Liver disease is responsible for 2 million deaths annually.[1] This week marks World Liver Day (April 19th), an initiative to raise awareness of liver health that is supported by major liver associations, such as the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD).[2][3] Medical imaging plays a key role in detecting liver diseases, supporting informed diagnosis, guiding treatment selection, and continued monitoring.[4] Here, we look at the underlying principles, benefits and limitations of specific imaging modalities used for the detection and characterization of focal liver lesions (FLLs) and liver cancer.
Liver cancer and focal liver lesions
Liver cancer ranks as the third-leading cause of cancer-related deaths worldwide.[5] The dominant form of liver cancer is hepatocellular carcinoma (HCC), accounting for 80% of primary liver cancers.[6] HCC is a type of FLL; however, FLLs also encompass other malignant lesions, such as intrahepatic cholangiocarcinoma and hepatic metastasis, as well as benign lesions such as hepatic haemangioma and focal nodular hyperplasia. Early detection and accurate characterization of FLLs are crucial for optimal treatment decisions and prognostic predictions.[7]
FLLs are often found incidentally during imaging for other purposes, such as the assessment of abdominal pain or during surveillance for liver metastases in patients with non-liver cancer.[8] Three main imaging modalities are used for the detection and characterization of FLLs: conventional ultrasound is often the modality to first detect FLLs, after which contrast-enhanced computed tomography (CECT), contrast-enhanced magnetic resonance imaging (CEMRI), or contrast-enhanced ultrasound (CEUS) are used for FLL characterisation.[8][9][10]
Key modalities used for liver imaging
Ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI) are non-invasive imaging modalities, and each relies on different underlying physical principles (Figure 1). Ultrasound uses sound waves that pass into the body and bounce back from the tissues inside, like an echo. Different tissue types reflect the sound waves differently and software is used to process these echoes to create images of the body.[11][12]
CT uses a series of X-rays to build images by acquiring multiple projections of the same location from different orientations. Tomographic reconstruction then generates 3D cross-sectional images of the body. The individual X-ray images quantify the reduction in X-ray intensity as they pass through tissues. Different tissue types absorb different levels of radiation (e.g. bones absorb the most) and the resulting differential generates contrast.[11][12]
MRI employs strong magnets to create a magnetic field in which protons (mostly hydrogen atoms in water molecules) in the body will preferentially align with the magnetic field. By pulsing a specific radiofrequency through the patient’s body, the protons can be forced to spin out of alignment with the magnetic field. After the radiofrequency is turned off, the protons relax back to their resting alignment and release energy. Different tissue types have different relaxation properties, and the released energy can be measured to create an image.[11][12]
Figure 1: Non-invasive modalities for liver imaging
Enhancing contrast to enhance categorisation
For all three imaging modalities, contrast agents can be used to improve their diagnostic capability. Contrast agents for CEUS consist of microbubbles containing an inert gas stabilized by a shell, enhancing the echo (and thus signal intensity) from the blood.[13][14] Contrast agents for CECT typically contain iodine atoms that increase image contrast by absorbing X-rays.[15] CEMRI often uses gadolinium-based contrast agents that shorten the relaxation times of proton nuclei in the tissues, improving signal intensity from contrast-enhanced tissues.[16][17]
For characterization of FLLs, particularly in patients at high risk of HCC, a Liver Imaging Reporting and Data System (LI-RADS) has been developed to categorize FLLs from LR-1 (definitely benign) to LR-5 (definitely HCC). LI-RADS algorithms specific to CECT/CEMRI and CEUS are available.[18] Categorization considers factors such as the lesion size and flow of contrast agent through the liver. Because the liver has a dual blood supply (from the hepatic artery and the portal vein), three distinct phases can be assessed during imaging, in which the injected contrast agents (for any of the modalities) ‘wash in’ and ‘wash out’ of the liver: the arterial phase, portal venous phase, and late phase. Depending on the pattern of contrast enhancement of FLLs compared with the surrounding liver parenchyma, the FLLs can be categorized by CEUS, CECT and/or CEMRI.[19][20][21][22]
Advantages and limitations of modalities for liver imaging
All three contrast-enhanced modalities play a role in charactering FLLs, and each has advantages and limitations. For example, CEUS offers real-time imaging, has wide accessibility, can be performed with the clinician/radiographer at the patient’s bedside and is relatively inexpensive.[10][23][24] However, CEUS has limited penetration depth, affecting imaging in overweight/obese patients, and only one lesion can be studied at a time. [22][23][24] Conversely, CECT and CEMRI can visualize deep structures and enable evaluation of the whole liver. [10][15][23][24] A limitation of CECT is that it uses ionising radiation, and contrast agents for both CT and MRI have restricted use in patients with renal impairment due to nephrotoxic effects.[10][23][25] CECT and CEMRI cannot be performed in real-time and imaging is performed at predetermined times following contrast agent administration.[22] They are also performed in a dedicated room, where the patient is confined to a large scanner on their own and may experience discomfort.[24]
Depending on multiple factors, one modality may be preferred over the other, or multiple modalities may be used, complementing each other.[8][10][22] Understanding the benefits and limitations of these techniques is necessary to guide the selection of the most appropriate imaging modalities for specific individuals, and assist in accurate characterization and diagnosis of FLLs to avoid delays in diagnosis and treatment, thereby improving patient outcomes.[4] Such insights can also help optimize medical workflows, and ultimately reduce healthcare utilisation.[9][24][26]
The Clarivate Value Communication team, helps life science companies present the benefits of innovative and highly technical medical technologies to market access stakeholders in clear, impactful ways. We specialize in the development of robust and compelling value communication materials, including value story slide decks, global value and reimbursement dossiers, objection handlers and publications. We also have extensive experience in primary payer and KOL research, and in developing interactive client workshops and training.
To learn more about our capabilities and how we can support you, please get in touch at https://clarivate.com/products/life-sciences-and-healthcare-consulting-services/evidence-value-access-consulting/.
This post was written by Ulrike Jahnke, Medical Writer, and Paul Cowling, Medical Writer.
References
[1]Devarbhavi H, Asrani SK, Arab JP, Nartey YA, Pose E, Kamath PS. Global burden of liver disease: 2023 update. J Hepatol. 2023 Aug;79(2):516-537
[3]European Association for the Study of the Liver (EASL) press release
[4]Singh S, Hoque S, Zekry A, Sowmya A. Radiological Diagnosis of Chronic Liver Disease and Hepatocellular Carcinoma: A Review. J Med Syst. 2023 Jul 11;47(1):73
[5]Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249
[6]Rumgay H, Ferlay J, de Martel C, Georges D, Ibrahim AS, Zheng R, Wei W, Lemmens VEPP, Soerjomataram I. Global, regional and national burden of primary liver cancer by subtype. Eur J Cancer. 2022 Jan;161:108-118
[7]Marrero JA, Ahn J, Rajender Reddy K; Americal College of Gastroenterology. ACG clinical guideline: the diagnosis and management of focal liver lesions. Am J Gastroenterol. 2014 Sep;109(9):1328-47
[8]Algarni AA, Alshuhri AH, Alonazi MM, Mourad MM, Bramhall SR. Focal liver lesions found incidentally. World J Hepatol. 2016 Mar 28;8(9):446-51
[9]O’Brien M, Oliver L, Proctor N, Siakantari M, Cantin P, Griffin CP, Stenberg B. Assessing the impact and resource implications of contrast-enhanced ultrasound on workflow of patients with incidental focal liver lesions on the UK national health service. Acta Radiol Open. 2023 Jun 13;12(6):20584601231183131
[10]Burrowes DP, Medellin A, Harris AC, Milot L, Lethebe BC, Wilson SR. Characterization of Focal Liver Masses: A Multicenter Comparison of Contrast-Enhanced Ultrasound, Computed Tomography, and Magnetic Resonance Imaging. J Ultrasound Med. 2021 Dec;40(12):2581-2593
[11]Medical Imaging Signals and Systems. Second Edition. Eds: Prince CL, Links JM. Pearson Education Inc. 2015
[12]Medical Imaging Systems. An Introductory Guide. Eds: Maier M, Steidl S, Christlein V, Hornegger J, Springer Open 2018
[13]Frinking P, Segers T, Luan Y, Tranquart F. Three Decades of Ultrasound Contrast Agents: A Review of the Past, Present and Future Improvements. Ultrasound Med Biol. 2020 Apr;46(4):892-908
[14]Yusefi H, Helfield B. Ultrasound Contrast Imaging: Fundamentals and Emerging Technology. Front Phys. 2022;10:791145
[15]Owens TC, Anton N, Attia MF. CT and X-ray contrast agents: Current clinical challenges and the future of contrast. Acta Biomater. 2023 Nov;171:19-36
[16]Lohrke J, Frenzel T, Endrikat J, Alves FC, Grist TM, Law M, et al. 25 Years of Contrast-Enhanced MRI: Developments, Current Challenges and Future Perspectives. Adv Ther. 2016 Jan;33(1):1-28
[17]Chandra T, Mohan S. Role of Contrast in MR Imaging. Top Magn Reson Imaging. 2016 Aug;25(4):151-6
[18]Marks RM, Masch WR, Chernyak V. LI-RADS: Past, Present, and Future, From the AJR Special Series on Radiology Reporting and Data Systems. AJR Am J Roentgenol. 2021 Feb;216(2):295-304
[19]Bargellini I, Battaglia V, Bozzi E, Lauretti DL, Lorenzoni G, Bartolozzi C. Radiological diagnosis of hepatocellular carcinoma. J Hepatocell Carcinoma. 2014;1:137-48
[20]Dietrich CF, Nolsoe CP, Barr RG, Berzigotti A, Burns PN, Cantisani V, et al. Guidelines and Good Clinical Practice Recommendations for Contrast-Enhanced Ultrasound (CEUS) in the Liver-Update 2020 WFUMB in Cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS. Ultrasound Med Biol. 2020 Oct;46(10):2579-604
[21]Kim TK, Noh SY, Wilson SR, Kono Y, Piscaglia F, Jang HJ, et al. Contrast-enhanced ultrasound (CEUS) liver imaging reporting and data system (LI-RADS) 2017 – a review of important differences compared to the CT/MRI system. Clin Mol Hepatol. 2017 Dec;23(4):280-9
[22]Wilson SR, Lyshchik A, Piscaglia F, Cosgrove D, Jang HJ, Sirlin C, et al. CEUS LI-RADS: algorithm, implementation, and key differences from CT/MRI. Abdom Radiol (NY). 2018 Jan;43(1):127-42
[23]Yang Q, Zheng R, Zhou J, Tang L, Zhang R, Jiang T, et al. On-Site Diagnostic Ability of CEUS/CT/MRI for Hepatocellular Carcinoma (2019-2022): A Multicenter Study. J Ultrasound Med. 2023 Dec;42(12):2825-38
[24]Islam, S.K.M.S., Nasim, M.A.A., Hossain, I., Ullah, D.M.A., Gupta, D.K.D., Bhuiyan, M.M.H. (2023). Introduction of Medical Imaging Modalities. In: Zheng, B., Andrei, S., Sarker, M.K., Gupta, K.D. (eds) Data Driven Approaches on Medical Imaging. Springer, Cham
[25]American College of Radiology (ACR). ACR Manual On Contrast Media – 2023
[26]Thrall JH. Appropriateness and imaging utilization: “computerized provider order entry and decision support”. Acad Radiol. 2014 Sep;21(9):1083-7
