|Year : 2020 | Volume
| Issue : 3 | Page : 987-992
In-phase and out-of-phase MRI: a quantitative method for assessment of nonalcoholic fatty liver disease
Shaimaa A Hassanein1, Hala H Mohamed1, Aya Y Mostafa2, Manal I Gomaa2
1 Department of Radiology, Faculty of Medicine, National Liver Institute, Menoufia University, Menoufia, Egypt
2 Department of Radiology, National Liver Institute, Menoufia University, Menoufia, Egypt
|Date of Submission||18-Feb-2019|
|Date of Decision||20-Feb-2019|
|Date of Acceptance||05-Mar-2019|
|Date of Web Publication||30-Sep-2020|
Aya Y Mostafa
Department of Radiology, National Liver Institute, Menoufia University, 1st Settlement, New Cairo 32717, Cairo Governorate
Source of Support: None, Conflict of Interest: None
The objective of this study was to assess the efficacy of MRI in-phase and out-of-phase (IPOP) technique in the diagnosis of nonalcoholic fatty liver disease (NAFLD).
NAFLD is raising great concern nowadays due to its prevalence. It was routinely diagnosed by liver biopsy, which is a highly invasive procedure; hence, the need for a noninvasive method for diagnosis was required. MRI IPOP technique was introduced to fulfill this role.
Patients and methods
This prospective study was carried out during the period spanning from July 2016 to December 2017; 50 asymptomatic patients with clinical diagnosis of NAFLD and diffuse hyperechogenicity of the liver by ultrasound underwent MRI of the liver with IPOP technique. Manually placed region of interest and two equations, namely F1 and F2, for determination of the grades of steatosis were used.
The first equation (F1) revealed one patient (male individual) to have minimal steatosis, 24 patients (17 female individuals, seven male individuals) to have mild steatosis, 22 patients (15 female individuals, seven male individuals) to have moderate steatosis and three patients (two female individuals, one male individual) to have marked steatosis, whereas the second equation (F2) revealed one patient (male individual) to have minimal steatosis, 20 patients (13 female individuals, seven male individuals) to have mild steatosis, 26 patients (19 female individuals, seven male individuals) to have moderate steatosis and three patients (two female individuals, one male individual) to have marked steatosis.
Liver MRI with IPOP technique can be used rapidly and quantitatively to estimate the liver fat content in patients with NAFLD.
Keywords: in-phase and out-of-phase, MRI, nonalcoholic fatty liver disease, signal intensity, steatosis
|How to cite this article:|
Hassanein SA, Mohamed HH, Mostafa AY, Gomaa MI. In-phase and out-of-phase MRI: a quantitative method for assessment of nonalcoholic fatty liver disease. Menoufia Med J 2020;33:987-92
|How to cite this URL:|
Hassanein SA, Mohamed HH, Mostafa AY, Gomaa MI. In-phase and out-of-phase MRI: a quantitative method for assessment of nonalcoholic fatty liver disease. Menoufia Med J [serial online] 2020 [cited 2020 Nov 26];33:987-92. Available from: http://www.mmj.eg.net/text.asp?2020/33/3/987/296711
| Introduction|| |
The emerging epidemic of nonalcoholic fatty liver disease (NAFLD) is raising great concerns, as it is identified in ∼10% of children and 20–30% of adults in the Western world ,. Its association with type 2 diabetes mellitus (DM) and obesity is adding to the importance of its accurate diagnosis, as many patients with NAFLD may develop further serious complications such as nonalcoholic steatohepatitis, cirrhosis, and even end-stage liver failure ,.
Several imaging techniques have been utilized to detect hepatic steatosis noninvasively, such as ultrasonography (US), computed tomography, MRI, and magnetic resonance spectroscopy . US has been the initial imaging modality used due to its wide availability, low cost, noninvasive nature, and lack or radiation. However, it remains a highly subjective method, as it depends on the qualitative assessment of the hepatic hyperechogenicity on US, which is highly subjective ,.
Computed tomography has good accuracy, with semiquantitative diagnosis, but its utilization in the diagnosis and monitoring of treatment response is limited because of the ionizing radiation .
MRI is an attractive modality to quantify the degree of hepatic steatosis. In-phase and out-of-phase (IPOP) technique, calibrated with robust liver/fat standards, has been found to be superior to other noninvasive imaging techniques in quantifying hepatic steatosis, making MRI the most accurate technique capable of detecting fat amount below 0.5% ,.
The aim of our study was to emphasize the quantitative ability of MRI for detection of hepatic steatosis using the different proposed equations.
| Patients and Methods|| |
This was a prospective study carried out during the period spanning from July 2016 to December 2017, which included patients who presented at the Ultrasound Unit of Radiology Department at National Liver Institute, Menoufia University, with clinical suspicion of NAFLD and/or an incidentally discovered diffuse liver disease by US performed for another complaint. The study protocol was approved by the Medical Ethical Committee of Faculty of Medicine, Menoufia University. After informed consent was taken from each patient included in the study, all the patients underwent MRI IPOP technique.
Inclusion criteria: patients of both sexes who were diagnosed to have NAFLD were included.
Exclusion criteria: those with a contraindication to MRI examination, those with a history of drug or alcohol abuse and those with detected hepatic focal lesions were excluded.
Patient preparation: 50 patients (17 male individuals and 33 female individuals) were included in the study. All patients were referred to the MRI Unit at Radiology Department, National Liver Institute, Menoufia University for liver MRI IPOP. Thorough history taking emphasizing on the presence of DM and hypertension (HTN) and drug or alcohol abuse was taken for all patients; clinical examination and BMI calculation were also performed.
US examination: real-time US was carried out including conventional B-mode scanning using US machines with 2.5–5 MHZ curved probe [(Nemio XG ultrasound, Chrysler; Toshiba, Tokyo, Japan) and (HD7 Philips ultrasound; Philips Healthcare, Bothell, Washington, USA)]. The US examinations were performed with the patients in a supine position, with deep inspirations to fully visualize the superior borders of the liver. The following items were considered: the liver homogeneity, echotexture, size, focal lesions and intrahepatic vessels' patency. After exclusion of hepatic focal lesions by US, all patients were then sent to the MRI Unit.
MRI examination: liver MRI examination with IPOP technique was performed using a 1.5-T MRI system (Optima 450 W GEM suite MRI; GE Healthcare, Seattle, Washington, USA) using an integrated body coil with additional linear general purpose flexible phased-array surface coil. Patient preparation included fasting for 4 h before the procedure. Patients were examined in the supine position with the dedicated coil fixed in place. After the patients were in the center of the magnet, a three-plan localizer was taken with the required axial images planned on coronal scout. Axial T1-weighted image dual-echo fast spoiled-gradient-recalled sequence was taken including the whole liver from the diaphragm down to the iliac crest. Patients were instructed to breath hold during the scan. Saturation bands were used above and below the scan block to reduce the arterial pulsation and breathing artifacts. The used imaging parameters were as follows: time of repetition, 75–100 ms; time to echo, 2.3 ms (for out-of-phase) and 4.6 ms (for in-phase); slice thickness of 7–8 mm, and the acquisition time was 23 s.
Postscan processing: the MR examinations were then transferred to a workstation (Osirix system; Pixmeo Sàrl, Geneva, Switzerland) through a picture archive and communication system for qualitative and quantitative assessment of the existence of hepatic steatosis and its degree.
Subjective evaluation of the overall image quality was performed. The presence of diffuse fatty infiltration was determined by the characteristic signal change features, recognized as regions of the liver that showed a decrease in signal intensity (SI) on out-phase images, as compared with the in-phase images at the same levels [Figure 1] and [Figure 2]. The signals of the spleen and skeletal muscle were used as a reference for SI changes, as they contain little intracellular lipid.
|Figure 1: Axial MRI of the liver of a female patient at the level of segments VII and VIII (region of interest at the area of the liver parenchyma with no passing blood vessel nor biliary tract: (a) In-phase and (b) out-of-phase revealing evident drop of signal in the out-of-phase scan with the mean value of 160 in (a) and 503 in (b). Both FI1 and FI2 equations revealed marked steatosis with FI1 = 68.2% and FI2 = 34%.|
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|Figure 2: Axial MRI of the liver of a male patient at the level of segment VI (region of interest at the area of the liver parenchyma with no passing blood vessel nor biliary tract: (a) In-phase and (b) out-of-phase revealing drop of signal in the out-of-phase scan with the mean value of 480 in (a) and 300 in (b). Both FI1 and FI2 equations revealed moderate steatosis with FI1 = 37.5% and FI2 = 18.75%.|
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The quantitative assessment was then performed using a manually placed region of interest (ROI) that was used to assess the SI from three areas of the liver (two at the right lobe and one at the left lobe) in the T1-weighted IPOP gradient echo sequences. The ROIs were manually drawn so as to be 2 cm 2 to include representative areas of hepatic parenchyma that did not contain major blood vessels or an artifact. For each sequence, the ROIs were matched on the same locations. A mean of the three ROI results was used to calculate fat indices using two types of equations, namely FI1 and FI2 as follows:
- FI1=(SIin − SIout)/(SIin)×100; the following grading system was used for reporting the degree of steatosis (according to FI1 equation): grade 0 (minimal steatosis)=up to 5%, grade 1 (mild) = 5.1–33%, grade 2 (moderate) = 33.1–66% and grade 3 (severe) >66% 
- FI2=(SIin − SIout)/(2SIin)×100; the following grading system was used for reporting the degree of steatosis according to FI2 equation: grade 0 (minimal steatosis)=up to 5% of cells affected, grade 1 (mild) = (5.1: <15%), grade 2 (moderate) = (15: <30%), and grade 3 (severe) = (≥30%: 50%) .
SIout denotes out-of-phase SI, and SIin denotes in-phase SI.
The collected data were tabulated and statistically analyzed using an IBM statistical package for social sciences, version 20 (SPSS Inc., Chicago, Illinois, USA) and Epi Info 2000 programs (Centers for Disease Control and Prevention, Atlanta, Georgia, USA) on a personal computer. The Student t-test and Mann–Whitney U-test were used as tests of significance for comparison between the two groups with the P-value of (≤ 0.05) considered statistically significant.
| Results|| |
Fifty patients were included in our study. There were 17 (34.0%) male individuals and 33 (66.0%) female individuals, with their ages ranging from 30 to 73 years (53.5 ± 9.3 years). The mean BMI for the studied patients was 36.9 ± 8.3. It was significantly higher among female patients (37.5 ± 8.8), when compared with males (32.9 ± 6.6); categorization of the BMI showed that 26/33 (78.8%) female patients were obese, whereas 12/17 (70.5%) male patients were obese. Multiple comorbidities were noticed, including DM detected in 32 (64%) patients and HTN detected in 21 (42%) patients. Previous history of chemotherapy was present in 12 (24%) patients.
Increased liver size on US was noted in 33/50 (66%) patients; most of them were female individuals (24/33; 72.7%).
Evaluation of the percentage of hepatic steatosis by IPOP MRI using the FI1 equation showed a mean steatosis of 34.4 ± 16.2%. It was not significantly differing between both sexes (P = 0.85), categorization of the hepatic steatosis by IPOP MRI in the studied patients revealed a higher percentage of mild steatosis among male and female is 48% between them males 41.2% and females 45.5%. However, 44.0% of patients were found to have moderate steatosis [male patients (41.2%) and female patients (45.5%)]. These differences were not found to be statistically significant (P = 0.30) [Table 1].
Evaluation of the percentage of hepatic steatosis by IPOP MRI using the FI2 equation showed a mean steatosis of 17.2 ± 8.12%. It was not significantly differing between both sexes (P = 0.84); categorization of the hepatic steatosis by IPOP MRI in the studied patients revealed a higher percentage of moderate steatosis among male and female is 52% between them males 41.2% and females 45.5%. However, 40.0% of patients were found to have mild steatosis [male patients (41.2%) and female patients (39.2%)]. These differences were also not found to be statistically significant (P = 0.27) [Table 2].
Comparing the FI1 equation results with the FI2 equation results revealed a difference of categorization of the degree of steatosis, with most female patients being in the group of mild steatosis in the MR FI1 equation, and most of the female patients being in the group of moderate steatosis in the MR FI2 equation; the difference is probably attributable to the fact that the grading system is different [Figure 3]. Otherwise, no significant statistical differences were noted.
|Figure 3: Chart shows comparison between FI1 equation results and FI2 equation results.|
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| Discussion|| |
NAFLD (consisting of both simple steatosis and nonalcoholic steatohepatitis) is currently raising more interest throughout the world as a growing epidemic due to obesity and insulin resistance, leading to liver accumulation of triglycerides and free fatty acids. NAFLD patients are at increased risk of liver-related diseases and cardiovascular mortality, and NAFLD is rapidly becoming one of the leading cause of liver cirrhosis .
Therefore, risk stratification of those diagnosed with or suspected of having NAFLD is of utmost importance. As liver biopsy is a highly invasive diagnostic method with expected complications, the need for noninvasive methods arose. MRI is gaining more popularity, as it is noninvasive, with no ionizing radiation; moreover, its capability of detecting intracellular fat with its in-phase/opposed-phase technique provides a quantitative method for assessment and follow-up of patients with suspected NAFLD.
We studied 50 patients with a clinical suspicion of NAFLD; 66% of the patients were women (22 were postmenopause and 11 premenopause), and 34% were men. Thus, this study reinforces that NAFLD was slightly more common in postmenopausal women. This was consistent with the studies by Polyzos and Venetsanaki  and Reeder et al.  who emphasized that NAFLD was slightly more common in postmenopausal women. This is probably attributed to the estrogen effect on fat metabolism. In contrast, Dean et al.  found that NAFLD was common in men in their study. The difference is attributed to the different study populations and the fact that they were studying the presence of NAFLD in DM type II patients.
The mean age for our study group was 53.5 ± 9.9 years. The mean age of men was 56.4 ± 9.3 years (range: 30–70 years), and the mean age of women was 52.1 ± 9.9 years (range: 32–73 years). This was consistent with the study by Browning et al.  who emphasized that the occurrence of NAFLD seems to increase with age. In their study, the mean age of the studied patients was 46 ± 10, with the mean age of female patients being 45 ± 9, and the mean age of male patients being 46 ± 10.
There was an insignificant statistical positive correlation between the BMI for the studied patients and the percentage of hepatic steatosis by IPOP MRI. This was in agreement with the previous study by Eguchi et al.  who stated that hepatic steatosis can be influenced by the accumulation of visceral fat regardless of the BMI.
The measures of SI on the IPOP images at our study population provided a helpful method to quantify the liver fat content (LFC), which is far more reliable than the subjective image interpretation, even if it is performed by an experienced radiologist. For this reason, this method can be used as a guideline for the less experienced radiologists, the wide range of LFCs often observed in patients with NAFLD.
A study by Hamaguchi et al.  demonstrated that patients with comorbidities at baseline were more likely to develop NAFLD during a 14-month follow-up. Their study showed that 95% of the patients with one or more of the comorbidities showed NAFLD. This was consistent with our study, in which there were 32 (64%) patients with type II DM and 21 (42%) patients with HTN. This also was consistent with the study of Bang et al., which also showed an increase in the incidence of NAFLD with the presence of comorbidities.
The use of F1 and F2 equations showed better results compared with visual assessment alone, as they provide a quantitative assessment of the hepatic fat content. Abdeldaym et al.  showed that the correlation determined with use of FI1 was slightly stronger than that determined with FI2, as, in their study, FI1 showed overall accuracy for evaluation of the hepatic steatosis of 88.0% in comparison with the gold-standard test (liver biopsy), whereas using F2 showed overall accuracy for evaluation of the hepatic steatosis of 84% in comparison with the gold-standard test (liver biopsy).
Studies by Bahl et al.  found a good correlation between IPOP MRI using the FI1 equation and liver biopsy in the estimation of the percentages of hepatic steatosis (significant P value), emphasizing the good capabilities of this technique. In contrast, another work by Westphalen et al.  revealed a weak correlation between the SI changes on IPOP images and the hepatic fat content in liver biopsy samples. This weak correlation was attributed to the fact that increased liver iron content in their study group (they studied those with established and advanced cirrhosis) altered T2* in the liver and, consequently, the IPOP imaging measurements. Patients in our study did not have features of cirrhosis or other severe liver diseases, and hence their liver iron content was likely to be low; thus, the fat index calculated from IPOP imaging is reliable.
The simple calculations: FI1=(SIin−SIout)/(SIin)×100 and FI2=(SIin−SIout)/2 (SIin)×100 provide the radiologist an objective tool for assessment of the hepatic fat content.
Certain precautions with regard to the application of our results need to taken. Our study showed that the use of this technique is accurate in those patients with NAFLD without other liver abnormalities, as iron accumulation within the liver tissue is a pitfall of liver fat determination with IPOP imaging. This can occur in cases with established cirrhosis, hemochromatosis, and hemosiderosis. Repeated blood transfusions as a cause of secondary hemochromatosis also can change the liver SI on MRIs. Moreover, the fact that NAFLD itself can progress to cirrhosis with associated fibrosis and hemosiderosis can hamper this technique in advanced cases .
| Conclusion|| |
Our results show that IPOP imaging can provide a quantitative tool for the initial assessment and further follow-up of the LFC in patients with NALFD. Increased use of IPOP imaging to assess LFC and grade hepatic steatosis has the potential to encourage early detection of NAFLD and to subsequently improve treatment evaluation.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bellentani S, Scaglioni F, Marino M, Bedogni G. Epidemiology of non-alcoholic fatty liver disease. Dig Dis 2010; 28
Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics 2006; 118
Angulo P, Lindor KD. Non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2002; 17 (Suppl)
Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver disease. Semin Liver Dis 2008; 28
Wieckowska A, McCullough AJ, Feldstein AE. Noninvasive diagnosis and monitoring of nonalcoholic steatohepatitis: present and future. Hepatology 2007; 46
Cassidy FH, Yokoo T, Aganovic L, Hanna RF, Bydder M, Middleton MS, et al
. Fatty liver disease: MR imaging techniques for the detection and quantification of liver steatosis. Radiographics 2009; 29
Chan DF, Li AM, Chu WC, Chan MH, Wong EM, Liu EK, et al
. Hepatic steatosis in obese Chinese children. Int J Obes Relat Metab Disord. 2004; 28
Raptis DA, Fischer MA, Graf R, Nanz D, Weber A, Moritz W, et al
. MRI: the new reference standard in quantifying hepatic steatosis. Gut 2012; 61
Bohte AE, van Werven JR, Bipat S, Stocker J. The diagnostic accuracy of US, CT, MRI and 1
H-MRS for the evaluation of hepatic steatosis compared with liver biopsy: a meta-analysis. Eur Radiol 2011; 21
Borra RJ, Qayyum A, Bahl M. Nonalcoholic fatty liver disease: rapid evaluation of liver fat content with in-phase and out-of-phase MR imaging. Radiology 2009; 250
Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease – Meta-analytic assessment of prevalence, incidence and outcomes. Hepatology 2016; 64
Bendict M, Zhang X. Nonalcoholic fatty liver disease: an expanded review. Hepatology 2017; 8
Polyzos SA, Venetsanaki V. Menopause and nonalcoholic fatty liver disease: a review focusing on therapeutic perspectives. Curr Vasc Pharmacol 2018; 29
Reeder SB, Cruite I, Hamilton G, Sirlin CB. Quantitative assessment of liver fat with magnetic resonance imaging and spectroscopy. Magn Reson Imaging 2011; 34
Dean K, Lautamäki R, Nuutila P, Komu M, Borra RJH, Salo S, et al
. Nonalcoholic fatty liver disease: rapid evaluation of liver fat content with In-phase and out-of-phase MR Imaging. Radiology 2009; 250
Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al
. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004; 40, 6
Eguchi Y, Eguchi T, Mizuta T, Ide Y, Yasutake T, Iwakiri R, et al
. Visceral fat accumulation and insulin resistance are important factors in nonalcoholic fatty liver disease. J Gastroenterol 2006; 41
Hamaguchi M, Kojima T, Takeda N, Nakagawa T, Taniguchi H, Fujii K, et al
. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med 2005; 143
Bang KB, Cho YK. Comorbidities and metabolic derangement of NAFLD. J Lifestyle Med2016; 5
Abdeldaym MR, Elsabaa BM, Ibrahim ME, Mohamed AM. Role of chemical shift magnetic resonance imaging in liver fat quantification in cases of nonalcoholic fatty liver disease; 2015.
Bahl M, Qayyum A, Westphalen AC, Noworolski SM, Chu PW, Ferrell L, et al
. Liver steatosis: investigation of opposed-phase T1-weighted liver MR signal intensity loss and visceral fat measurement as biomarkers. Radiology 2008; 249
Westphalen AC, Qayyum A, Yeh BM, Merriman RB, Lee JA, Lamba A, et al
. Liver fat: effect of hepatic iron deposition on evaluation with opposed-phase MR imaging. Radiology 2007; 242
Salo S, Alanen A, Leino R, Bondestam S, Komu M. The effect of haemosiderosis and blood transfusions on the T2 relaxation time and 1/T2 relaxation rate of liver tissue. Br J Radiol 2002; 75
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]