Version May 2024
INTRODUCTION — Contrast-enhanced ultrasound (CEUS) is a diagnostic technique for imaging the liver and other organs [1-7]. It is used in most of Europe and Asia, as well as in many other countries worldwide. Guidelines for the use of ultrasound and CEUS-guided applications of the liver have been published [7-14].
This topic will review the role of CEUS in evaluating liver lesions, including the indications for the procedure and findings associated with various lesions. The general evaluation of liver lesions is discussed in detail elsewhere. (See "Approach to the adult patient with an incidental solid liver lesion" and "Diagnosis and management of cystic lesions of the liver".)
GENERAL PRINCIPLES
Standard CEUS — Contrast-enhanced ultrasound (CEUS) uses ultrasound contrast agents to improve visualization and characterization of anatomic structures and lesions. It is most often performed transcutaneously, though it can also be used intraoperatively. There are several contrast agents available for CEUS. Ultrasound contrast agents are microbubbles consisting of gas bubbles stabilized by a shell. The most commonly used include sulfur hexafluoride with a phospholipid shell (SonoVue/Lumason), octafluoropropane (perflutren with a lipid shell; Definity/Luminity), and perfluorobutane with a phospholipid shell (Sonazoid). The contrast agent Lumason (sulfur hexafluoride lipid microspheres) was approved by the Food and Drug Administration for the examination of the liver in adult and pediatric patients [15]. (See "Contrast echocardiography: Contrast agents, safety, and imaging technique", section on 'Second-generation contrast agents' and "Clinical features and diagnosis of hepatocellular carcinoma".)
Ultrasound contrast agents are 1 to 10 microns in size (equal to or smaller than red blood cells) and permit visualization of both macrovasculature and microvasculature. The minute bubbles survive transpulmonary passage and recirculate, producing systemic ultrasound enhancement. This is an advantage over larger molecules that are retained in vascular beds [1,2,16]. Most ultrasound contrast agents are confined to the vascular space. By contrast, most of the contrast agents used for computed tomography or magnetic resonance imaging (MRI) are rapidly cleared from the blood pool into the extravascular space [2]. Because ultrasound contrast agents remain within the vascular space, only a small amount of contrast agent is required (typically 1 to 2 mL).
CEUS permits real-time visualization of contrast-enhancement patterns during all vascular phases (arterial, portal-venous, and late) [17]. This results in higher temporal resolution than can be achieved with other imaging modalities. The arterial phase provides information on the extent and pattern of the vascular supply. The arterial phase starts 10 to 20 seconds after contrast agent injection and lasts approximately 25 to 35 seconds. The portal-venous phase starts a few seconds after the arterial phase. It typically lasts until two minutes after contrast agent injection. The portal-venous phase is followed by the late phase, which lasts until the ultrasound contrast agents are cleared from the circulation (typically four to six minutes). In the case of the contrast agent Sonazoid, it is not generally taken up by liver-specific phagocyting Kupffer cells, so there is an additional post-vascular (or Kupffer) phase that starts 10 minutes after injection and lasts for an hour or more [1,2,18-21]. The images are analogous to those obtained with liver-specific hepatocyte-excreting gadolinium-ethoxybenzyl-diethylenetriamine-enhanced MRI [17].
Additional CEUS imaging techniques — Dynamic CEUS is a method that evaluates the time intensity curves and, therefore, enhancement characteristics of a lesion [6]. It can be used to monitor the response of tumors being treated with antiangiogenic or antivascular treatments [1,2]. It is based on time intensity curve analysis (contrast kinetics), dynamic vascular patterns (which demonstrate variability in vascularization within a tumor) [22], and hepatic vein transit times (which are shortened in the presence of hepatic malignancies, presumably because of intrahepatic shunting, although similar findings may be seen in the setting of cirrhosis) [23-27].
Other CEUS techniques that have been developed include real-time three-dimensional CEUS imaging [28] and contrast-enhanced endoscopic ultrasound of the liver [29-31].
ADVANTAGES OF CEUS — Contrast-enhanced ultrasound (CEUS) of the liver has several advantages compared with other imaging modalities, including improved lesion characterization compared with grayscale (B-mode) ultrasound [1,2,32-35], portability, lack of radiation exposure (which may be of particular importance in patients who require repeated examinations) [36,37], and use of contrast agents that do not contain iodine and are not nephrotoxic [33]. In addition, the shorter contrast elimination time (ie, within approximately 20 minutes) is advantageous rather than the elimination times associated with other contrast-enhanced, cross sectional imaging techniques. (See "Principles of magnetic resonance imaging".)
Other advantages of CEUS include [38]:
●Most ultrasound contrast agents remain within the vascular space and do not extravasate into the interstitial space, resulting in isolated enhancement of the vascular system. This permits superior depiction of vascular morphology on CEUS compared with either CT or MRI [39].
●CEUS enhances and defines structural anatomy and can quantify tissue perfusion, even at the capillary level in vessels measuring less than 100 microns in diameter [16,40].
●CEUS can be performed without any previous laboratory testing for renal or liver function.
Imaging liver tumors with CEUS can give immediate results regarding malignancy, and studies have reported a reduction in time to diagnosis when using CEUS compared with CT or MRI [41]. A shorter time to diagnosis may result in decreased patient anxiety in the case of benign lesions, and permits swift therapeutic intervention when necessary. In addition, if CEUS is nondiagnostic, it can be used to guide a real time biopsy, avoiding unnecessary additional imaging.
INDICATIONS — Where available, contrast-enhanced ultrasound (CEUS) is used to evaluate focal liver lesions, to guide tissue sampling, to help plan and monitor treatment in patients with hepatic tumors or abscesses, to evaluate for hepatic trauma, and to assess patients undergoing liver transplantation. As with other imaging studies, CEUS results must be interpreted taking into account the patient’s clinical history, examination, and laboratory findings.
In the appropriate clinical setting, hemangiomas, focal nodular hyperplasia, focal fatty change, and malignancies (eg, metastases and primary liver tumors) can be diagnosed with confidence if typical enhancement patterns are seen. If the enhancement patterns are atypical or if the examination is technically suboptimal, additional investigation is required (typically contrast-enhanced magnetic resonance imaging [MRI] or liver biopsy) [1,2]. (See 'Findings associated with specific lesions' below.)
Detection and characterization of liver lesions — CEUS can be used to evaluate focal liver lesions discovered with other imaging modalities, including lesions discovered in patients undergoing surveillance for hepatocellular carcinoma (HCC).
CEUS can differentiate benign from malignant lesions in most patients with healthy liver parenchyma and can guide biopsies when needed. CEUS can also be used to detect liver metastases in patients with extrahepatic malignancies.
Focal liver lesions — One of the primary roles for CEUS is for the diagnosis, differential diagnosis, and follow-up of patients with focal liver lesions [32,42-46]. In this setting, CEUS has a sensitivity of approximately 95 percent and a specificity of approximately 94 percent for diagnosing malignancy. (See 'Accuracy' below.)
CEUS is used to characterize focal liver lesions in the following settings:
●A focal liver lesion is incidentally detected with B mode ultrasound.
●A nodule is detected in a patient undergoing surveillance for HCC. (See "Surveillance for hepatocellular carcinoma in adults".)
●A focal liver lesion is seen on computed tomography (CT) or MRI, but the findings are inconclusive (eg, an indeterminate lesion, especially in nodules not suitable for biopsy).
●To monitor changes in the size and enhancement patterns of a focal liver lesion over time when initial imaging is not diagnostic and the decision has been made to follow the lesion with serial imaging.
●To characterize focal liver lesions with inconclusive cytology or histology following tissue sampling.
CEUS can also be used to guide biopsies of focal liver lesions. CEUS-guided liver biopsies have a higher diagnostic accuracy than those guided by unenhanced ultrasound. In a study that looked at 107 patients with 140 lesions, CEUS-guided biopsies had a diagnostic accuracy of 95 percent, compared with 87 percent for biopsies guided by unenhanced ultrasound [47]. This improved accuracy may in part be due to the fact that CEUS can target vascularized (viable) areas of the tumor and avoid areas of necrosis. If there are multiple lesions seen, CEUS can be used to select the most appropriate lesion(s) for biopsy.
Liver metastases — CEUS is similar to CT and MRI for detecting liver metastases [1,2,48-51]. The dual blood supply of the liver from the hepatic artery (25 to 30 percent) and the portal vein (70 to 75 percent) permits detection and characterization of focal liver lesions based on vascular enhancement patterns. (See 'Malignant lesions' below.)
CEUS improves the detection of metastases in patients with a history of colorectal cancer who are undergoing surveillance [52].
Treatment planning — In patients with malignant lesions, CEUS can be used to plan for nonsurgical therapies for hepatocellular carcinoma (eg, radiofrequency ablation, microwave ablation, irreversible electroporation) [53,54], to assess lesions for resectability, and to help differentiate benign thrombi from neoplastic infiltration of the hepatic vessels. (See "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates who are eligible for local ablation".)
Transcutaneous CEUS — In patients undergoing radiofrequency ablation, CEUS can [1,2]:
●Complement contrast-enhanced CT or MRI for pretreatment staging and assessment of target lesion vascularity
●Facilitate needle positioning in cases of incomplete or poor lesion delineation on unenhanced ultrasound
●Evaluate the immediate treatment effect after ablation and guide immediate retreatment of residual tumor
CEUS is also helpful for differentiating between venous thrombosis and tumor infiltration of hepatic vessels. Venous thrombi are avascular, so they are nonenhancing in all phases, whereas neoplastic infiltration displays the same enhancement characteristics as the tumor from which it originated. (See "Chronic portal vein thrombosis in adults: Clinical manifestations, diagnosis, and management", section on 'Differential diagnosis'.)
Intraoperative CEUS — Intraoperative CEUS can be used to determine whether a hepatic tumor (either a primary tumor or metastatic lesion) is resectable [19,21,55-57]. It is also used to characterize nodules detected with unenhanced intraoperative ultrasound in patients with cirrhosis who are undergoing liver resection for HCC [1,2].
Studies suggest that intraoperative CEUS is more sensitive, specific, and accurate than unenhanced intraoperative ultrasound, contrast-enhanced CT, or contrast-enhanced MRI for assessing tumor resectability [57], and that CEUS leads to a change in surgical management in up to 30 percent of cases [2,55-57]. However, in practice, positioning of the transducer may be more difficult than has been described in studies.
Treatment monitoring — Patients with liver tumors that are being treated with ablation or chemotherapy/radioembolization need follow-up imaging to assess the initial treatment response and to look for signs of tumor progression (image 1) [1,2]. CEUS can be used if contrast-enhanced CT or MRI are inconclusive, to avoid radiation exposure, or in addition to CT or MRI. (See "Assessment of tumor response in patients receiving systemic and nonsurgical locoregional treatment of hepatocellular cancer".)
Liver transplantation — Prior to liver transplantation, CEUS can be used to rapidly assess patency of the hepatic artery and portal vein and to characterize focal liver lesions. CEUS can be helpful in the post-surgical phase to detect vascular complications noninvasively, particularly at the bedside or in the intensive care unit, avoiding most of the risks associated with contrast-enhanced CT or angiography.
Other diagnostic and therapeutic uses — CEUS can also be used to [1,2]:
●Evaluate vascular lesions, such as aneurysms and pseudoaneurysms of the hepatic arteries.
●Diagnose liver infarction in patients with sickle cell anemia.
●Guide percutaneous transhepatic cholangiography and drainage [58].
ACCURACY — Studies looking at CEUS for the characterization of focal liver lesions have estimated that CEUS has a sensitivity of approximately 95 percent and a specificity of approximately 94 percent for diagnosing malignancy [59-63]. Studies also suggest that CEUS is similar (or possibly superior) to contrast-enhanced computed tomography (CT) and contrast-enhanced magnetic resonance imaging (MRI) for the diagnosis of focal liver lesions [33,48,49,59-61,64-69].
A meta-analysis of 21 studies (22 publications) compared CEUS with other imaging modalities for a variety of indications [60]. Using variable diagnostic criteria, the sensitivity for diagnosing malignancy was 27 to 98 percent for CEUS, 47 to 98 percent for contrast-enhanced CT, and 44 to 97 percent for contrast-enhanced MRI. Sensitivities were generally lower for small lesions compared with larger lesions. Specificities were 50 to 100 percent, 71 to 100 percent, and 62 to 100 percent, respectively. For incidentally detected liver lesions, the pooled sensitivity for CEUS was 95 percent (95% CI 93-97 percent) and for CT was 95 percent (95% CI 93-96 percent), based on the data from four studies. The pooled specificity for CEUS was 94 percent (95% CI 90-96 percent) and for CT was 93 percent (95% CI 90-96 percent).
Discordant findings between CEUS and contrast-enhanced CT could occur for several reasons, including differences in timing of contrast administration and imaging, diffusion of contrast, and the influence of fat on lesion characterization [62,70]. With CEUS, the bolus of microbubbles (1.2 to 4.8 mL) is administered over a few seconds, which may be more temporally sensitive than the larger volume CT contrast agent (140 mL) injected over 40 seconds. In addition, diffusion into the interstitium of the contrast agent used for CT and the subsequent slow wash-out can result in erroneous diagnoses based on portal-venous phase enhancement patterns. Portal-venous phase wash-out that is evident with CEUS may not be apparent with contrast-enhanced CT. In addition, the predetermined scan delay in contrast-enhanced CT can miss the rapid initial wash-in and arterial phase hypervascular response that can be seen with CEUS, which acquires images in real-time. (See 'Standard CEUS' above.)
The fat content of the liver lesion and surrounding parenchyma may also result in discordant results between CEUS and contrast-enhanced CT. Fat is echogenic and can attenuate the difference in appearance between the microbubbles and the tissue, making lesion characterization with CEUS more difficult [70].
FINDINGS ASSOCIATED WITH SPECIFIC LESIONS — Liver lesion characterization is based on real-time evaluation of contrast enhancement of the lesion (hypoenhancing, isoenhancing, hyperenhancing) compared with the surrounding liver parenchyma. It is assessed during the arterial phase, portal-venous phase, and late phase.
Characterization starts by assessing the initial pattern of contrast enhancement within the lesion (central or peripheral) and specific vascularization patterns (eg, wheel-spoke pattern, nodular or rim enhancement, diffuse enhancement) seen in the arterial and portal-venous phases. Vascularization patterns are helpful because benign lesions (except cysts and calcifications) contain, in addition to hepatic arteries, liver-specific portal veins and sinusoids [33,71].
Enhancement patterns during the portal-venous and late phases provide additional important information for characterizing liver lesions; typically, malignant lesions are hypoenhancing (image 2), whereas the majority of solid, benign lesions are isoenhancing or hyperenhancing [1,2,72,73].
Published data on CEUS characterization of liver lesions include histologically confirmed hemangioma [74], focal nodular hyperplasia [34,75], hepatocellular adenoma [34,75,76], cholangiocellular adenoma [77], cystadenoma and cystadenocarcinoma [78], and hemangioendothelioma [79,80]. Furthermore, data are available on the characterization of fibrolamellar HCC [81,82], very small HCC (HCC, sHCC <10 mm) [83], mixed HCC and cholangiocellular carcinoma (mHCC/CCC) [84], nodular regenerative hyperplasia [85], sarcoma [86], inflammatory pseudotumour [87], sarcoidosis [88-91], tuberculosis [92,93], hydatid cysts [94-97], alveolar echinococcosis [95], schistosomiasis [98,99], ascariasis [100,101], fasciolosis [102], clonorchis and opisthorchis [103], toxocariasis [104], bacillary angiomatosis [105], amyloidosis [106], as well as rare focal liver lesions in pediatric patients [107,108].
Benign lesions — Benign liver lesions that can be characterized by contrast-enhanced ultrasound (CEUS) include hemangiomas, focal nodular hyperplasia (FNH), hepatic adenomas, focal fatty infiltration, abscesses, and hematomas [109].
●Hemangiomas – CEUS improves the rate of correct diagnosis of hemangiomas from approximately 75 percent with unenhanced ultrasound to more than 95 percent [2,62,74]. In hemangiomas, the most common findings on CEUS are peripheral nodular enhancement in the arterial phase, followed by partial or complete centripetal fill-in (the iris diaphragm phenomenon) (image 3 and table 1) [17]. Enhancement is sustained through the late phase and, if Sonazoid was used as the contrast agent, through the post-vascular phase. (See 'Standard CEUS' above.)
Atypical features include [17]:
•Incomplete late filing in large (>4 cm) hemangiomas.
•"Shunt hemangiomas" (functionally described as high-flow hemangiomas) – These hemangiomas show rapid enhancement during the arterial phase (in a peripheral nodular pattern), markedly hypervascular appearance, and arterio-portovenous shunts with early opacification of the draining portal vein [74,110]. Shunt hemangiomas are typically surrounded by focal hypoechoic areas, which represent reduced fat content in comparison with the surrounding liver parenchyma [74]. The reduced fat content may be explained by a mainly arterial blood supply of the hypoechoic areas, whereas blood supply of the surrounding liver parenchyma is mainly by portal vessels that contain more lipids and insulin. Shunt hemangiomas can be mistaken for hepatocellular carcinoma (HCC) or FNH.
•Sclerosing hemangiomas with abundant regressive changes and thrombosis.
●Focal nodular hyperplasia – The CEUS characteristics seen with focal nodular hyperplasia (FNH) reflect its central or eccentric vascular supply (image 4). FNH is hyperenhancing in the arterial and portal-venous phases in more than 90 percent of cases [111] (table 2). False hypoenhancement can sometimes be observed due to bubble destruction. Fill-in starts from the center of the lesion and then spreads outward in a wheel-spoke pattern. In the late phase, the perfusion pattern is typically hyperechoic or isoechoic.
●Hepatic adenomas – Hepatic adenomas typically show rapid arterial hyperenhancement that progresses from the periphery to the center (image 5) [17,75,112,113]. This pattern is also found in HCC and metastases, but is the opposite of what is seen in FNH, in which filling starts centrally and moves peripherally. In the late phase, there is gradual washout due to missing portal veins. Hemorrhagic areas are avascular and thus do not enhance in any phase.
Glycogen storage disease-associated hepatic adenomas typically show slight hypoenhancement in the portal-venous phase [75], whereas telangiectatic lesions may show hyperenhancement. In the case of portal-venous hypoenhancement, biopsy is required to make the diagnosis. In the case of suspected hepatic adenoma, biopsy should include the surrounding liver parenchyma to look for evidence of liver storage disease and for histology which has prognostic value [76]. Cholangiocellular adenomas also show hypoenhancement in the portal-venous phase [77].
●Focal fatty lesions (focal fatty infiltration) – Focal fatty changes (either fat infiltration or fatty sparing) are typical features of hepatic steatosis. They may simulate neoplasia on unenhanced ultrasound [4]. In the arterial, portal-venous, and late phases, focal fatty changes show similar enhancement patterns to those of the adjacent liver parenchyma [1,2]. Typically, centrally located arteries can be identified in focal fatty sparing [114-116], explaining the relatively lower fat concentration in such areas (arterial blood contains less lipids and insulin than blood from the portal vein). In focal fatty infiltration, portal-venous branches enter from the liver hilum and account for the higher fat concentration in such areas. Focal fatty sparing seen on ultrasound examination may be a sign of an adjacent focal liver lesion, so additional lesions should be sought during the CEUS examination [117,118].
●Abscess – Phlegmonous inflammation is sometimes confusing since it changes over time. Early lesions are hyperenhancing, while mature lesions develop hypo- or nonenhancing foci. Mature abscesses typically show marginal enhancement in the arterial phase. However, enhancement of septae followed by portal-venous hypoenhancement may also be seen. The most prominent feature is lack of enhancement in the liquefied portions [2,119-121].
●Hematoma – Circumscribed hematomas or diffuse (subcapsular) hemorrhages of the liver and spleen are most often a consequence of trauma [122-124]. CEUS has been proven to be especially helpful in the emergency setting [5,125]. Since ultrasound contrast agents are intravascular, it is easy to identify hematomas, which are nonenhancing. Computer tomography (CT) contrast agents, on the other hand, diffuse into the surrounding extravascular spaces. CEUS can also detect active bleeding by visualizing echoes within the collection and detecting possible vascular malformations that can cause bleeding [126].
●Other benign focal liver lesions – The use of CEUS has been described in case reports and case series with cystadenomas [78,127,128] inflammatory pseudotumors [87], fasciola hepatica [129], hydatid cysts [96], granulomas [34,130], tuberculosis [93], sarcoidosis [88,89,131], nodules in Wilson disease, peliosis hepatis [132-134], angiomyolipomas [135,136], hemangioendotheliomas [41,80], liver actinomycosis [137], hamartomas [138], nodular regenerative hyperplasia [85], echinococcosis [139], sickle cell anemia with liver infarction, bartonellosis [105], and pseudoaneurysms of hepatic arteries [140] and portal veins [141].
Malignant lesions — CEUS can detect malignant liver lesions such as HCC, cholangiocarcinoma, metastatic lesions, lymphoma, and angiosarcomas of the liver [86]. Malignant focal liver lesions appear variably as hyper-, iso-, or hypoenhancing lesions during the arterial phase, and as hypoenhancing during the portal-venous and late phases.
●Hepatocellular carcinoma – The appearance of HCC varies depending on whether the patient has cirrhosis.
•Patients without cirrhosis – HCC in the noncirrhotic liver is typically hyperenhancing in the arterial phase with a chaotic vascular pattern, and hypoenhancing in the portal-venous and late phases (image 2) [1,2,112,142,143]. However, well-differentiated (borderline) HCC is less likely to show arterial enhancement and is more likely to be isoenhancing in the late phase [17]. During the post-vascular phase (if Sonazoid is used as the contrast agent), HCC is typically hypoenhancing, which helps differentiate it from benign lesions that are iso- or hyperenhancing.
•Patients with cirrhosis – The development of HCC in patients with cirrhosis is explained by a multistep pathway [144-146], from regenerative nodule, low- or high-grade dysplastic nodule, dysplastic nodule with a focus of HCC, well-differentiated HCC, and finally moderately to poorly differentiated HCC. Progression along this pathway is accompanied by a decrease in both normal arterial and portal blood flow and is characterized by a progressive increase in arterial flow from newly formed tumor vessels (neoangiogenesis) and a concurrent disappearance of normal intranodular vessels. Therefore, hyperenhancement in the arterial phase can be seen in HCC of all stages of differentiation [1,2].
HCC shows homogenous (non-rim-like) arterial enhancement, especially in smaller lesions (<50 mm), with nonenhancing areas in larger lesions due to hemorrhage, necrosis, and calcifications. Atypical neoplastic vessels can be displayed in the arterial phase by their short course and tortuous pattern. The enhancement pattern in the portal-venous phase depends on the vascularity of the surrounding cirrhotic liver parenchyma, with most lesions showing mild hypoenhancement that is late in onset (>60 sec). Some HCCs do not demonstrate wash-out until three to four minutes after contrast injection. Studies with extended late phases have demonstrated that the timing of HCC wash-out correlates with tumor differentiation [147-152]. Well-differentiated HCCs wash out more slowly than poorly differentiated tumors. Therefore, the CEUS protocol is extended to at least four minutes to ensure that hypoenhancement is not missed. In such circumstances, intermittent imaging is performed to avoid bubble destruction [86]. By contrast, regenerative and dysplastic nodules are typically isoenhancing in all phases.
Following the FDA approval of the ultrasound contrast agent Lumason (sulfur hexafluoride lipid microspheres) for assessment of focal liver lesions, the American College of Radiology (ACR) endorsed a proposed Liver Imaging Reporting and Data System (LI-RADS) classification system for estimating the likelihood of HCC in at-risk patients based upon CEUS, and this has been subsequently updated [153-156]. Lesions are classified from 'definitely benign' (LR-1) to 'definitely HCC' (LR-5) based upon specific imaging criteria [157]. With use of the algorithm, LI-RADS provides standardized terminology, interpretation, and reporting of CEUS in at-risk patients and is not intended for use in the general population. (See "Clinical features and diagnosis of hepatocellular carcinoma".)
The key feature of CEUS in the diagnosis of hepatocellular carcinoma (HCC) in patients with cirrhosis is the detection of hyperenhancement of the nodule in comparison to the surrounding parenchyma in the arterial phase (whole or in part, not globular or rim-like), followed by washout in the late phase (late in onset ≥ 60 sec and mild in degree), when the nodule becomes hypoenhanced in comparison to the surrounding parenchyma. Sonographically distinct solid nodules ≥10 mm in diameter may be diagnosed as definite HCC (CEUS LR-5) if they show both of the mentioned two criteria [157].
●Intrahepatic cholangiocarcinoma – The typical CEUS pattern seen with intrahepatic cholangiocarcinomas is peripheral, rim-like contrast enhancement in the arterial phase and early hypoenhancement in the portal-venous and late phases, irrespective of whether the liver parenchyma is cirrhotic. This differs from the homogenous (non-rim-like) arterial enhancement of HCC, which often demonstrates isoenhancement during the later phases in liver cirrhosis [73,158]. Mixed forms of HCC and cholangiocarcinoma may occur [84].
●Metastases – Liver metastases show various contrast enhancement patterns during the arterial phase and are almost always hypoenhancing during the portal-venous and late phases [17]. CEUS is particularly sensitive for detecting metastases from neuroendocrine tumors [159,160]. If neuroendocrine tumor metastases are suspected, the CEUS evaluation should be prolonged up to five minutes [159,161]. False-negative findings are mainly explained by rarefaction of portal vein branches in the surrounding liver parenchyma, which may occur in severe, diffuse liver disease. False-positive findings are seen with focal inflammation, abscess, necrosis, fibrous tissue, and scarring. Since hypoenhancing lesions have to be biopsied for histologic confirmation, false-positive lesions are generally not a clinically significant problem.
●Lymphoma – Lymphoma shows variable arterial enhancement, depending on the underlying entity, and characteristic hypoenhancement in the portal-venous and late phases.
SAFETY — Ultrasound contrast agents are safe, with a very low incidence of side effects [1,2,162,163]. In the United States, the contrast agent sulfur hexafluoride lipid microspheres (Lumason) contains a boxed warning regarding the risk of rare but serious cardiopulmonary reactions and hypersensitivity reactions [164]. Patients should be assessed for conditions that preclude administration, and resuscitation equipment and trained personnel should be on site. The incidence of severe hypersensitivity events is lower than with iodinated contrast agents and is comparable to those encountered with magnetic resonance imaging contrast agents [1,2,162].
There are no hepatotoxic or nephrotoxic effects of ultrasound contrast agents. Therefore, it is not necessary to perform laboratory tests to assess liver or kidney function before administration.
Although Lumason (sulfur hexafluoride lipid microspheres) has been approved by the FDA for use in adult and pediatric patients [107,165], there are limited data on the use of ultrasound contrast agents in pregnancy and during breastfeeding [1,2,166]. We will use CEUS if clinically indicated after explaining to the patient and parent that data on CEUS in this setting are limited and after obtaining informed consent.
LIMITATIONS — Limitations of contrast-enhanced ultrasound (CEUS) include:
●The smallest detectable lesions are typically between 3 and 5 mm in diameter. As a result, smaller focal liver lesions may be missed. The use of high frequency transducers may help to detect small lesions [167,168].
●Limited penetration into the liver, so deep lesions may not be seen. This is particularly a problem in the setting of steatosis.
●Subdiaphragmatic lesions in liver segments 7 and 8 may not be accessible. This limitation can be minimized by performing intercostal scanning and positioning the patient in the left decubitus or standing position.
●The falciform ligament and surrounding fat may be confused with a focal liver lesion.
●False-positive findings may be seen with scars and fibrosis, necrosis, phlegmonous infiltration, sarcoidosis, and inflammatory pseudotumors of the liver [114,169].
●It can be difficult to position the probe for intraoperative CEUS. In addition, intraoperative CEUS may be limited by the relatively short duration of contrast enhancement [55].
●In patients with cirrhosis, benign liver lesions can be difficult to diagnose since the portal vein branches are reduced in favor of a more arterial vascular supply [170,171]. Focal nodular hyperplasia can be particularly difficult to diagnose in patients with cirrhosis.
●Bubble destruction and shadowing may result in artifacts [114,169,172].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Focal liver lesions".)
SUMMARY
●Contrast-enhanced ultrasound (CEUS) is a technique for imaging the liver and other organs. It is used most frequently in Europe and Asia, as well as in other countries worldwide. The contrast agent, Lumason (sulfur hexafluoride lipid microspheres) was approved by the US Food and Drug Administration for the examination of the liver in adults and pediatric patients. (See 'Introduction' above.)
●CEUS uses ultrasound contrast agents to improve visualization and characterization of anatomic structures and lesions. It is most often performed transcutaneously, though it can also be used intraoperatively. Ultrasound contrast agents are microbubbles consisting of gas bubbles stabilized by a shell. They are 1 to 10 microns in size (equal to or smaller than red blood cells) and permit visualization of both macrovasculature and microvasculature. The minute bubbles survive transpulmonary passage and recirculate, producing systemic ultrasound enhancement. (See 'Standard CEUS' above.)
●CEUS permits real-time visualization of contrast-enhancement patterns during all vascular phases (arterial, portal-venous, and late). This results in higher temporal resolution than can be achieved with other imaging modalities. (See 'Standard CEUS' above.)
●CEUS of the liver has several advantages compared with other imaging modalities, including improved lesion characterization compared with grayscale (B-mode) ultrasound, portability, lack of radiation exposure (which may be of particular importance in patients who require repeated examinations), and use of contrast agents that do not contain iodine and are not nephrotoxic. Use of a contrast agent with a short elimination time (within approximately 20 minutes) allows for subsequent examinations within short time intervals. (See 'Advantages of CEUS' above.)
●CEUS is used to evaluate focal liver lesions, to guide tissue sampling, and to help plan and monitor treatment in patients with hepatic tumors. In the appropriate clinical setting, hemangiomas, focal nodular hyperplasia, focal fatty change, and malignancies can be diagnosed with confidence if typical enhancement patterns are seen. If the enhancement patterns are atypical or if the examination is technically suboptimal, additional investigation is required. (See 'Indications' above.)
●CEUS has an estimated sensitivity of approximately 95 percent and a specificity of approximately 94 percent for diagnosing malignancy. It also appears to be similar (or possibly superior) to contrast-enhanced CT and contrast-enhanced MRI for the diagnosis of focal liver lesions. (See 'Accuracy' above.)
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