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Imaging in Assessment of Liver Disease and Lesions
Abbreviations
ALD
active liver disease
BDH
cystic bile duct hamartoma
CT
computed tomography
DWI
diffusion-weighted imaging
FNH
focal nodular hyperplasia
HCC
hepatocellular carcinoma
MRE
magnetic resonance elastography
MRI
magnetic resonance imaging
MRS
magnetic resonance spectroscopy
NASH
nonalcoholic steatohepatitis
T1W
T1 weighted
T2W
T2 weighted
US
ultrasonography
Introduction
Liver disease is a major public health problem in the United States and worldwide. Diffuse liver disease and focal hepatic lesions are common problems encountered in clinical practice, and the presence or absence of background liver disease impacts the differential management of associated focal hepatic tumors. Regardless of the presentation, specific characterization of hepatic lesions is essential to accurately guide management decisions.
Medical imaging plays a critical role in the diagnosis and staging of diffuse liver disease and focal hepatic lesions. There has been an impressive evolution of diagnostic imaging methods in recent years, expanding the array of imaging techniques that can be used to analyse hepatic disease. Imaging modalities range from conventional fluoroscopic studies to nuclear medicine techniques to cross-sectional methods based upon ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI). Considerations such as diagnostic accuracy, ease of use, access, and cost are all variables that influence the optimum method for imaging diagnosis. Due to recent advances in software and hardware development, MRI has emerged as the leading noninvasive diagnostic tool for the assessment of hepatic disease, including diffuse liver processes and focal hepatic lesions.
Diffuse Liver Disease
Active Inflammation
Active liver disease (ALD) can result from several etiologies, including idiopathic, drug-induced, viral, alcoholic, and gallstone bile duct obstruction that lead to active inflammation of various degrees and patterns. At this time, MRI is the only imaging technique that has shown sensitivity for detection of ALD. In MRI, the most sensitive images are the postgadolinium, breath-hold, T1-weighted, gradient-echo images that are acquired during the arterial phase ( Figs. 10-1 and 10-2 ). In a recent report, this abnormal enhancement becomes more marked and can persist into the venous and delayed phases as the severity of disease increases and can resolve in cases when the active inflammation resolves.
MRI may be used as a diagnostic aid in patients who have equivocal liver enzyme elevation and nonspecific symptoms and in patients who present with fatty infiltration. Findings that are suggestive of ALD (seen as irregular arterial-phase gadolinium enhancement) in the setting of fatty liver (seen as signal drop on out-of-phase gradient-echo images) are consistent with steatohepatitis and raise the possible diagnosis of nonalcoholic steatohepatitis (NASH) ( Fig. 10-3 ). NASH is believed to represent a hepatitis related directly to excess intracellular fat accumulation within hepatocytes. This disease has a strong association with obesity and a risk of progression to chronic hepatitis ( Figs. 10-4, A ; 10-5; and 10-6 ), fibrosis, and cirrhosis. Given that obesity has become an epidemic, the population health concern for NASH is high in the United States and increasing in other developed and developing nations. MRI has the added value of providing a test with greater sensitivity and specificity for detection of fatty liver.
Chronic Hepatitis and Cirrhosis
A major complication of chronic hepatitis is cirrhosis. In the West the most common etiology has been alcohol-induced hepatitis; however, viral hepatitis has become the most common cause over the past 20 years and, globally, viral hepatitis remains the most common association with chronic liver disease, hepatic fibrosis leading to cirrhosis, and hepatocellular carcinoma (HCC).
The characteristic feature of fibrosis in MRI is progressive enhancement of delayed images within the fibrotic bands of tissue that surround regenerative hepatic nodules. This results from leakage of gadolinium contrast agent from the intravascular into the interstitial space within the fibrotic regions. This is a favorable characteristic of the extracellular gadolinium-based contrast agents, which behave much like a histologic stain for fibrotic tissues. In delayed interstitial-phase images acquired between 3 and 5 minutes after gadolinium administration, strong quantitative correlation between delayed-phase liver enhancement pattern and hepatic fibrosis have been reported. The typical patterns of hepatic fibrosis include fine reticular and coarse linear patterns, with the fibrotic bands outlining foci of regenerative nodules.
Different innovative MRI techniques are in development for quantifying hepatic fibrosis as a surrogate for histologic markers of hepatic fibrosis. Uptake of extracellular gadolinium-based contrast agents in hepatic fibrosis has been shown to correlate with the histologic stage of fibrosis. Diffusion-weighted imaging (DWI) has been proposed for assessment of hepatic fibrosis. DWI is a method for determining relative levels of restriction to the movement of water in the imaged tissues. In hepatic fibrosis, free unbound water should be diminished and the accumulation of fibrosis should cause a reduction in the amount of water proton diffusion in affected liver tissue. However, DWI is not showing reliable and quantitative sensitivity for different stages of fibrosis.
Magnetic resonance elastography (MRe) is based upon applying a displacement pressure externally over the liver, timed to trigger phase-sensitive MRI. The group from the Mayo Clinic has developed this technique and the MRe system is now commercially available and configured to function on most MRI systems. It requires placement of a compression paddle along the right upper quadrant of the abdomen, overlying the lower right hemithorax. Tubing extends from a speaker placed within a closed system outside of the MRI room and connected to the compression paddle with tubing that is passed through a wave-guide to avoid radio frequency leakage. The driver for the enclosed speaker is connected to an external trigger in the MRI equipment room to achieve controlled and coordinated triggering of pressure pulses generated from the speaker with the MRI excitation image acquisitions. These acquisitions are based on gradient echo producing phase contrast changes from tissue movement that can be measured and translated into the colorized wave dispersion maps ( Fig. 10-7 ). By acquiring images with increasing time delays over several pressure pulses, the displacement compression waves traversing the liver may be determined and the tissue stiffness measured. MRe has been shown to derive stiffness measures that correlate with the different stages of fibrosis on histology. It should be noted that an analogous technique using ultrasound combined with mechanical operator–applied pressure over the liver to create the displacement has also been found to correlate with tissue stiffness and hepatic fibrosis (see Fig. 10-7 ). Further validation and relative comparison of these techniques remains an area of active study.
Magnetic resonance spectroscopy (MRS) is most commonly used to assess signals from hydrogen ( H) and phosphorus ( P). An increased hepatic phosphomonoesters (PME) signal measured by MRS and increasing PME/PDE (phosphodiesters) has been reported ; however, the relationship between PDE and fibrosis is not well understood.
A more recent MRS technique has been proposed using the combination of a highly spatially sampled linear MRS acquisition followed by postprocessing with mapping the magnitude of the signal against the wavelength. This has yielded an analysis that corresponds to tissue features and appears to correlate with the degree of hepatic fibrosis in human livers (see Fig. 10-7 ).
Focal Hepatic Lesions
Imaging Modalities
Ultrasound
Ultrasonography (US) is a nonionizing technique which produces images in real time. Strengths of US include its safety profile, noninvasive nature, portability, and widespread availability, with a lower initial test cost compared to CT or MRI. Additionally, US may be performed in patients with renal failure, as iodinated contrast is not required. However, US is inherently limited by a lack of sufficient soft tissue contrast to provide reliable sensitivity and specificity for liver lesion detection and characterization. In addition, image quality is often limited by a patient's body habitus and operator skills. Compared with the latest generation of CT and MRI techniques, accurate lesion diagnosis and full-body staging (essential components of workup for patients with hepatic tumors) cannot be adequately performed with US.
US is currently the mainstay of surveillance imaging for HCC in chronic liver disease (CLD) at many centers, primarily due to ease of access, lack of ionizing radiation, and a relative low cost compared to CT and MRI. However, reports indicate highly variable sensitivity for the detection of HCC with US, ranging between 33% and 96%. Multiple studies have shown a lower detection rate of HCC by US when compared with CT and MRI. In addition, the sensitivity for the detection of dysplastic nodules and small HCCs is poor; regenerative nodules, dysplastic nodules, and small HCCs may be indistinguishable with US. The use of contrast-enhanced US with microbubbles improves the diagnostic performance of US for HCC screening, however the use of ultrasound contrast adds both time and cost to the test and is not yet approved for use in all countries, including the United States.
Computed Tomography
In the last several decades, CT has played an important role in the diagnosis and staging of hepatic tumors. CT provides excellent spatial resolution imaging, with detailed anatomy of vasculature structures and organ morphology in the abdomen and pelvis. The introduction of multidetector CT systems allows for 0.5-mm-resolution imaging that may be acquired in seconds. Dual-energy computed tomography (DECT) is a recent advancement in CT hardware that provides information about how substances behave at different photon energies. The ability to generate virtual unenhanced datasets and the improved detection of iodine-containing substances on low-energy images are promising grounds for continued research and development in DECT. These newer generation CT systems also have the capability to deliver marked reduction in radiation dose to the patient, with overall maintenance of image quality and speed.
Despite the advantages of CT with regard to imaging speed and spatial resolution, the main limitation inherent to the technology is a relative deficiency of soft tissue contrast in comparison to MRI. CT may reliably differentiate soft tissue, calcium, simple lipid, and air; however, differentiation between soft tissues (such as between liver parenchyma and a tumor) may be challenging, and requires multiphase imaging after the administration of iodinated intravenous contrast to optimize diagnostic sensitivity. Administration of iodinated contrast introduces risks of contrast-induced nephropathy and renal dysfunction, and most patients with background Stage III to Stage V chronic kidney disease are not candidates for iodinated contrast administration. Even with optimized multiphase precontrast and postcontrast CT, multiple studies have demonstrated reduced rates of lesion detection and characterization when compared with MRI for many organ systems involved in gastrointestinal malignancies, especially the liver, bile ducts, prostate, and cystic neoplasms. Moreover, repeated use of CT for follow-up in patients that have received curative therapy raises safety concerns with regard to cumulative X-ray dose effects. The diagnostic benefits of CT should always be weighed against the cancer induction risk of ionizing radiation.
Magnetic Resonance Imaging
MRI plays an important role in the diagnosis and staging of hepatic tumors. The primary strength of MRI is its superb soft tissue contrast, which allows for reliable detection of tumors. This is sometimes possible even without the aid of intravenous contrast, relying instead on the intrinsic signal differences between normal soft tissue and tumors. The soft tissue resolution of MRI also provides more reliable characterization of focal lesions. This allows more accurate distinction of benign from malignant disease and impacts therapeutic decision-making with potentially reduced need for invasive tissue sampling/biopsy. A limitation of MRI has been the relative complexity of the image acquisition and decreased availability compared with CT and US; however, newer advances in technology have allowed for more robust imaging with reliable image quality even in sick and freely breathing patients, and an increasing number of tertiary cancer centers rely heavily on MRI to guide management in hepatic lesions.
Whereas MR imaging protocols have the potential to be complex and widely varied, we have advocated a simplified uniform protocol that may be applied to multiple indications, including tumor assessment and staging of the liver, pancreas, and bowel. This protocol consists of dynamic contrast-enhanced T1-weighted (T1W) multiphase imaging which allows for assessment of tumor perfusion patterns that may be indicative of certain tumor histologies. Arterial-phase images are acquired at an 8- to 10-second delay after the bolus trigger point; venous-phase imaging is initiated at 70 seconds and delayed-phase imaging at 180 seconds after the trigger point. Motion-insensitive T2-weighted (T2W) sequences are the second major component of this simplified imaging protocol, providing an alternate method of tissue interrogation which helps to increase the specificity of diagnosis, especially to more reliably differentiate metastases from benign entities such as cysts and hemangiomas. Magnetic resonance cholangiopancreatography (MRCP) techniques are T2W sequences that provide excellent visibility of the bile duct morphology, and are helpful in tumor diagnosis and presurgical planning of tumors involving the bile ducts. Finally, DWI is an additional noncontrast technique that has the potential to improve sensitivity for small malignant lesions in certain tumor subtypes.
Hepatobiliary-Specific Contrast Agents
Newer gadolinium-based contrast agents which have come to market in recent years that have both a renal and hepatic route of excretion. Gadoxetate disodium (Gd-EOB-DTPA; Eovist or Primovist, Bayer Healthcare, Leverkusen, Germany) is a liver-specific agent that is excreted 50% by the liver and 50% by the kidneys (assuming normal hepatic and renal function). Gd-EOB-DTPA is taken up by hepatocytes via an ATP-dependent transporter and subsequently excreted into the bile duct canaliculi. This imaging method has been advocated as a way to differentiate certain types of tumor (i.e., focal nodular hyperplasia) from other tumors that do not possess normal hepatocytes to take up this contrast (i.e., hepatocellular carcinoma, hepatic adenoma, and metastatic disease). Imaging protocols must be tailored to the specific biliary excretion properties of Gd-EOB-DTPA, which is typically seen within the biliary system at 7 to 10 minutes postinjection. Delayed-phase images conducted at 20 minutes postinjection are routine to assess hepatocyte uptake, and are sensitive for the detection of focal hepatic lesions that do not contain the ATP-dependent transporter.
The utility of hepatobiliary-specific contrast agents must be assessed by contrasting against the performance of standard extracellular gadolinium-contrast agents, which have already demonstrated sensitivities and specificities greater than 95% for the detection and characterization of HCC. In addition, approximately 10% of HCCs have been shown to express the ATP-dependent transporter that takes up the hepatocyte-specific agent, a confounding factor that may lead to a fixed percentage of false-negative studies when using this contrast agent. In addition, the altered soft tissue contrast may confound the ability to assess dynamic perfusion characteristics of hepatic tumors and also reduces the ability to reliably assess vascular structures, such as the portal vein. These issues must be taken into consideration prior to routine use of hepatocyte-specific contrast agents for the assessment of focal liver lesions. However, this contrast agent has allowed for new methods of bile duct imaging, which hold promise for preoperative planning and for assessment of bile duct injuries. It should be noted that the optimum excretion of a hepatocyte-specific agent into the bile duct canaliculi is dependent upon properly functioning hepatocytes. Inflamed liver tissue, whether related to intrinsic acute or chronic hepatitis or alternatively bile duct obstruction, may not take up and excrete the contrast into the biliary system in a reliable fashion.
Benign Lesions
Solid
Hemangioma
In adults, hemangiomas are the most common benign mesenchymal hepatic lesion and are most often identified incidentally. Occasionally, especially large lesions may result in pain and have rarely been reported to bleed, typically secondary to traumatic injury. In histopathology, hepatic hemangiomas are nonencapsulated tumors with a lobular growth pattern consisting of large endothelial cell–lined spaces filled with blood separated by fibrous tissues. The larger lesions or giant hemangiomas are less common and can range in size from 5 cm to greater than 20 cm. These larger lesions are noted to have a more heterogeneous imaging appearance related to the development of thrombosis, hemorrhage, and degeneration.
Imaging
Hepatic hemangiomas on MRI show a characteristic lobulated morphology with homogeneous, elevated T2 signal ( Fig. 10-8 ). Typical postcontrast imaging reveals early peripheral, interrupted, nodular enhancement with progressive filling of the more central aspects of the lesion. Some smaller lesions are characterized by similar T2 features but show uniform arterial enhancement (flash-filling hemangiomas), subsequently equilibrating with the blood pool on the remaining delayed sequences. Atypical features can be seen in lesions that have undergone sclerosis, resulting in a lower-than-expected T2 signal ( Fig. 10-9 ). A subset of patients can present with symptoms correlating to giant hepatic hemangiomas, with one study showing a mean size of 4.4 cm. They are more often complicated by internal hemorrhage and focal areas of sclerosis. As a group of lesions, hepatic hemangiomas rarely present a diagnostic dilemma in MRI.
Focal Nodular Hyperplasia
Focal nodular hyperplasia (FNH) is the second most common benign liver tumor. It is most frequently identified in premenopausal females and less commonly in males and children. They are lesions that represent hyperplasia of hepatocytes in response to a localized vascular abnormality. On histopathologic analysis, they are composed of cellular areas of hepatic proliferation interposed by fibrous septations. Within the lesion is an extensive network of capillaries. When enlarged (>5 cm) they often show a central fibrous scar consisting of abnormal vessels and proliferated connective and ductal epithelial tissue. Importantly, malignant degeneration has not been identified in these lesions. Multiplicity is a common finding; in one analysis of surgically resected lesions, approximately 25% had two or more lesions.
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