Review Article

Hepatic Elastography and Other Advanced MRI Sequences (Multiparametric MRI)

Andrés Domínguez1, Maximiliano Noceti1, Daniel Fino1, Pablo Ariza1

1 Fundación Escuela de Medicina Nuclear (FUESMEN), City of Mendoza, Mendoza, Argentina

Abstract Fibrosis is a common destination where multiple liver disorders converge. Due to its dynamic and reversible nature, an early detection and timely therapeutic intervention may stop its progression. Magnetic Resonance Elastography (MRE) is a non-invasive method with remarkable efficacy for assessing the degree of liver fibrosis. The current trend is to combine this technique with lipid and iron quantification sequences, which allows a multiparametric approach to diffuse liver disorders.

Keywords Hepatic fibrosis; Magnetic resonance elastography; Multiparametric approach

Introduction In this article, we will develop the protocol used at our institu- tion, with special emphasis on the novel techniques of mag- Hepatic fibrosis is a response to chronic or acute liver injury of netic resonance elastography (MRE), fat-water ratio quanti- any cause.1,2 It is a scarring process of hepatocellular regenera- fication (IDEAL-IQ) and iron quantification by T2-weighted tion by activation of stellate cells, with fibroblast proliferation sequences. and extracellular matrix deposition. Fibrotic bands develop, which distort hepatic architecture and compromise the func- tion of the organ.1 Hepatic fibrosis has the peculiarity of being Magnetic Resonance Elastography a dynamic process that may be potentially reversible if its cause is identified and removed.1,2 Hence the importance of its early The study of liver fibrosis is one of the main indicators in the detection, as simple actions such as lifestyle changes in the characterization of the most important liver disorders that af- case of nonalcoholic fatty liver (NAFL) or nonalcoholic steato- fect humans.7 In industrialized countries, the main causes of hepatitis (NASH) may stop its progression.3 chronic liver disease include hepatitis C and B virus infection, Until recently, hepatic fibrosis could only be confirmed by in- excessive alcohol use and disorders associated with obesity vasive tests such as percutaneous or transjugular biopsy. Even and metabolic syndrome, such as NAFL and NASH.8 if biopsy continues to be the gold standard, its high cost and MRE is a technique that enables non-invasive assessment the potential for complications constitute limiting factors for of the stiffness of tissue.9 Since its origin, there has been a diagnostic confirmation in many cases.4 In addition, serum growing interest worldwide in its potential applications (pros- biomarkers are useful for detecting advanced stages of fibro- tate, brain, pancreas, etc.), with measurement of the degree sis, but have low sensitivity for differentiating early stages.5,6 of liver fibrosis being the most widely studied. 9.10 The trend in recent years has been to include imaging meth- Among the various scales for fibrosis staging, the METAVIR ods for the assessment of these patients, with transition elas- scoring system is traditionally used for evaluating patients tography (TE) being the most widely available in our setting. with chronic viral liver disease and autoimmune hepatitis. This At present, studies with advanced magnetic resonance (MR) system classifies patients into five groups: F0 = no fibrosis; F1 sequences have awakened growing interest worldwide, as = mild fibrosis (portal fibrosis without septa); F2 = moderate they allow a more extensive and detailed assessment of the fibrosis (portal fibrosis with rare septa); F3 = advanced fibrosis liver parenchyma, with less limiting factors than ultrasound (extensive bridges of fibrosis that link up portal areas and lob- elastography (USE) or biopsy. ules), and F4 = cirrhosis (thick bands of fibrosis with distorted

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architecture and regenerative nodules)11 The scoring system In addition, in a systematic review of 153 studies, Bonekamp proposed by Brunt et al.12, used in patients with NASH, clas- et al.16 concluded that MRE was the only noninvasive method sifies these patients into B1 to B4, with the main difference capable of accurately staging fibrosis. being the distribution of fibrosis, which differs depending on the various conditions (portal fibrosis in the former and central fibrosis in the latter). Even if MRE cannot differenti- Technique ate fibrosis distribution as histologic examination does, it may distinguish the various degrees of tissue stiffness, which can • It consists in generating low frequency (60 Hz) acoustic be extrapolated to both scoring systems. Degrees of fibrosis waves inside the tissues and assessing how they propagate in by MRE are classified into: F1: mild fibrosis, F2: moderate fi- such tissues.9,10,14,15 A round driver with a plastic membrane brosis, F3: severe fibrosis and F4: cirrhosis.9-12 (passive driver) is placed on the patient’s abdomen. This driver Since the development of MRE, many publications have dem- is connected by a plastic tube to a pneumatic pump located onstrated its high performance in differentiating healthy liv- in the control room (active driver), from which the waves are ers from those with fibrosis. In the Asian consensus of 2016, generated (Fig. 1). Deformation of tissue by these mechani- where various methods for the assessment of liver fibrosis cal transverse or shear waves is captured by a surface coil, were evaluated, MRE was recommended as a method for to be then reconstructed by a motion-sensitive (phase-con- quantifying fibrosis with an A1 level of evidence.13 A retro- trast) sequence and converted by specific software. Results spective study conducted by Dr. Yin et al.,14 in 1377 patients, are expressed in three ways: a) raw-data images, on which showed a success rate of 94.4% for differentiating livers with reprocessing is made, b) shear waves or imaging waves that advanced fibrosis (F3 to F4) from those with mild fibrosis (F1 allow rapid visual assessment of the presence or absence of to F2); while the meta-analysis performed by Singh et al.,15 in adequate wave propagation and c) elastogram maps, show- 697 patients, showed a high consistency of the technique ir- ing color maps of tissue stiffness, which allow visual com- respective of body mass index (BMI) and the etiology of fibro- parison with the scale generated by the scanner and from sis, with an area under the ROC curve for the diagnosis of the where quantitative measurements will be performed using various stages of fibrosis ranging from 0.84 to 0.92 (CI 95%). the “confidence map”, in which a checkerboard pattern is

passive driver

active driver

Fig. 1. A) Active driver located in the control room, generating the mechanical wave; B) the wave is transmitted through a plas- tic tube to the passive driver, which is placed on the abdominal wall. C) images obtained: phase-contrast raw-date (top), shear waves or imaging waves (middle) and elastogram map (bottom). Red color in the elastogram map represents areas of advanced fibrosis (F4), in a 47-year-old patient followed-up for HCV.

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placed over the regions where measurement has not been the patient’s liver (Fig. 4).20 This also establishes MRE as a use- reliable (Fig. 2). 15-17 ful reference, which may serve as a guide for biopsy. For obtaining results, a ROI is manually drawn, trying to ex- MRE also allows assessment of treatment response, which clude from the sample the areas with a checkerboard pattern is a limitation for biopsy given its invasive nature, and it is on the “confidence map” as well as the vascular structures, superior to USE in that the latter is an operator-dependent the gallbladder and any hepatic lesions that may appear (Fig. method, which makes it less reproducible than MRE.21 A fur- 3). It is also necessary to avoid some artifacts inherent to the ther advantage is that obesity does not affect results, which technique, as the so-called hot spots, which are rounded ar- is important if we consider the growing incidence of obesity eas mimicking advanced fibrosis, which appear immediately and metabolic syndrome as causes of chronic liver disease, below the passive driver or those generated by the liver edge, associated with NAFL and NASH. The latter feature differenti- known as edge artifacts.18 Results are expressed in kilopascals ates MRE from USE, in which obesity is a known limitation for (kPA) and compared with reference values,18, where: the conduction of ultrasound.19,21 It should also be noted that - Normal value: less than 2.5 kPa. results are not affected by mild to moderate degrees of asci- - Normal or chronic inflammation: 2.5 to 2.9 KPa. tes, which may be a limiting factor in percutaneous biopsy.22 - Mild fibrosis (F1 to F2): 2.9 to 3.5 kPA. Additional advantages of MR include detection of complica- - Moderate fibrosis (F2 to F3): 3.5 to 4 kPA. tions of cirrhosis such as HCC, when combined with conven- - Advanced fibrosis (F3 to F4): 4 to 5 kPa tional sequences, as well as the possibility of quantifying iron - Cirrhosis (F4): More than 5 kPa. and lipid content during the same study, without significantly increasing the scan time (Fig. 5).23

Advantages Limitations • Some of the advantages of MRE over USE and biopsy is • One of the main limitations is moderate to severe that the former assesses much more extensive areas of tis- iron overload, as it alters the signal/noise ratio (SNR) and it sue, since among all commercially available USE systems, the may lead to errors in measurement, not including measurable maximum tissue volume that can be assessed is up to 20 cc, regions in the confidence map.24 For this reason, we think it while in MRE approximately 250 cc can be assessed.19 This is advisable to include iron quantification in this protocol. It is a crucial fact if we consider that fibrosis may not be ho- should be noted that for these cases other MRE acquisition mogeneous and, therefore, the larger the volume of tissue techniques are available, with are based on echo gradient assessed, the higher the correlation with the actual status of sequences that may, at least partly, counteract this effect.

Fig. 2 .Magnetic resonance elastography (MRE) confidence image, showing a checkerboard pattern, area which should be ex- cluded when drawing the ROI. (A) Healthy volunteer, whose liver stiffness is similar to that of the subcutaneous tissue and the quantitative analysis yields a stiffness of 2.2 kPa, consistent with F0. (B) Chronic alcoholic patient with an area in the lateral seg- ment with no checkerboard pattern, eligible for measurement, which was 3.8 kPa,, consistent with moderate fibrosis (F2 to F3).

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Fig. 3. (A and B) Images show the manually drawn ROI avoiding the checkerboard pattern on the confidence map, as well as vascular structures, the gallbladder and artifacts inherent to the technique. In this case, in the dotted circle, the average stiffness is indicated in those 2 slices, which is approximately 4.4 kPa, consistent with advanced fibrosis (F3 to F4).

Fig. 4. (A and B) Axial T2-weighted image and MRE in a patient being followed for HCV. Notice the heterogeneous distribution of fibrosis, which is advanced, towards segments V and VIII (8.5 kPa) and which progressively decreases towards the lateral seg- ment (3.5 kPa) and posterior segments. Should a biopsy have been taken from the less compromised segments, disease would have been underestimated.

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In a recent study, in addition to iron overload, massive ascites significantly increase stiffness, not necessarily representing is mentioned as a limiting factor, with more failures being a disadvantage, but being indeed a factor that should be found in measurements performed with 3T than with 1.5T considered for the interpretation of the study.18 New three- systems.25 dimensional elastography techniques are currently being in- Among the limitations associated with the technique, it is vestigated, which may enable differentiation of the different worth mentioning that as MRE is a breath-hold sequence, causes that increase stiffness. patient’s cooperation is required. Furthermore, a nonfasting Finally, as MRE is relatively new technology in our setting, it status may (slightly) overestimate the degree of stiffness due is less widely used and more costly than USE, although the to increased portal venous flow; therefore total fasting is re- MRE’s possibility of quantifying lipids and iron in the same quired for at least 6 hours.26 examination may compensate the latter limitation.23 Additionally, even if as mentioned above, obesity does not alter measurements, the size of the scanner bore and the fact that patients should fit into the bore is a limiting factor. Other Potential horizons limitations are common to all MR scans, such as non-com- patible pacemakers or mechanic valve replacements, cochlear • Many studies mention the usefulness of MRE in the field of implants, etc. oncology. One of these studies mentions MRE as a biomarker Liver stiffness may be slightly increased for causes such as of early response, where changes in tumor tissue stiffness in chronic inflammation, portal hypertension and congestive response to treatment precedes both changes in tumor size liver disease, while acute inflammation and amyloidosis may and in other biomarkers such as diffusion (cellularity) or per-

Fig. 5. Hepatic multiparametric study in a 19-year-old patient on antiretroviral therapy. (A) DIXON sequence showing a lipid content of 27% due to severe steatosis. (B) MRE with a slight increase in stiffness (3.1 kPa), probably in NASH. (C and D) Map- ping techniques showing a T2* value of 15. Estimation of liver iron concentration yields 1.9 mg/g, with this value being within normal ranges.

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fusion (neovascularization).27 Another recent study showed a ders reaching epidemic rates in industrialized countries.30,31 significant difference in the degree of stiffness in treated (RE Hence the importance of adding sequences for lipid quantifi- and TACE/RF) hepatocellular carcinoma (HCC) vs. untreated cation to MRE studies. HCC, being lower in the latter in than in the former.28 Fur- Among the various imaging techniques for lipid quantifica- thermore, it is thought that MRE may be useful in differenti- tion, we use the single-breath-hold multipoint Dixon-based ating benign from malignant liver tumors, with a higher de- acquisition (IDEAL-IQ-GE), which enables measurement of gree of stiffness in the latter.29 proton density fat fraction without significantly increasing the scan time (< 2 minutes).32,33 This feature distinguishes this technique from spectroscopy, which would significantly Proton Density Fat Fraction increase the acquisition time, and enables us to include the IDEAL-IQ-GE technique in routine protocols for diffuse liver Techniques for lipid quantification also constitute an impor- disorders. A rate below 6% is considered normal, with a 15% tant advance in the management of patients with diffuse liver cutoff value for differentiating mild from moderate to severe disease. Several studies demonstrate the growing incidence degrees.33 of NAFL and NASH as causes of chronic liver disease associ- Recent studies suggest the possibility of differentiating NAFL ated with obesity and metabolic syndrome, with these disor- from NASH by MR upon combination of lipid quantification

Fig. 6 Fifty-five year-old patient with metabolic syndrome and elevated liver enzymes of unknown etiology. (A and B) chemical shift images show a loss of signal intensity with opposed-phase image due to steatosis. C) DIXON sequence (IDEAL-IQ) shows 15% lipid rate vs. the spleen (<5%), due to moderate /severe steatosis. (D) MRE with significant increase in liver tissue stiffness (8.2 Kpa), findings which are consistent with nonalcoholic steatohepatitis (NASH) associated with advanced fibrosis (F4).

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and MRE techniques, where liver tissue stiffness is not affected paring the signal intensity of the liver to that of paraspinal by the former, while being increased by the latter (Fig. 6).34,35 muscles.41

Iron quantification by T2*-weighted Protocols for evaluation of diffuse sequences (mapping techniques) liver disorders

For liver iron concentration (LIC) quantification we use a gra- All images were acquired using a Signa PET-MR 3T (GE dient-recalled echo sequence, which provides T2* value in Healthcare) scanner. milliseconds.36 This allows calculation of the R2* relaxometry The complete protocol consisted in axial and coronal T2- rates (1000/T2*) in units of 1 second to subsequently ob- weighted single shot fast spin echo (SS-FSE), axial chemical tain, by means of a mathematic algorithm [(0.0254 x R2*) + shift sequences and advanced sequences: MRE, IDEAL-IQ and 0.202)], the LIC, which is expressed in milligrams of iron by T2*-weighted sequences for iron quantification. The net ac- gram of dry liver tissue weight (mg/g).37 A value <3.5 mg/g is quisition time was approximately 15 minutes, with an aver- considered acceptable; a value of 3.5 to 7 mg/g is considered age of less than 25 minutes from time of patient entry into as mild overload; 7 to 12 mg/g as moderate overload and the scanner to patient exit <12 mg/g as severe overload (Fig. 7).36 This method maxi- mizes the signal/noise ratio (SNR) as it does not rely on an internal (anatomic) or external reference for determining R2 Conclusion or R2*, showing a strong correlation with the LIC obtained in liver biopsies.38-40 It should be noted that these techniques re- MRE is a suitable method for liver fibrosis assessment. When quire specific software and are not widely available; instead, combined with advanced sequences for lipid and iron quantifi- the SIR (signal intensity ratio) method may be used, which is cation, it enables a noninvasive and multiparametric evaluation widely used worldwide (University of Rennes method), com- of diffuse liver disease, applicable to clinical practice. Even if

Fig. 7 Thirty-eight-year-old patient with a history of thalassemia. Iron quantification of this patient yielded a T2* value of 7.05, with the liver iron concentration being 3.8 mg/g, consistent with mild overload. The plot on the left shows a progressive decline in signal in relation to TE increase, which allows T2* quantification, necessary for obtaining the relaxometry rate and subse- quently the LIC.

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its use is currently limited because of its low availability in our agnose and stage hepatic fibrosis and cirrhosis accurately? J Hepatol 2009;50(01):17–35 setting, with the advent of new technologies it is mandatory 17 Rustogi R, Horowitz J, Harmath C, et al. Accuracy of MR elastography and for radiologists to become familiarized with these techniques. anatomic MR imaging features in the diagnosis of severe hepatic fibrosis and cirrhosis. J Magn Reson Imaging 2012;35(06):1356–1364 18 Srinivasa Babu A,WellsML, TeytelboymOM, et al. Elastography in chronic liver disease: modalities, techniques, limitations, and future directions. Ra- Ethical responsibilities diographics 2016;36(07):1987–2006 Protection of human subjects and animals. The authors 19 Barr RG, Ferraioli G, PalmeriML, et al. Elastography assessment of liver fibrosis: Society of radiologists in ultrasound consensus conference state- declare that no experiments were performed on humans or ment. Radiology 2015;276(03):845–861 animals for this investigation. 20 Marcellin P, Asselah T, BoyerN. Fibrosis and disease progression in hepatitis C. Hepatology 2002;36(05, Suppl 1):S47–S56 Confidentiality of data.The authors declare that they have 21 Huber A, Ebner L, Heverhagen JT, Christe A. State-of-the-art imaging of followed the protocols of their work center on the publica- liver fibrosis and cirrhosis: A comprehensive review of current applications and future perspectives. Eur J Radiol Open 2015;2:90–100 tion of patient data . 22 Grant A, Neuberger J; British Society of Gastroenterology. Guidelines on Right to privacy and informed consent. The authors de- the use of liver biopsy in clinical practice. Gut 1999;45(Suppl 4):IV1–IV11 clare that no patient data appear in this article. 23 Banerjee R, Pavlides M, Tunnicliffe EM, et al. Multiparametric magnet- ic resonance for the non-invasive diagnosis of liver disease. 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