; F = 71.354; P < 0.001.

In the HBP-ET, ALT, TBIL, GGT, and prothrombin time were scored on a 4-point scale, albumin on a 3-point scale, and PLT on a 2-point scale (Table 4). The score of all parameter were summed as the final predictive score of each patient (Fig. 2). The total scores were in the range of 0–15, with the higher scores indicating poorer liver function and therefore lower RER of liver parenchyma during HBP. The number of patients in each total score was as follows: Score 0 = 20; Score 1 = 36; Score 2 = 21; Score 3 = 17; Score 4 = 17; Score 5 = 10; Score 6 = 11; Score 7 = 4; Score 8 = 1; Score 9 = 10; Score 10 = 4; Score 11 = 2; Score 12 = 2; Score 13 = 1; Score 14 = 0; Score 15 = 0.

Table 4.

The scoring scales of HBP-ET.

	HBP-ET score	n
ALT
Normal	0	98
Mild (≤2-fold NV)	1	45
Moderate (>2-fold NV)	2	9
Severe (>5-fold NV)	3	4
TBIL
Normal	0	126
Mild (≤2-fold NV)	1	25
Moderate (>2 to ≤5-fold NV)	2	3
Severe (>5-fold NV)	3	2
GGT
Normal	0	53
Mild (≤3-fold NV)	1	60
Moderate (3 to 5-fold NV)	2	22
Severe (>5-fold NV)	3	21
Prothrombin time
Normal	0	104
Mild (delay 1–4 s)	1	36
Moderate (delay 4–6 s)	2	7
Severe (delay >6 s)	3	9
Albumin
Normal (40 g/L)	0	60
Mild (25–40 g/L)	1	58
Severe (<25 g/L)	2	38
PLT
Normal	0	108
Abnormal (<10 × 10¹⁰/L)	1	48

NV, normal value.

Fig. 2.

T1W 3D THRIVE liver images of two patients at pre-contrast (a1, b1) and 20 min after contrast media injection (a2, b2). The summed HBP-ET score and RER were 2 and 1.7 in patient A and 10 and 0.60 in patient B, respectively.

Evaluation and validation of the HBP-ET

Correlation analysis: In Spearman’s correlation analysis, the HBP-ET scores were significantly correlated with the RER (Development group: r = −0.787, P < 0.001; Validation group: r = −0.727, P < 0.001; Fig. 3a and b).

Fig. 3.

Scatter plot of the correlation between HBP-ET scores and RER in the datasets of the Development (a) and Validation (b) groups.

Clinical validity: Patients in the Development and Validation groups were further stratified into a Sufficient enhancement subgroup and an Insufficient enhancement subgroup, according to the degree of enhanced image during HBP. The mean HBP-ET of the insufficient enhancement subgroup was statistically higher than that of the sufficient enhancement subgroup, in both the Development and Validation groups (Table 5).

Table 5.

Results of two-sample t-tests of mean HBP-ET scores between the Development and Validation groups differing in enhanced degree during HBP.

	Enhanced degree	n	Mean ± SD	t	P
Development	Sufficient enhancement	106	2.000 ± 1.830	−11.484	<0.001
	Insufficient enhancement	50	6.520 ± 3.059
Validation	Sufficient enhancement	34	1.971 ± 2.276	−5.844	<0.001
	Insufficient enhancement	18	6.500 ± 3.277

Performance evaluation of HBP-ET score: For the Development group, the ROC curves based on the assessment of enhanced image during HBP showed an area under the ROC curve (AUC) = 0.895, 95% confidence interval (CI) = 0.835–0.938. The HBP-ET was the best predictor for insufficient enhancement of liver parenchyma during HBP, in comparison to CPS (AUC = 0.707, 95% CI = 0.629–0.777), MELD (AUC = 0.798, 95% CI = 0.726–0.858), and TBIL (AUC = 0.729, 95% CI = 0.652–0.797). The z-test also showed the ROC curves of HBP-ET was significantly different from CPS (z = 3.490, P = 0.0005), MELD (z = 2.502, P = 0.0124), and TBIL (z = 4.368, P < 0.0001) (Fig. 4a).

Fig. 4.

HBP-ET (AUC = 0.895), CPS (AUC = 0.707), MELD (AUC = 0.798), TBIL (AUC = 0.729) ROC curve in (a) the Development group and (b) the Validation group (AUC = 0.877, 0.667, 0.739, 0.753 respectively).

In the Validation group, HBP-ET (AUC = 0.877, 95% CI = 0.775–0.952) was also better than CPS (AUC = 0.667, 95% CI = 0.522–0.791), MELD (AUC = 0.739, 95% CI = 0.598–0.851), and TBIL (AUC = 0.753, 95% CI = 0.614–0.862) in predicting insufficient enhancement during HBP. The z-test also showed the ROC curves of HBP-ET was significantly different from CPS (z = 2.015, P = 0.0439), MELD (z = 2.629, P = 0.0086), and TBIL (z = 2.537, P = 0.0112) (Fig. 4b).

Discussion

Underlying hepatic dysfunction causes a decrease in hepatocyte uptake of gadoxetic acid, reducing enhancement of the liver parenchyma during Gd-EOB-DTPA-enhanced MRI. Several studies have shown that insufficient enhancement of liver parenchyma will negatively affect the diagnostic accuracy of Gd-EOB-DTPA-enhanced MRI (12,20). Therefore, it is crucial to develop a predictor for insufficient enhancement during HBP before MRI, which would allow for optimization in image acquisition. In this study, ALT, TBIL, PLT, GGT, albumin, and prothrombin time were identified as independent factors in predicting the RER of liver parenchyma during HBP in Gd-EOB-DTPA-enhanced MRI. In addition, the HBP-ET based on the independent factors above showed better performance than CPS, MELD, TBIL in predicting insufficient enhancement during HBP.

Because Gd-EOB-DTPA shares the transport and excretion pathways with bilirubin, elevated serum TBIL levels will lead to a decrease in hepatocyte uptake and bile secretion of Gd-EOB-DTPA through competition (21), and subsequently decreases in the signal enhancement of liver parenchyma during HBP. However, it is noted that decreased RER can also be caused by hepatitis, hepatic fibrosis, and steatosis. Hence, a HBP-ET composed of various parameters is desirable for evaluating the RER of liver parenchyma during HBP in Gd-EOB-DTPA-enhanced MRI. ALT exists abundantly within the cytoplasm of hepatocytes and GGT is a sensitive indicator of bile duct obstruction. Liver function impairment can also negatively influence the synthesis of blood coagulation factors and prolong prothrombin time. Furthermore, impaired liver function will decrease the level of thrombopoietin, which will cause decreases in both albumin and PLT. In this study, all the parameters above showed a strong correlation with RER and were used to established the predictor of HBP-ET. Moreover, the mean HBP-ET score in patients with insufficient enhancement during HBP was significantly higher than in patients classified as sufficient enhancement and it was closely correlated with RER. This suggests that the proposed predictor is competent to predict the insufficient enhancement caused by impaired liver function. Similar results were achieved in the Validation group, which confirmed the repeatability and validity of the HBP-ET.

The comparison ROC analysis showed HBP-ET was more efficient than routine indicators (CPS, MELD, and TBIL) in predicting insufficient enhancement during HBP. Although CPS can indicate the overall liver function to a degree, there are several inherent problems with this system, including subjective assessment of hepatic encephalopathy and difficulty in detecting small volume of ascites clinically. MELD was originally developed to predict mortality in patients undergoing transjugular intrahepatic portosystemic shunt (TIPS), and then used to prioritize organ allocation in patients awaiting liver transplantation. It was not specifically designed to evaluate the impaired enhancement during HBP. The TBIL value is another common indicator in the clinical practice, but impaired enhancement during HBP will not only be affected by biliary condition, but also the hepatocyte function, fibrosis, or other factors related to liver function. Hence, the ability of these indicators in predicting insufficient enhancement during HBP are limited. By contrast, the essential parameters of the HBP-ET are easy to obtain, and the performance is efficient, convenient, and objective. Therefore, HBP-ET is more suitable and accurate for predicting the insufficient enhancement during HBP in Gd-EOB-DTPA-enhanced MRI than routine indicators such as CPS, MELD, or TBIL.

Limitations in this study include the effect of liver volume, fibrosis, and deposition of iron and fat on the overall enhancement of liver parenchyma during HBP (22,23). Second, there were significantly fewer patients with normal liver function (n = 29) than there were with chronic liver disease (n = 179), which could result in potential bias of HBP-ET. Further investigation should include a prospective study with a larger normal population.

In conclusion, the HBP-ET is a simple, reliable and accurate tool to predict the enhanced degree of liver parenchyma during HBP in Gd-EOB-DTPA-enhanced MRI prior to MR examination. This can assist radiologists adjust the scanning strategy of the HBP and help to avoid an invalid or insufficient examination. In turn, this may lower the overall rate of misdiagnosis. Additional research should include prospective studies in larger population with normal baseline liver function to further assess the clinical utility of HBP-ET.

Footnotes

Acknowledgements

The authors thank Yu Deng (MD) and Nathan Coleman (MD) for suggestions.

Declaration of Conflicting Interests

The author(s) declared that no conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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