Ultrasound (US) is often the first-line test used to examine the liver because of its low cost, lack of ionizing radiation, and accessibility. US produces images by imparting sound waves into the tissues at a high
frequency, typically between 3 and 7 MHz. Lower frequencies travel further into the tissues, allowing deeper tissues to be visualized, whereas the higher frequencies provide better spatial resolution and anatomic detail with more limited depth of penetration. As sound waves travel into the liver, they encounter tissues that transmit the sound waves at different speeds (e.g., transmission speed in liver is 1,570 m/s, in water is 1,489 m/s and within fat is 1,450 m/s). Interfaces between these tissues result in a change in transmission speed and the reflection of sound waves back to the transducer, where they are detected and used to form an image. The US images of a liver mass are described in terms of relative echogenicity, with areas of the mass that are brighter than the background liver referred to as hyperechoic
, areas that are similar in brightness referred to as isoechoic
, areas that are darker referred to as hypoechoic
, and areas with an absence of any signal referred to as anechoic
. It is important to note that the background liver can have abnormally increased echogenicity in the setting of steatosis or fibrosis, which can alter the US appearance of liver masses.
Doppler imaging is used to assess blood flow within the liver. As sound waves encounter moving elements within the blood, not only are the sound waves are reflected back to the transducer, but the movement of the object alters the frequency of the reflected waves. This phenomenon is analogous to the higher pitched sound of a train horn while it is moving toward you and lower pitch while it is moving away. Detecting this change in frequency allows calculation of the direction and velocity of the flowing blood. This property can be used to assess flowing blood within the vasculature and within liver tumors.
The strengths of US include its ability to assess the liver parenchyma, biliary tree, and vascular supply of the liver. In the evaluation of liver masses, US is primarily useful for mass detection and for its ability to differentiate between cystic and solid lesions. US is limited by its inability to penetrate bone or gas filled organs. Overlying ribs and gas-containing bowel or lung tissue occasionally results in regions of the liver that cannot be adequately visualized. The depth of sound wave penetration is also limited, which can lead to incomplete parenchymal evaluation. This is particularly a problem in obese patients, where there is increased thickness of subcutaneous fat, and in livers with poor penetration because of parenchymal disease such as steatosis or fibrosis. Of note, liver evaluation with US is highly operator dependent. Sonographers working in a low-volume practices may be prone to inadequate evaluation of the entire liver parenchyma, or not optimizing the scanner settings to demonstrate cystic components of a mass or internal blood flow.
Computed tomography (CT) is commonly used to evaluate liver tumors because of its accessibility, reproducibility, and its relative simplicity to perform and interpret. CT produces images by generating high-energy photons (typically up to 140 keV), which are a transmitted through the patient and are received by a detector on the opposite side of the patient. The photon generator and detector are mounted on a gantry, which rotates around the patient in a helical pattern. Tissues of different composition attenuate photons to varying degrees. These differences in attenuation result in contrast, which is used to generate a CT image. Bright regions of a CT image are referred to as high attenuation or hyperdensity and dark regions as low attenuation or hypodensity. Attenuation of tissue substances on CT images are often measured in terms of Hounsfield units (HU). Hounsfield units are a measure of relative attenuation and calculated by the formula HU = 1,000 × (µ – µwater)/(µwater – µair), where µ is the linear attenuation coefficient. For reference, common HU include air = -1,000, fat = -100 to -50, water = 0, blood = 30 to 45, liver 40 to 60, and bone 700 to 3,000.
Iodine-containing contrast medium is routinely injected intravenously into the patient to increase contrast between tissues. Iodinated contrast injection provides information regarding the anatomic vascular supply, the rate of blood flow, and the volume of distribution within tissue. These characteristics are very useful for describing and categorizing liver masses. Increased attenuation of tissue in response to IV contrast uptake is referred to as enhancement. In the first few minutes following contrast injection, the relative amount of iodinated contrast changes rapidly within tissues of different composition. This change is typically assessed by scanning the patients multiple times to provide a dynamic evaluation.
The time at which a patient is scanned after injection is referred to as the phase
of contrast enhancement. The most important phases of contrast enhancement for liver tumor characterization include the late arterial phase, the portal venous phase, and the delayed (or equilibrium) phase. The late arterial phase is the time at which the injected contrast bolus has opacified the hepatic arteries and has just begun to opacify the portal veins; this typically occurs 15 to 35 seconds after contrast injection. Imaging at time points earlier than this may fail to show enhancement in tumors with hepatic arterial vascular supply. The portal venous phase is defined as the time at which the contrast bolus has opacified the portal veins and has just begun to opacify the hepatic veins; this occurs roughly 60 seconds after injection. This is typically the time at which the hepatic parenchyma is maximally
enhanced. The delayed or equilibrium phase includes imagings that are usually performed between 3 and 10 minutes after injection. Most iodinated IV contrast agents used for CT remain within the extracellular compartment of tissues. Over time, these contrast agents diffuse through the extracellular space to equilibrate between the extracellular intravascular and extravascular compartments. Fibrotic or sclerotic tissues remain enhanced in the delayed phases because of large extracellular spaces associated with fibrosis.
CT has several advantages, including its ability to scan rapidly and to provide a comprehensive assessment for metastatic disease. CT examinations are often performed for liver mass evaluation out of convenience, as the entire body can be quickly assessed for metastatic disease in a single setting. The ability to acquire an imaging data set within a few seconds is a major advantage for patients who cannot hold their breath or cannot breathe consistently, as is required for MRI. An inability to adequately suspend respiration can render an abdominal MRI nondiagnostic. CT is also able to acquire high spatial resolution, 3D image data sets that can be reformatted in any plane. These types of data sets are difficult to acquire at MRI and, with current technology, most MRI images are acquired with the intention of being viewed in a single plane.
Specific limitations of CT include inferior soft-tissue and IV contrast resolution when compared with MRI. The limited soft-tissue contrast can create difficulty differentiating a low-attenuation solid mass from a cystic mass or lipid-containing tissue. Similarly, high-attenuation tissue or calcification can occasionally be difficult to differentiate from iodine-containing contrast media. Despite these limitations, CT has a very high sensitivity for detection of small calcifications and gas, when compared with either MRI or US. The radiation exposure imposed by CT is another limitation, one that frequently restricts the number of phases obtained during an examination and the frequency of follow-up exams. However, in the presence of malignancy or in advanced patient age, the risk imposed to the patient because of radiation exposure at CT is probably negligible.
Magnetic resonance imaging
MRI provides the best discrimination between soft tissues of different types and is the modality of choice for both liver mass detection and liver mass characterization. MRI uses a strong static magnetic field, weak gradient magnetic fields, and radiofrequency transmission coils to alter the orientation of protons found within hydrogen atoms, which are the most abundant element in the human body. Protons are imaged by specifically changing gradient field strengths, applying energy through radiofrequency transmissions, and recording signal from the tissue at varying time points. The combinations of the steps required to produce images are referred to as pulse sequences.
In a strong static magnetic field, the axis of a proton’s magnetic dipole will tend to align with that of the static magnetic field. The axis of a proton’s dipole is not aligned exactly with that of the magnet but slightly off center and precesses (rotates) around it at a frequency proportional to the strength of the magnetic field. This precessional frequency is specific to particular protons and can be exploited by using an applied radiofrequency electromagnetic pulse at the same frequency to shift proton orientation away from that of the magnetic field. After protons have been shifted, they will relax (or reorient) with the direction of the static magnetic field.
There are two basic ways in which protons relax after being stimulated by a radiofrequency pulse: T1 (or longitudinal) relaxation and T2 (or transverse) relaxation. These two types of relaxation occur at different rates, which are affected by a proton’s surrounding magnetic micro-environment or tissue type. Measuring differences in the T1 and T2 relaxation rates between different tissues creates contrast. This contrast in turn forms the basis for creating images at MRI. When reviewing MRI images, bright regions of the image are referred to as having high signal or hyperintense and dark regions as low signal or hypointense.
A typical liver imaging protocol includes a combination of pulse sequences designed to show contrast differences between T1 and T2 relaxation rates of different tissue and are referred to as T1-weighted and T2-weighted images. Images of each sequence are specifically used to reveal different anatomic features or abnormalities of tissue content, so characterization of a tumor using MRI requires review of several image sets.
A basic knowledge of typical tissue signal intensities on MRI images is necessary for image review. On T1-weighted images, water is low in signal and fat is high in signal. On T2-weighted images, both water and fat are high in signal. The weighting of an image can often be determined by looking at the signal of cerebrospinal fluid in the spinal canal. T2-weighted images are predominantly used to image water content of tissues. An extreme example of T2-weighted image is magnetic resonance cholangiography, in which the images are very heavily T2-weighted, such that the only structures clearly visible on the images are fluid-containing structures, such as the bile ducts and renal collecting system. It is important to know that both T1- and T2-weighted images are often altered by suppressing the signal from fat. This is accomplished by a variety of techniques and allows
increased dynamic range of the images, increased conspicuity of liver parenchyma, and detection of fat-containing structures.
Specialized MRI techniques that are used to image the liver include in-phase and opposed-phase imaging and diffusion-weighted imaging. Protons within water precess at a slightly different frequency than those found in fat. When T1-weighted image acquisition is timed so that the magnetic dipoles of both water and fat are oriented in the same direction, the signal intensities from both tissue types are additive; this produces an in-phase image. When the timing of image acquisition is altered so that the dipoles of fat and water are oriented in opposite directions, the signal intensities cancel out and the overall signal intensity decreases, this produces an opposed-phase image.
These properties can be exploited to identify tissues that contain elements of both water and fat. When the signal from a voxel (a position in a 3 dimensional image) of an image of tissue originates from 50% water and 50% fat, the signal intensity of that voxel should be near zero on the out-of-phase image. Because of this, lesions that drop in signal intensity on the opposed-phase image, when compared to in-phase image, are likely to have fat.
Diffusion-weighted imaging basically measures the Brownian motion of water molecules. Tissues that are either very cellular or swollen tend to have restricted motion on diffusion-weighted imaging. Diffusion-weighted imaging is a technique in which specialized gradient magnetic fields are added to a T2-weighted image. These gradients fields are designed such that bound protons that are unable to move (their ability to diffuse is restricted) do not lose signal, whereas moving protons lose signal rapidly. The most common explanation for restricted diffusion in tissues is increased cellularity, in which a greater percentage of the imaged protons are within cells and their movement is physically restricted by cellular membranes. Another common reason for restricted diffusion includes abscess formation, in which the protons are extracellular but free diffusion is restricted by the highly viscous and proteinaceous environment. The resulting diffusion-weighted image shows areas of high signal, which could represent either an intrinsically T2 hyperintense tissue or a tissue with restricted diffusion. Multiple diffusion-weighted images are produced with increasing strengths of the gradient fields. The relative change in signal of each pixel over the series of images is used to calculate an apparent diffusion coefficient (ADC) map. The apparent diffusion coefficient map shows pixels on the diffusion-weighted image, with true restricted diffusion showing low-signal intensity, whereas regions of high-signal intensity that are seen on both diffusion-weighted image and the ADC map represent tissue with intrinsically high T2 signal (on the diffusion-weighted image these regions are referred to as T2 shine through) and/or unrestricted diffusion.
IV contrast-enhanced MRI imaging of the liver is typically performed with fat saturated T1-weighted sequences. IV gadolinium shortens the T1 relaxation time of tissues, resulting in higher signal intensity. Most gadolinium contrast agents are extracellular and have dynamic enhancement properties similar to those discussed previously for iodinated CT contrast agents. The phases of dynamic contrast enhancement that are routinely acquired at MRI are the same as those acquired at CT. MRI contrast agents, referred to as hepatobiliary agents, are also available. These agents are actively taken up into hepatocytes and excreted into the bile ducts. The most commonly used is disodium gadoxetate (Gd-EOB-DTPA; Eovist; Bayer Corporation, Pittsburgh, PA) and gadobenate dimeglumine (Gd-BOPTA; MultiHance; Bracco Diagnostics Inc, Princeton, NJ). These contrast agents are typically imaged in a dynamic fashion similar to extracellular agents. Additional images at delays of 20 to 120 minutes are referred to as the hepatobiliary phase. During the hepatobiliary phase, the normal liver is diffusely high signal and contrast agent increases the signal intensity of the biliary tree. These images have a high sensitivity for detection of liver masses that do not contain hepatocytes and thus do not retain the contrast agent.
MRI is considered the preferred modality for liver mass evaluation.1
MRI pulse sequences are exquisitely sensitive to changes in normal liver parenchymal composition and are highly sensitive for detection of liver masses.2
MRI is more sensitive than CT or US for detection of substances such as fat or iron.3
Despite these advantages MRI does have limitations, including cost and patient contraindications to the MRI scanner. Many metallic implanted foreign bodies and pacemakers are not compatible with the strong magnetic fields and radiofrequency gradient pulses. Patient inability to cooperate can also result in a severely limited MRI exam. Acquisition of MRI images takes a relatively long time and patients who cannot hold their breath or cannot breathe at a consistent rate will result in images with substantial motion artifact. MRI is also limited by a number of image artifacts because of magnetic susceptibility of metallic foreign bodies, pulsation artifacts from vessels, and other artifacts when patients are large in size or have significant ascites. A detailed discussion of these artifacts is beyond the scope of this chapter, but it is important to recognize that these artifacts can impair the interpretation of images and occasionally simulate liver pathology.