State of the Art Imaging for Chronic Liver Disease

Chronic liver disease is an increasingly common and important disorder, now afflicting more than 25% of the world’s population. Regardless of its underlying cause, chronic liver disease can progress to cirrhosis, development of liver cancer, and liver-related death. Recent advances in imaging knowledge and technology have elevated the role of radiology in the diagnosis and management of patients with or at risk for chronic liver disease across its entire spectrum and course.

Noninvasive Monitoring of Chronic Liver Disease

With a rising epidemic of obesity and metabolic syndrome in the United States, nonalcoholic fatty liver disease and its progressive form, nonalcoholic steatohepatitis, are increasingly encountered in practice. Additionally, overconsumption of alcohol and viral hepatitis remain common causes of chronic liver disease. Irrespective of etiology, chronic liver disease represents a spectrum of inflammation, injury, fibrosis, and eventually, cirrhosis. Although in the past, cirrhosis was considered an irreversible injury, recent medical advances provide opportunities to halt and even reverse fibrosis. Likewise, identification and modulation of risk factors, like fat and iron deposition in the liver, are essential to managing patients at risk for or with chronic liver disease. Pathological assessment remains a reference standard, but risks and cost associated with biopsy reduce the benefit in the setting of longitudinal monitoring. Radiologists play an essential role in providing noninvasive quantitative information to direct management.

State of the art imaging options for assessing chronic liver disease focus on three key elements: liver fat, iron, and fibrosis. Liver fat can be identified by ultrasound, CT, and MRI. The most accurate, accessible, and precise method for monitoring patients with chronic liver disease is MRI-proton density fat fraction (PDFF). MRI-PDFF takes advantage of the fact that owing to differences in molecular structures, fat and water protons experience different magnetic fields and precess at different rates. This offset in frequency (“chemical shift”) is the basis for in- and opposed-phase dual echo imaging with its familiar appearance, including “India ink” etching at fat-water interfaces on opposed-phase images, due to signal cancellation when water and fat are precessing directly opposite each other. MRI-PDFF expands on this concept and is estimated by acquiring images at multiple echo times, selected to optimize separation of fat and water signals, and by taking into account several confounders that otherwise introduce errors into fat quantification. Iron is one of the most important confounders and is also an important factor contributing to chronic liver disease. Iron is ferromagnetic and causes signal decay (T2*), due to disruption of local magnetic fields. The decay of signal over time (R2*) is directly proportional to iron content over a wide pathophysiological spectrum, allowing us to estimate R2* values and convert them to liver iron concentrations. Hence, MRI-PDFF quantifies both fat and iron.

The most validated and clinically used method for estimating liver fibrosis is elastography. Elastography can be done with ultrasound or MRI. Elastography is an imaging technique that quantifies the stiffness of tissue, or resistance to deformation following application of external pressure. Imaging methods estimate stiffness by generating shear waves in the liver and measuring their propagation. Ultrasound methods differ based on how they generate shear waves and whether they produce gray-scale images (point shear wave elastography and 2D elastography) or not (vibration controlled transient elastography). Ultrasound methods measure shear wave speed, which can be converted into tissue stiffness values. The speed measurements may differ between manufacturers and etiologies of chronic liver disease, which challenges establishment of universal thresholds for stages of fibrosis. Magnetic resonance elastography (MRE) utilizes a standard system for shear wave generation and measurement across all vendors and platforms; as a result, the tissue stiffness values obtained from MRE are thought to be more reproducible.

Standardizing Diagnosis of Liver Cancer in Patients with Chronic Liver Disease

Hepatocellular carcinoma (HCC) can be confidently diagnosed based on imaging, in contradistinction to most malignancies that require tissue examination for their diagnosis. The noninvasive diagnosis of HCC is justified by the high positive predictive value of CT and MRI for this purpose when stringent criteria are applied in high-risk patients (i.e., high pre-test probability). Filippone A, Blakeborough A, Breuer J, et al. Enhancement of liver parenchyma after injection of hepatocyte-specific MRI contrast media: a comparison of gadoxetic acid and gadobenate dimeglumine. J Magn Reson Imaging 2010; 31:356–364

Roberts LR, Sirlin CB, Zaiem F, et al. Imaging for the diagnosis of hepatocellular carcinoma: A systematic review and meta-analysis. Hepatology 2018; 67:401–21

Hanna RF, Miloushev VZ, Tang A, et al. Comparative 13-year meta-analysis of the sensitivity and positive predictive value of ultrasound, CT, and MRI for detecting hepatocellular carcinoma. Abdom Radiol (NY) 2016; 41:71–90 Additionally, cross-sectional imaging assesses local spread and distant metastases.

Current standards in the noninvasive diagnosis of HCC follow the guidelines of the American Association for the Study of Liver Disease (AASLD), Organ Procurement and Transplantation Network (OPTN), and Liver Imaging Reporting and Data System (LI-RADS). Duncan JK, Ma N, Vreugdenburg TD, Cameron AL, Maddern G. Gadoxetic acid-enhanced MRI for the characterization of hepatocellular carcinoma: a systematic review and meta-analysis. J Magn Reson Imaging 2017; 45:281–290

Guo J, Seo Y, Ren S, et al. Diagnostic performance of contrast-enhanced multidetector computed tomography and gadoxetic acid disodium-enhanced magnetic resonance imaging in detecting hepatocellular carcinoma: direct comparison and a meta-analysis. Abdom Radiol (NY) 2016; 41:1960–1972

Liu X, Jiang H, Chen J, Zhou Y, Huang Z, Song B. Gadoxetic acid disodiumenhanced magnetic resonance imaging outperformed multidetector computed tomography in diagnosing small hepatocellular carcinoma: a meta-analysis. Liver Transpl 2017; 23:1505–1518 These guidelines agree on certain imaging features that should be present in an observation to provide the required high positive predictive value for HCC, such as a maximum diameter of at least 10 mm and characteristic dynamic enhancement characteristics discussed further below. Distinct differences used to exist between the three guidelines in the categorization of hepatic lesions, until the release of the latest LI-RADS guidelines for CT and MRI in 2018. The latest release comprised minor modifications to LI-RADS version 2017 to facilitate its integration into the AASLD clinical practice guidelines in August 2018. Matsui O, Kobayashi S, Sanada J, et al. Hepatocelluar nodules in liver cirrhosis: hemodynamic evaluation (angiography-assisted CT) with special reference to multi-step hepatocarcinogenesis. Abdom Imaging 2011; 36:264–272 LI-RADS and AASLD now have identical criteria for definite HCC, and the OPTN criteria are nearly identical to LI-RADS and AASLD.

LI-RADS is a comprehensive system that provides standards for terminology, technique, interpretation, and reporting of liver imaging. It has been developed by a multi-disciplinary and increasingly international team of diagnostic and interventional radiologists, hepatobiliary surgeons, hepatologists, and hepatopatholgists, alongside support from the American College of Radiology. Choi YS, Rhee H, Choi JY, et al. Histological characteristics of small hepatocellular carcinomas showing atypical enhancement patterns on gadoxetic acid enhanced MR imaging. J Magn Reson Imaging 2013; 37:1384–1391 Since its first release in 2011, LI-RADS has been updated periodically, with the latest update in 2018. Kitao A, Matsui O, Yoneda N, et al. The uptake transporter OATP8 expression decreases during multistep hepatocarcinogenesis: correlation with gadoxetic acid enhanced MR imaging. Eur Radiol 2011; 21:2056–2066

Kim BR, Lee JM, Lee DH, et al. Diagnostic performance of gadoxetic acid-enhanced liver MR imaging versus multidetector CT in the detection of dysplastic nodules and early hepatocellular carcinoma. Radiology 2017; 285:134–146

Nakamura S, Nouso K, Kobayashi Y, et al. The diagnosis of hypovascular hepatic lesions showing hypo-intensity in the hepatobiliary phase of Gd-EOBDTPA-enhanced MR imaging in high-risk patients for hepatocellular carcinoma. Acta Med Okayama 2013; 67:239–244
LI-RADS assigns a diagnostic category code for each observation to communicate the likelihood of being benign or being HCC, ranging from LR-1 (definitely benign) to LR-5 (definitely HCC). The LR-5 category has a reported specificity of 95% for HCC. In addition to the previous five categories, LI-RADS also provides three other categories—LR-NC (not categorizable), LR-TIV (tumor in vein), and LR-M (probably or definitely malignant, not necessarily HCC)—with certain criteria for each category.

The imaging diagnosis of HCC in LI-RADS is based on the presence or absence of five major imaging features and a number of ancillary features (AFs). Major features include nonrim arterial phase hyperenhancement (APHE), nonperipheral “washout” appearance, enhancing “capsule” appearance, size, and threshold growth.

The AFs are divided into three groups: AFs that favor malignancy in general, AFs that favor HCC in particular, and AFs that favor benignity. A preliminary LI-RADS category is assigned based on the present major features, then the AFs are used at the interpreter’s discretion to adjust the preliminary category.

In summary, the latest advances in imaging of HCC allow for a confident noninvasive diagnosis of this malignancy and comprehensive assessment of other lesions and pseudolesions depicted by imaging.

Improving Sensitivity for Liver Cancer Diagnosis with HBAs

HBAs are gadolinium-based intravenous MR contrast agents that permit hepatobiliary phase (HBP) imaging, in addition to conventional dynamic post-contrast phases. Gadoxetate disodium is the most commonly utilized HBA, due to high hepatobiliary excretion and convenient HBP timing of 10–30 minutes.

Gadoxetate offers several advantages for patients with cirrhosis. Of all available modalities, gadoxetate-enhanced MRI has the highest overall per-lesion sensitivity (86%) and positive predictive value (94%) for diagnosis of HCC, as well as the highest sensitivity (84–96%) for detection of ≤ 2 cm HCCs. Unlike APHE, reduced gadoxetate uptake is an early event in hepatocarcinogenesis: up to 38% of early HCCs may be seen only on the HBP, and 82% of high-grade dysplastic nodules (DN) and 76% of early HCCs are hypointense on the HBP.

HBP hypointense nodules without APHE are unique to HBA MRI. If sampled histologically, 74% of such nodules are HCCs, and 10% are DN, although these numbers may be inflated by selection bias; if followed, 16–43% progress to hypervascular HCC within 24 months. Nakamura S, Nouso K, Kobayashi Y, et al. The diagnosis of hypovascular hepatic lesions showing hypo-intensity in the hepatobiliary phase of Gd-EOBDTPA-enhanced MR imaging in high-risk patients for hepatocellular carcinoma. Acta Med Okayama 2013; 67:239–244

Cho YK, Kim JW, Kim MY, Cho HJ. Non-hypervascular hypointense nodules on hepatocyte phase gadoxetic acid-enhanced MR images: transformation of MR hepatobiliary hypointense nodules into hypervascular hepatocellular carcinomas. Gut and Liver 2018; 12:79–85

Saitoh T, Sato S, Yazaki T, et al. Progression of hepatic hypovascular nodules with hypointensity in the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI in hepatocellular carcinoma cases. Intern Med 2018; 57:165–171

Yang HJ, Song JS, Choi EJ, Choi H, Yang JD, Moon WS. Hypovascular hypointense nodules in hepatobiliary phase without T2 hyperintensity: longterm outcomes and added value of DWI in predicting hypervascular transformation. Clin Imaging 2018; 50:123–129

Hwang JA, Kang TW, Kim YK, et al. Association between non-hypervascular hypointense nodules on gadoxetic acid-enhanced MRI and liver stiffness or hepatocellular carcinoma. Eur J Radiol 2017; 95:362–369

Briani C, Di Pietropaolo M, Marignani M, et al. Non-hypervascular hypointense nodules at gadoxetic acid MRI: hepatocellular carcinoma risk assessment with emphasis on the role of diffusion-weighted imaging. J Gastrointest Cancer 2018; 49:302–310

Kim YS, Song JS, Lee HK, Han YM. Hypovascular hypointense nodules on hepatobiliary phase without T2 hyperintensity on gadoxetic acid-enhanced MR images in patients with chronic liver disease: long-term outcomes and risk factors for hypervascular transformation. Eur Radiol 2016; 26:3728–3736

Rosenkrantz AB, Pinnamaneni N, Kierans AS, Ream JM. Hypovascular hepatic nodules at gadoxetic acid-enhanced MRI: whole-lesion hepatobiliary phase histogram metrics for prediction of progression to arterial-enhancing hepatocellular carcinoma. Abdom Radiol (NY) 2016; 41:63–70 In patients who undergo resection for early-stage HCC, the presence of HBP hypointense nodules predicts high HCC recurrence risk and lower overall survival. Toyoda H, Kumada T, Tada T, Sone Y, Maeda A, Kaneoka Y. Nonhypervascular hypointense nodules on Gd-EOB-DTPA-enhanced MRI as a predictor of outcomes for early-stage HCC. Hepatol Int 2015; 9:84–92 Intermediate to long-term recurrence-free survival may be improved, if these nodules are treated concomitantly at the time of HCC resection. Matsuda M, Ichikawa T, Amemiya H, et al. Preoperative gadoxetic acid-enhanced MRI and simultaneous treatment of early hepatocellular carcinoma prolonged recurrence-free survival of progressed hepatocellular carcinoma patients after hepatic resection. HPB Surg 2014; 2014:641685

HBP hypointense nodules without APHE are also markers of increased HCC risk elsewhere in the liver: the cumulative three year rate of HCC elsewhere in the liver is 22%, compared to 6% in patients with no such nodules. Komatsu N, Motosugi U, Maekawa S, et al. Hepatocellular carcinoma risk assessment using gadoxetic acid-enhanced hepatocyte phase magnetic resonance imaging. Hepatol Res 2014; 44:1339–1346 Presence of these nodules in patients with early HCC is associated with decreased recurrence-free survival and higher intrahepatic recurrence rates following resection or ablation. Inoue M, Ogasawara S, Chiba T, et al. Presence of non-hypervascular hypointense nodules on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging in patients with hepatocellular carcinoma. J Gastroenterol Hepatol 2017; 32:908–915

Lee DH, Lee JM, Lee JY, et al. Non-hypervascular hepatobiliary phase hypointense nodules on gadoxetic acid-enhanced MRI: risk of HCC recurrence after radiofrequency ablation. J Hepatol 2015; 62:1122–1130

Song KD, Rhim H, Lee MW, Kim YS, Kang TW. Intrahepatic distant recurrence after radiofrequency ablation for hepatocellular carcinoma: precursor nodules on pre-procedural gadoxetic acid-enhanced liver magnetic resonance imaging. Acta Radiol 2017; 58:778–785

The degree of gadoxetate uptake may predict tumor differentiation: poorly-differentiated HCCs are more frequently HBP hypointense (98%), compared with well- or moderately-differentiated HCCs (86%). Erra P, Puglia M, Ragozzino A, et al. Appearance of hepatocellular carcinoma on gadoxetic acid-enhanced hepatobiliary phase MR imaging: a systematic review. La Radiol Med 2015; 120:1002–1011 Up to 15% of HCCs may be iso- or hyperintense on the HBP, and such HCCs have more favorable outcomes, including improved recurrence-free and overall survival. Kim JY, Kim MJ, Kim KA, Jeong HT, Park YN. Hyperintense HCC on hepatobiliary phase images of gadoxetic acid-enhanced MRI: correlation with clinical and pathological features. Eur J Radiol 2012; 81:3877–3882

Kitao A, Matsui O, Yoneda N, et al. Hypervascular hepatocellular carcinoma: correlation between biologic features and signal intensity on gadoxetic acid-enhanced MR images. Radiology 2012; 265:780–789

Kitao A, Zen Y, Matsui O, et al. Hepatocellular carcinoma: signal intensity at gadoxetic acid-enhanced MR Imaging–correlation with molecular transporters and histopathologic features. Radiology 2010; 256:817–826

Use of gadoxetate in patients with cirrhosis is associated with several important pitfalls. Smaller contrast dose and volume affect timing of the arterial phase (AP) and may lead to reduced peak enhancement of HCC in the AP. Fujinaga Y, Ohya A, Matsushita T, Kurozumi M, Ueda K, Kitou Y, et al. Effect of hepatobiliary uptake of Gd-EOB-DTPA on the hepatic venous phase of dynamic magnetic resonance imaging on a 3.0-T apparatus: comparison between Gd-EOB-DTPA and Gd-DTPA. Jpn J Radiol 2011; 29:695–700

Tirkes T, Mehta P, Aisen AM, Lall C, Akisik F. Comparison of dynamic phase enhancement of hepatocellular carcinoma using gadoxetate disodium vs gadobenate dimeglumine. J Comput Assist Tomogr 2015; 39:479–482 Furthermore, gadoxetate is associated with higher incidence (5–22%) of transient severe motion, which occurs at or around the time of the late AP and leads to image degradation. Davenport MS, Viglianti BL, Al-Hawary MM, et al. Comparison of acute transient dyspnea after intravenous administration of gadoxetate disodium and gadobenate dimeglumine: effect on arterial phase image quality. Radiology 2013; 266:452–461

Davenport MS, Bashir MR, Pietryga JA, Weber JT, Khalatbari S, Hussain HK. Dose-toxicity relationship of gadoxetate disodium and transient severe respiratory motion artifact. AJR 2014; 203:796–802

Kim SY, Park SH, Wu EH, et al. Transient respiratory motion artifact during arterial phase MRI with gadoxetate disodium: risk factor analyses. AJR 2015; 204:1220–1227 Poor quality of the AP may affect depiction of APHE, a feature that is required for noninvasive HCC diagnosis. Chernyak V, Fowler KJ, Kamaya A, et al. Liver imaging reporting and data system (LI-RADS) version 2018: imaging of hepatocellular carcinoma in at-risk patients. Radiology 2018; 289:816–830

Portal venous phase (PVP) “washout” appearance in combination with APHE allows for nearly 100% specificity of HCC diagnosis. Marrero JA, Hussain HK, Nghiem HV, Umar R, Fontana RJ, Lok AS. Improving the prediction of hepatocellular carcinoma in cirrhotic patients with an arterially-enhancing liver mass. Liver Transpl 2005; 11:281–289 Parenchymal uptake of gadoxetate starting as early as the PVP results in observations potentially appearing relatively hypointense to the parenchyma, due to lower uptake of gadoxetate rather than true “washout.” As a result, hypointensity in the transitional phase (TP) is not equivalent to hypointensity during the PVP or delayed phases with extracellular agents: if hypointensity in the TP is considered “washout,” the specificity for HCC decreases from 98–100% to 86–95%. Choi SH, Lee SS, Kim SY, Park SH, Park SH, Kim KM, et al. Intrahepatic cholangiocarcinoma in patients with cirrhosis: differentiation from hepatocellular carcinoma by using gadoxetic acid-enhanced MR imaging and dynamic CT. Radiology 2017; 282:771–781 Therefore, LI-RADS restricts assessment of “washout” with gadoxetate to the PVP. Santillan C, Fowler K, Kono Y, Chernyak V. LI-RADS major features: CT, MRI with extracellular agents, and MRI with hepatobiliary agents. Abdom Radiol (NY) 2018; 43:75–81 Another effect of the early parenchymal enhancement with gadoxetate is the potential to obscure enhancement of the “capsule.”

In patients with decompensated cirrhosis, diminished parenchymal uptake of gadoxetate results in less enhancement during the TP and the HBP. Motosugi U, Ichikawa T, Sou H, et al. Liver parenchymal enhancement of hepatocyte-phase images in Gd-EOB-DTPA-enhanced MR imaging: which biological markers of the liver function affect the enhancement? J Magn Reson Imaging 2009; 30:1042–1046 As a result, conspicuity of HCC in the HBP is decreased in patients with poor hepatic function. Kim JY, Lee SS, Byun JH, et al. Biologic factors affecting HCC conspicuity in hepatobiliary phase imaging with liver-specific contrast agents. AJR 2013; 201:322–331 Additionally, interpretation of HBP intensity of liver observations—particularly if iso- or hyperintense to the background— may be unreliable in the setting of suboptimal HBP enhancement.

Although HBP hypointensity improves detection of HCC and high-grade DN, TP and HBP hypointensity are not specific to HCC, as any lesion without functional hepatocytes (e.g., cysts, hemangiomas, non-HCC malignancies, etc.) will appear hypointense in the HBP. Joo I, Lee JM, Lee DH, Jeon JH, Han JK, Choi BI. Noninvasive diagnosis of hepatocellular carcinoma on gadoxetic acid-enhanced MRI: can hypointensity on the hepatobiliary phase be used as an alternative to washout? Eur Radiol 2015; 25:2859–68

In conclusion, use of gadoxetate in patients with cirrhosis offers certain advantages—particularly higher sensitivity for HCC, if liver function is preserved and AP quality is adequate—but radiologists should be aware of the various pitfalls of gadoxetate to optimize patient selection and image interpretation.

Acknowledgements
Kathryn Fowler, Claude Sirlin, and Victoria Chernyak also contributed to this article.

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