You are in: eMedicine Specialties > Radiology > GASTROINTESTINAL CirrhosisArticle Last Updated: Jan 2, 2008AUTHOR AND EDITOR INFORMATIONSection 1 of 12
  Author: Caroline R Taylor, MD, Associate Professor, Department of Diagnostic Imaging, Yale University School of Medicine; Chief, Diagnostic Imaging Service, Department of Radiology, VA Connecticut Healthcare System Caroline R Taylor is a member of the following medical societies: Radiological Society of North America Editors: Glenn Krinsky, MD, Chief of Abdominal Imaging Section, Associate Professor, Department of Radiology, New York University School of Medicine; Bernard D Coombs, MB, ChB, PhD, Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand; Udo P Schmiedl, MD, PhD, Clinical Professor, Department of Radiology, University of Washington; Consulting Staff, Swedish Medical Center, University of Washington Medical Center, Seattle Radiologists; Robert M Krasny, MD, Consulting Staff, Department of Radiology, The Angeles Clinic and Research Institute; John Karani, MBBS, FRCR, Consulting Staff, Department of Radiology, King's College Hospital, London Author and Editor Disclosure Synonyms and related keywords: hepatic fibrosis, chronic end-stage liver disease, transjugular intrahepatic portosystemic shunt, TIP, hepatocellular carcinoma, HCCA, HCC, hepatic arterial circulation, portal venous circulation, hepatic vein pressure gradient, HVPG INTRODUCTIONSection 2 of 12
  BackgroundCirrhosis of the liver is the end stage of a complex process—resulting from hepatocyte injury and the response of the liver—that leads to partial regeneration and fibrosis of the liver. Cirrhosis poses a difficult challenge for management, while the disease's prevention, detection, and therapy engender major health costs. Diagnostic imaging offers diverse modalities for use in the noninvasive evaluation of the liver, as well as in interventional techniques; the latter may be used to treat such complications as portal hypertension and neoplasia. The diagnosis, management, and treatment of cirrhosis are reviewed in this article. PathophysiologyCirrhosis may develop as a chronic, insidious process; it most commonly results from continued exposure to toxic agents (such as long-term ethanol abuse), from chronic viral infection, from disorders of metabolism (such as hemochromatosis) or of biliary origin, or from autoimmune disease. It may occur in response to massive injury from toxins, infection, or ischemia that has resulted in acute hepatocyte necrosis. Occasionally, the etiology is never determined and is labeled "cryptogenic." The role of marrow stem cells in the cycle of hepatocyte renewal has been recognized through the work of Alison and colleagues.1 Regeneration and scarring lead to gross morphologic and pathophysiologic changes in hepatic circulation; these changes contribute to morbidity through reduced metabolic function and elevation of portal venous pressures, with a resultant risk of fatal variceal hemorrhage. FrequencyUnited StatesUsing statistics from 1976-1980, the National Digestive Diseases Information Clearinghouse (NDDIC) quotes a prevalence of 400,000 persons in the United States who have cirrhosis or some other type of chronic liver disease.2 InternationalCirrhosis is among the leading causes of death, and a disturbing epidemic of hepatitis has contributed to a rising incidence of HCCA, a serious complication of chronic hepatitis and cirrhosis. Using official death certification data from 1955-1990, derived from the World Health Organization (WHO) database, an analysis was made of cirrhosis-related trends in mortality rates in 38 countries (2 countries from North America, 6 from Latin America, 5 from Asia, 23 from Europe, 1 each from Australia and New Zealand).3 The study found that the highest reported death rates occurred in Chile and Mexico (60 deaths per 100,000 males; 15 deaths per 100,000 females) during the late 1980s. In Canada, the United States, and Latin America, mortality rates from cirrhosis ranged from 5-17 deaths per 100,000 for males and 3-5 deaths per 100,000 for females over the same calendar period, with similar trends. In 1990, mortality rates in Japan were 13.6 deaths per 100,000 males. Appreciable downward trends were observed in Hong Kong and Singapore, whereas Thailand's cirrhosis-related mortality rate increased. In the late 1950s, the highest European rates were registered in Portugal (33.6 deaths per 100,000 males; 14.6 deaths per 100,000 females), followed by France (31.8 deaths per 100,000 males; 14.1 deaths per 100,000 females), with a decline after the 1970s. Mortality rates in the late 1980s or early 1990s for Austria, Italy, and Portugal were 30 deaths per 100,000 males and 10 deaths per 100,000 females. Britain, Ireland, and the Nordic countries had far lower mortality rates (2-4 deaths per 100,000 males), but showed an upward, although discontinuous, trend. Mortality/MorbiditySince 1994, cirrhosis and other types of chronic liver disease have been the 10th most common cause of death in the United States. In 2002, these disorders accounted for 27,257 deaths, according to the NDDIC.2 The clearinghouse also reported that chronic liver disease accounted for disability in 130,000 persons between 1990 and 1992, as well as for 421,000 hospitalizations in 2002. From 1980-1989, however, the age-adjusted death rate for chronic liver disease fell from 13.5 persons per 100,000 to 10.4 persons per 100,000, a reduction of 23%.4 Statistics from the Department of Health and Human Services indicate that alcohol is a contributing factor in 50% of deaths from chronic liver disease. The WHO estimates that cirrhosis is responsible for 1.1% of all deaths worldwide. Other cirrhosis-related trends include the following:
See also the following on eMedicine: RaceGenerally, the regions of highest prevalence of HCCA occur in Asia, South Africa, and some areas of the Middle East. Susceptibility to the disease is believed to be based not on race but rather on prevalent environmental factors, including epidemiologic factors and exposure to environmental toxins (such as aflatoxin). In the United States, death rates from HCCA between 1980 and 1989 were 50% higher in the black population than in the white population. SexThe male-to-female ratio for cirrhosis is 1.5-3:1 (see Frequency/International), based on etiologic differences. Ethanol-related cirrhosis has a male predominance, but primary biliary cirrhosis (accounting for only 1.5% of deaths from cirrhosis) has a female predominance. AgeAge-specific death rates in the United States tend to be the highest in the older age ranges, peaking at 49 per 100,000 in males aged 65-74 years and at 26.7 per 100,000 in women aged 75-84 years. AnatomyHepatic morphologic changes Regardless of etiology, gross morphologic changes of cirrhosis are recognized by a variety of image techniques. Enlargement of the left lobe and caudate lobe, believed to be the result of lobar-relative regeneration rather than fibrosis, secondary to an accident of vascular supply, is recognized by any cross-sectional technique, such as computed tomography (CT) scanning (see Image 1), magnetic resonance imaging (MRI) (see Image 2), or ultrasonography (US) (see Image 3). In contradistinction to alcoholic and viral cirrhosis, cirrhosis from primary sclerosing cholangitis has a different morphology, including atrophy of the lateral segment of the left lobe and massive enlargement of the caudate lobe. This pattern also can be seen in autoimmune cirrhosis. Cirrhosis from hepatic veno-occlusive disease (Budd-Chiari) features a characteristic enlarged, massive caudate lobe that should not be confused with a neoplasm. Using MRI, Okazaki and colleagues determined that alcoholic cirrhosis is associated more frequently with caudate lobe enlargement and the presence of a right posterior hepatic notch than is virus-induced cirrhosis.7 Harbin, Hess, Giorgio, Torres, and their coauthors have described a number of indices, including the ratio of transverse caudate lobe width to right lobe width, multidimensional caudate lobe indices that can be obtained by US or CT scanning, and volume analysis of each liver segment, based on cross-sectional area by CT scanning or MRI.8, 9, 10, 11 Lafortune and colleagues suggested that a reduction in the medial segment of the left hepatic lobe diameter is a helpful adjunct finding of cirrhosis in ultrasonographic investigation.12 Another sign of cirrhosis, the expanded gallbladder fossa sign, has been described on MRI examination (see Image 5), based on an evaluation by Ito and coauthors of 190 patients with cirrhosis and of 123 control patients.13 The authors' criterion was enlargement of the pericholecystic space (ie, gallbladder fossa)—which had to be demarcated laterally by the edge of the right hepatic lobe, medially by the edge of the lateral segment of the left hepatic lobe, or posteriorly by the anterior edge of the caudate lobe—in conjunction with nonvisualization of the medial segment of the left hepatic lobe on the same axial image. This achieved a sensitivity, specificity, accuracy, and positive predictive value for the MRI diagnosis of cirrhosis of 68%, 98%, 80%, and 98%, respectively. On ultrasonographic examination, the liver contour may appear nodular (see Image 6), although Ladenheim and colleagues have questioned the specificity of this sign. Similar contour deformities are evident on examination by CT scanning or MRI (see Image 7). The echo texture appears coarsened. Increase in echogenicity (see Image 8) is caused by fatty infiltration, which may be diffuse in hepatitis or focal in hepatitis or cirrhosis. Intrahepatic vascular changes in cirrhosis In cirrhosis, the dynamics of the hepatic arterial and portal venous circulation change as the degree of fibrosis progresses. As portal hypertension develops, portal flow is reduced and subsequently reversed, with a compensatory increase occurring in hepatic arterial flow. The hepatic artery diameter grows, and absolute blood flow increases by as much as 100% (see Image 9). In addition, the vessels appear to elongate and become more tortuous because of the underlying parenchymal architectural distortion. This is recognized classically in angiography as "corkscrewing" of vessels (see Image 10) and can be appreciated on cross-sectional imaging (see Image 1). Secondary manifestations of cirrhosis may be seen as morphologic or physiologic evidence of the disease. The development of spontaneous shunts has been described in advanced cirrhosis and was initially demonstrated by angiography, although it is now demonstrable by noninvasive techniques, such as Doppler US, at an incidence of up to 7% (see Image 11). The presence of these high-velocity shunts appears to correlate with changes in commonly measured parameters on Doppler evaluation, such as the resistive index (RI) and the pulsatility (PI) index in the right and left branches of the hepatic artery. As criteria for the presence of a shunt, Bolognesi and colleagues used a decrease in RI of greater than 20% and a decrease in PI of greater than 30% in one hepatic lobe relative to the other lobe.14 The authors determined that patients with cirrhosis who possessed such shunts displayed a net increase in RI and PI. (All shunts were confirmed angiographically.) Mean RI in patients with a shunt was 35% ± 6 (range, 27%-42%) versus 5% ± 4 in controls (range, 0%-15%; P <0.001); mean PI was 50% ± 5 (range, 41%-58%) versus 11% ± 7 (range, 0%-26%; P <.001). Dual-phase CT scanning can demonstrate these shunts as early opacification of the intrahepatic veins during the early arterial phase-injection (see Image 12). The shunts are often accompanied by geographic, wedge-shaped perfusion abnormalities. Extrahepatic manifestations of cirrhosis detectable by imaging techniques Marshak, Karahan, and coauthors reported a higher frequency in the alteration in the thickness of the wall of the GI tract (see Images 13-14) in patients with cirrhosis than in controls (64% vs 7%).15, 16 This alteration is thought to represent edema. The gallbladder wall also may appear thickened (see Image 15). In a series by Chopra and colleagues, prominent mesenteric edema and stranding occurred with increased frequency in 86% (69) of the patients studied.17 Mesenteric edema existed alone in 38% of the 69 patients and was accompanied by omental or retroperitoneal edema in 58% of them. Although mild in most patients (see Image 16), mesenteric edema can appear as a severe, masslike sheath that engulfs the mesenteric vessels. This phenomenon is associated with the presence of ascites, pleural effusions, subcutaneous edema, and low mean serum albumin levels, but not with splenomegaly or varices. Functional imaging techniques, such as the use of technetium-99m (99mTc)–labeled sulfur colloid, which is taken up by reticuloepithelial cells, and the presence of "colloid shift" to the bone marrow in cirrhosis, in addition to the recognition of hepatic morphologic changes and splenomegaly, have been helpful in confirming the presence and severity of cirrhosis (see Image 17). Portal hypertension Portal hypertension occurs once portal pressures reach 5-10 mm Hg above normal as a complication of cirrhosis. The pathogenesis is complex, involving increased resistance within the liver and hyperdynamic flow mediated by circulating factors. The well-recognized effect of increasing portal pressures is the development of splenomegaly (see Image 18) and collateral portal-venous anastomoses, which occur at numerous sites, including gastroesophageal, paraumbilical, perirectal, and retroperitoneal locations. The consequences of portal hypertension include the development of ascites, GI tract hemorrhage, and enteropathy. Hepatic dysfunction affecting clotting factors and functional hypersplenism impacting platelet life increase the risk of massive GI hemorrhage. Encephalopathy may worsen significantly if shunts are large. It is not uncommon for patients with unsuspected cirrhosis to present with these manifestations. Varices are not found where the portal vein pressure (indirectly measured as the hepatic vein pressure gradient [HVPG]) is less than 12 mm Hg. However, not all patients with elevated portal pressures develop variceal bleeding. Noninvasive diagnostic imaging methods, such as color flow Doppler US, contrast-enhanced CT scanning, and MRI, can be used to identify the presence of collaterals (see Image 7, Images 19-30), but a major limitation is an inability to employ them in evaluating variceal pressures, which correlate more directly with the risk of hemorrhage. Noninvasive measurements of portal venous flow, although well correlated with physiologic measurements, and various indirect indices of portal circulatory function have proven of limited prognostic value. Portal vein thrombosis, depending on the extent and rapidity of thrombus formation, may further increase portal vein pressure and increase the risk of a variceal bleed. Bland thrombus can occur in the setting of reduced blood flow in portal hypertension (see Image 31,) Slow portal flow can mimic portal vein occlusion on cross-sectional imaging, and care must be taken when interpreting images in which not all diagnostic criteria are met. Long-standing thrombosis may be associated with cavernous transformation in which periportal collaterals re-establish flow to the liver, even in the setting of cirrhosis and elevated sinusoidal pressures. Neoplastic invasion of the portal veins must be differentiated from bland thrombus (see Images 31-32; Images 89-90). Clinical DetailsPatients with cirrhosis have a higher prevalence of gallstones than does the population at large. Gallstones are seen in 33-46% of patients with cirrhosis, and their prevalence is known to increase with the duration and severity of liver disease. Screening trends The development of HCCA may be expected 10-15 years after the onset of cirrhosis, although rarely, cases may occur in the setting of chronic hepatitis alone. Unlike patients with hepatitis C, in whom HCCA does not occur without cirrhosis, patients with hepatitis B can develop HCCA at any point after infection. The cumulative incidence of cirrhosis in patients with hepatitis C infection has been reported by Aizawa and colleagues to be as high as 42% at 15 years after diagnosis; thus, screening such patients represents a major public health challenge.19 Regeneration within the liver may result in a host of dysplastic lesions, the status of which can range from premalignant to frankly malignant and invasive. Neoplasms occur in markedly differing levels of aggressiveness and differentiation, with more aggressive lesions often arising in patients with multiple etiologies, such as alcohol-related cirrhosis in association with hepatitis C. A search for serologic markers for neoplastic disease has identified a number of promising markers, in addition to alpha fetoprotein (AFP). Serial measurement of AFP levels remains a mainstay of management, but the test is not particularly sensitive and certainly is nonspecific. However, levels greater than 200 ng/mL are highly suggestive of HCCA. Patients with persistently elevated values are at a higher risk of developing HCCA. Tarao and colleagues reported that patients with elevated alanine transferase levels are at greater risk as well.20 A better understanding of these risk factors allows patients to be stratified and enrolled in screening programs that incorporate imaging for focal masses. Preferred ExaminationUS is the most widely used worldwide imaging modality and is used in combination with serum AFP screening, based on evidence that increased frequency of examination leads to detection of HCCA at an earlier stage. It is common practice to screen patients with chronic hepatitis and/or biopsy-documented cirrhosis annually or semiannually with these techniques, although in the United States the American Gastroenterological Association (AGA) does not officially endorse this practice. The accuracy of US, as with CT scanning and MRI, is more limited in the advanced stages of cirrhosis. A US study from Korea, with transplant correlation in 52 patients, demonstrated a sensitivity for the detection of HCCA of only 33% (6 of 18) lesions. CT scanning is believed to be equivalent in sensitivity to, and more specific than, US. However, there are disadvantages related to contrast risk and radiation exposure, particularly if the modality is used over a lifetime for screening. Thus, CT scanning should be reserved for equivocal cases or for patients in whom disparate results are observed. For example, a heterogeneous appearance on US evaluation of the liver may mask malignant lesions and justify additional imaging (see Images 33-34). Conversely, persistent lesions that are noted on US, even if not confirmed on a CT scan, probably should be biopsied, particularly in the setting of serologic abnormalities (see Image 35). In end-stage patients who are destined for transplantation, the sensitivity of CT scanning is reduced (to as low as 37% in one series).21. MRI with gadolinium (or other contrast agents) can be used as an alternative (although more costly) study. Similar to US and CT scanning however, a reduction in sensitivity to below 50% has been reported, particularly for lesions under 2 cm, in patients with end-stage disease. Even more invasive and sophisticated techniques, such as CT scanning performed with a catheter in the hepatic artery, as well as angiography, are usually reserved for use in patients undergoing evaluation for transplant at regional centers, where the goal is to exclude or establish the presence and multiplicity of malignant lesions for pretransplant assessment. These techniques are not routinely employed in the United States but are used extensively in Asia. Unfortunately, for cultural reasons, orthotopic liver transplantation is not routinely performed in these countries; thus, pathologic correlation is limited to hepatic resections and biopsies. However, with the rapid increase in right lobe liver donation surgery, the pathologic correlation should be excellent because the entire explanted liver will be available. Limitations of TechniquesReal-time US is used extensively for screening, but biopsy or additional imaging modalities are required for confirmation. US is a nonspecific test and identifies many nodules, ranging from regenerative nodules, dysplastic nodules, and focal fat to benign neoplasms, such as hemangioma, many of which have no uniquely discriminating features on US. Because these occur with significant frequency, they pose a diagnostic challenge. For example, in a study of screened patients with cirrhosis, the authors discovered that although combined assessment with US and AFP was accurate in identifying patients with HCCA (who formed 24% of the study's population), 25% of patients had benign focal masses, such as hemangioma or focal fat, requiring further imaging evaluation, and another 20% had focal lesions that could not be corroborated on other imaging studies or on subsequent US. This relatively high prevalence of benign lesions in patients with cirrhosis appears to be corroborated by a study by Horigome and colleagues.22 Therefore, it is necessary to commit either to the biopsy of all persistent lesions or to the corroboration of them prior to biopsy with other techniques, such as CT scanning (helical or multislice) or MRI, using dynamic imaging with contrast to obtain multiple vascular-phase images. Clinician preferences in the United States, as surveyed by Chalasani and coauthors, suggest an empirical trend toward routinely incorporating CT scanning in screening.23 Some cause for optimism is warranted in terms of reduction in the incidence of HCCA in patients with hepatitis C following interferon therapy. A meta-analysis by Papatheodoridis and colleagues of 11 studies involving more than 2000 patients determined that the incidence of HCCA in patients who underwent interferon therapy was reduced to 8.2%, compared with 21.5% in untreated patients, and was even lower in sustained responders (0.9%).24 A major unresolved problem is the evaluation of the efficacy of screening and the economic consequences of aggressive screening. Bolondi and coauthors, in Italy, and Larcos and colleagues, in the United States, estimated that each case of HCCA that is detected costs $8000-$24,000.25, 26 Despite the best efforts of the worldwide medical community in screening for HCCA, no evidence exists that mortality has been affected, because therapeutic options, although expanding, remain relatively limited. Survival in patients undergoing liver transplant who have unsuspected HCCA is adversely affected by tumor recurrence (reported in a French series by Adam and colleagues as reaching 5%).27 The presence of neoplasm is not a contraindication to transplant, although survival in patients with tumors larger than 3 cm, with multiple nodules or portal invasion, is sufficiently impacted to preclude consideration in this subgroup. DIFFERENTIALSSection 3 of 12
Cirrhosis Hepatocellular Carcinoma Portal Hypertension Portal Vein Thrombosis RADIOGRAPHSection 4 of 12
FindingsRadiography has a modest place in the diagnosis and management of patients with cirrhosis, being used, for example, in screening for ascites (see Image 38), seeking evidence of bowel perforation in patients with suspected bacterial peritonitis, and monitoring bowel distension in acutely ill patients admitted for treatment of decompensation or variceal hemorrhage. Routine chest radiography in a patient with cirrhosis may demonstrate elevation of the diaphragms from ascites. Gynecomastia may be appreciated. The azygos vein may be enlarged because of collateral flow (see Image 39), and pleural effusions may occur from the presence of pleuroperitoneal fistulas (see Images 40-41). Rarely, giant esophageal varices may be appreciated as a soft-tissue mass at the gastroesophageal junction (see Image 42). An upper GI study can demonstrate varices at the gastroesophageal junction (see Image 43), but for the most part, endoscopy has superseded fluoroscopic techniques. Degree of ConfidencePlain film findings are generally confirmed by other imaging modalities or by clinical evidence. CT SCANSection 5 of 12
FindingsCT scanning is useful for demonstrating the morphologic evidence of cirrhosis within the liver (see Image 1, Image 4, Image 7, Image 15) and in showing mesenteric and GI tract abnormalities (see Images 13-16), as well as the development of collateral vessels in portal hypertension (see Image 4, Images 19-21, Images 25-26, Images 28-30). Splenomegaly and the presence of ascites are readily determined (see Image 4). CT scanning is commonly used to evaluate acutely decompensated patients with suspected subacute bacterial peritonitis, in order to exclude other inflammatory causes. CT scanning is valuable in characterizing lesions shown by US techniques or in evaluating decompensated patients with cirrhosis. In addition, it is increasingly being incorporated into the management of stable patients undergoing screening to identify neoplastic lesions. Delineating lesions With improved technology, which permits rapid dynamic scanning using helical or multi-slice CT scanners, scanning of the liver in multiple phases of contrast enhancement is now routinely recommended as the most sensitive method of detecting space-occupying lesions and evaluating vascular structures. However, substantial limitations remain in delineating small lesions (<2 cm), particularly in patients with advanced cirrhosis (see Degree of Confidence, below). Characteristic form of HCCA The most characteristic form of HCCA is a hyperattenuating nodule noted on arterial-phase imaging, with hyperattenuation and/or hypo-attenuation developing on portal venous–phase imaging (see Images 34-46). On CT scanning, hyperattenuation in the arterial phase occurs in a variable proportion of cases, and in many instances, it is characteristic enough to permit confident diagnosis. Attenuation Nino-Murcia and colleagues described arterial enhancement with abnormal internal vessels or a variegated appearance.28 In some instances, a single hyperattenuating focus may be the only evidence of HCCA, with no distinguishing characteristics on precontrast or portal venous-phase images. However, a proportion of lesions are hypo- or iso-attenuating on arterial-phase imaging. Dysplastic nodules also may be very similar to HCCA in their enhancement characteristics (see Image 47). CT scanning is useful in documenting complications associated with HCCA, such as portal vein thrombosis, and can be used to identify malignant invasion with a high specificity (see Image 32). Multifocal HCCA is commonly associated with extensive portal vein thrombosis and/or invasion at the time of diagnosis (see Image 32, Images 48-50). Often, extensive portovenous shunts are present (see Images 51-53). Degree of ConfidenceThe enlargement of the caudate lobe in cirrhosis, with other regions of retraction, may be mimicked in patients with breast carcinoma metastatic to the liver who are undergoing chemotherapy (see Image 54). Young and colleagues suggest that the mechanism is through nodular regeneration.30 Outcome Concerns regarding the evaluation of patients with cirrhosis and HCCA for transplant are related to the likelihood of a successful outcome based on the stage of the carcinoma; solitary HCCAs that are smaller than 2 cm can be treated successfully with transplantation. Survival rates diminish with the presence of additional or larger lesions, with a 5-year survival rate of only 75% reported by Mazzaferro and coauthors for patients with up to 3 discrete lesions that are smaller than 3 cm or with solitary lesions of 2-5 cm.31 Transplantation Transplantation is of no benefit when the lesions are diffuse or multiple, because metastatic disease is usually present. The discovery of a lesion or multiple lesions in a patient with cirrhosis who is otherwise well compensated necessitates further imaging evaluation or biopsy to characterize the lesions accurately. This assists in deciding whether to refer the patient for transplant or other therapy. Multiple abnormalities Often, multiple abnormalities are present in 1 patient, including a spectrum of nodules in various stages of malignant transformation. One or more frank HCCAs may coexist with several dysplastic nodules and/or a multiplicity of regenerative nodules, making the likelihood of accurate pretransplant diagnosis minimal without highly refined imaging techniques. In patients with advanced cirrhosis, peak enhancement of the liver is reduced and enhancement may appear heterogeneous, reducing the level of detection of focal lesions. Distinguishing nodules from HCCA Much effort has been devoted to distinguishing regenerative nodules from dysplastic ones, and dysplastic nodules from HCCA. CT scanning techniques, such as CT arterial portography ([CTAP], in which the liver is visualized following a superior mesenteric artery [SMA] injection in the portal phase) and CT arteriography (which utilizes direct injection into individual hepatic arteries, with imaging performed in the arterial phase), have been extensively investigated. Matsui and coauthors asserted that most low-grade dysplastic nodules have almost the same histopathologic and hemodynamic characteristics as those of regenerative nodules; therefore, they are iso-attenuating to regenerative nodules at CT scanning and are not usually visualized on CT arterial portography. High-grade dysplastic nodules may have a decreased portal supply and an increased arterial supply, but Lim and colleagues found the presence of such changes to be extremely variable; the grade of nodular dysplasia does not seem to affect the presence of the portal and arterial supplies.32 Differentiating dysplastic nodules from HCCA is a difficult task because some low-grade dysplastic nodules lose the portal supply and gain an arterial supply, while some high-grade dysplastic nodules retain the portal supply without gaining an increased hepatic arterial supply. Monzawa and colleagues reported that small HCCAs may be detected more accurately by combining the characteristics of arterial-phase, portal venous–phase, and delayed-phase images.33 A receiver operating characteristic (ROC) analysis for combination 3-phase imaging was significantly higher than for arterial-phase and portal venous–phase imaging (Az = 0.940 vs 0.917). Characterizing nonmalignant lesions CT scanning is useful in the characterization of nonmalignant lesions, such as hemangiomata, which occur with relatively high frequency in patients with cirrhosis. Other, more invasive forms of CT scanning have been evaluated over the past few years; Jang and colleagues reported evidence that CTAP and CT hepatic arteriography add little or no additional information to that obtained using triple-phase, helical CT scanning in the detection of HCCA.36 False Positives/NegativesDysplastic nodules may mimic HCCA. Nontumorous arterioportal shunt in livers with cirrhosis has been reported by Kim and colleagues as mimicking hypervascular tumor.37 MRISection 6 of 12
FindingsMRI offers an alternative noninvasive method of imaging the liver based on tissue-specific characteristics. In addition to demonstrating morphologic changes in cirrhosis, MRI is suited for the evaluation of vascular structures for patency or tumor invasion. T1-weighted images are valuable in providing anatomic detail, and T2-weighted images are more sensitive in detecting mass lesions and characterizing cysts and hemangiomata. MRI technology continues to evolve rapidly, with the development of techniques, such as the use of gradient-echo and fast spin-echo (SE) sequences, that permit the rapid acquisition of images required in association with paramagnetic contrast use. MRI has been studied extensively in diffuse liver disease. Tani and coauthors reported that focal and diffuse steatosis are recognized as increased signal intensity on T1-weighted MRI scans, and as diffuse low signal intensity on opposed-phase, T1-weighted images.39 Regenerative nodules are seen as small, masslike structures and are hypointense on T2-weighted images. Hemochromatosis Hemochromatosis is particularly suited to MRI; iron has a superparamagnetic effect on signal intensity that is best appreciated on T2-weighted images. The deposition of iron in siderotic nodules, which can be readily evaluated using MRI techniques, has been suggested by Ito and colleagues as an indicator of risk for malignant degeneration in patients with cirrhosis.40 Increased iron deposition associated with hemochromatosis is one of the well-recognized risk factors for HCCA. Ernst and coauthors described a statistically significant correlation between the hepatic iron concentration revealed at MRI with T1- or T2-weighted sequences,41 and the hepatic iron concentration value measured at biopsy. To quantify the amount of hepatic iron, Ito and colleagues used T2-weighted SE or fast SE images and gradient-recalled echo (GRE) images (echo time 6.0 ms), which they had determined were sensitive to the paramagnetic effects of hepatic iron among the MRI scans obtained at routine abdominal examination.40 At MRI, hepatic parenchymal iron deposition was seen in 79 patients (40%) and iron deposition in regenerative nodules was seen in 71 patients (36%). The mean signal-intensity ratio of GRE images in 125 patients with hepatic iron deposition was significantly lower than that in patients without such deposition (P <.001). The frequency of HCCA in patients with iron deposition in regenerative nodules was 52%, significantly higher (P = .015) than that in patients without iron in regenerative nodules (34%). Ito and coauthors suggested a role for MRI in monitoring patients undergoing phlebotomy, because this may reduce iron deposition in regenerative nodules and potentially decrease the risk of HCCA. Patients without hemochromatosis In patients without hemochromatosis, no association has been shown between frequency of siderotic nodules and an increased incidence of HCCA.42 MRI may be useful in identifying intratumoral fat, tumor encapsulation, portal or hepatic vein invasion, and arterial-portal venous shunting, all of which are characteristic of HCCA and have been extensively described in papers by Ebara, Kadoya, Winter, and colleagues (see Images 55-56).43, 44, 45 Interest has focused on the use of gadolinium with currently available MRI sequences that incorporate gradient-echo (GE) imaging, recognizing that the above-mentioned tumor characteristics are not always present. Lauenstein and colleagues evaluated 115 patients undergoing MRI with gadolinium-enhanced, 3-dimensional, gradient-echo sequences in arterial, venous, and delayed phases.46 Using various imaging criteria, including arterial-phase enhancement, delayed-phase hypointensity, and capsular enhancement, the authors detected 28 of 36 pathologically confirmed HCCAs in 27 patients (with the lesion-based sensitivity being 77.8%; the patient-based sensitivity, 88.9%; and the specificity, 97.7%). The diagnosis of HCCA when tumors are under 2 cm remains a challenge; among 18 of these smaller lesions, only 10 were diagnosed, and another 2 had characteristics of dysplastic nodules. Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have recently been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the eMedicine topic Nephrogenic Fibrosing Dermopathy. The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or magnetic resonance angiography (MRA) scans. Degree of ConfidenceMRI has not been widely applied in screening except at specialized transplant centers. The level of confidence in MRI, particularly when newer contrast agents, such as hepatobiliary contrast, are used, appears to be equivalent to the level of confidence in dual-phase, spiral CT scanning. The overall sensitivity of MRI was reported by Bartolozzi and colleagues to be 86% for a prospective assessment of precontrast and postcontrast images.49 Similar sensitivity has been reported by Kondo and coauthors, who retrospectively analyzed images of the liver from 33 patients on a segment-by-segment basis. A total of 261 segments, which included 39 HCCAs and 21 metastases, were independently reviewed by 3 radiologists. Unenhanced and gadolinium-enhanced MRI scans were reviewed first, and then ferumoxides-enhanced MRI scans were added for a combined review. CTAP images and biphasic CT hepatic angiography (CTHA) scans were reviewed together. It was determined in the study that the sensitivity for the detection of hepatic tumors was equivalent for combined unenhanced, gadolinium-enhanced, and ferumoxides-enhanced MRI scans (86%) and for combined CTAP images and biphasic CTHA scans (87%). Specificity was higher with MRI scans (95%, P <0.01) than with CT scans (91%), with improved performance achieved by combining ferumoxides-enhanced MRI scans with unenhanced and gadolinium-enhanced MRI scans (Az = 0.9 vs 0.950, P = 0.0502). The radiologists' preoperative ability to detect malignant hepatic tumors using combined unenhanced, gadolinium-enhanced, and ferumoxides-enhanced MRI scans was analogous to that when combined CTAP images and biphasic CTHA images (Az = 0.959) were used. Therefore, it appears that MRI has a diagnostic accuracy similar to that of CT scanning for lesions over 1 cm. However, MRI has significant limitations in the specificity of small-tumor detection, although these may be overcome by the further development of tissue-specific contrast agents. MRI does appear to enable the distinction of arterioportal shunts associated with tumor from spontaneous shunts associated with cirrhosis alone. When a superparamagnetic agent (iron oxide) is used, Mori and coauthors noted that tumorous shunts have reduced signal loss, whereas nontumorous shunts resemble normal liver parenchyma in the degree of signal loss, particularly on T2-weighted GE images.52 False Positives/NegativesRegenerative nodules can resemble hypovascular HCCA; Kim and colleagues recognized that infarcted regenerative nodules can pose particular problems.53 The liver of patients with nodular regenerative hyperplasia, also known as idiopathic portal hypertension or hepatoportal sclerosis, has morphologic features that are indistinguishable from cirrhosis. However, the histologic features of these livers demonstrate nodules but not evidence of fibrosis, which is the hallmark of cirrhosis. ULTRASOUNDSection 7 of 12
FindingsReal-time US, in combination with color flow Doppler US, is currently the most frequently used diagnostic imaging modality worldwide in the screening and evaluation of patients with cirrhosis. In addition to demonstrating the morphologic characteristics of cirrhosis, including hepatic contour (see Image 3), texture, (see Image 6), and the presence of portal collaterals (see Image 23, Image 27), Doppler US provides useful information on portal hemodynamics (see Images 60-63). Real-time US can be used to detect ascites (see Image 8) and splenomegaly (see Image 18), to differentiate intrahepatic or extrahepatic causes of jaundice, and to detect portal vein thrombosis in patients who have decompensated (see Image 31). Portal blood flow Doppler evaluation in a patient with cirrhosis can demonstrate high-velocity blood flow in the enlarged hepatic artery, which becomes tortuous as the underlying degree of fibrosis increases (see Image 9). PI, a measure of hepatic arterial vascular resistance, is elevated in patients with cirrhosis, and Schneider and colleagues have determined that it correlates quite well (r = 0.7, P <.001) with the HVPG.54 The normal direction of portal blood flow is maintained initially, but as the degree of cirrhosis progresses, damping of the usual triphasic signal in the intrahepatic veins and loss of respiratory variation in the portal venous system occur. Flow within the main portal vein gradually diminishes; bidirectional and (subsequently) reversal of flow may be seen, usually with accompanying development of collateral vessels (see Images 60-63). Collateral vessels These collaterals are most frequently detected in the splenorenal region (21%) (see Image 27), or as patent paraumbilical collaterals (14%) (see Image 23). In a study by von Herbay and coauthors of 109 patients with cirrhosis, the presence of collaterals correlated significantly with the presence of ascites, esophageal varices, and the inversion of portal flow, but not with splenomegaly. Doppler US continues to be used in the noninvasive physiologic evaluation of the portal tract in patients who, in an attempt to reduce the risk of GI hemorrhage, undergo pharmacologic modulation of portal pressures. However, Doppler US does not correlate well with intrahepatic pressures or with the portal systemic pressure gradient. For example, the evaluation of systemic flow in the femoral or brachial artery also has been studied, but only a 50% correlation is observed in reduction of femoral blood flow and portal pressure in response to propranolol treatment. Effects of pharmacologic agents The potentially confounding effects of pharmacologic agents on portal and systemic blood flow and resistance, coupled with a wide range of variability in individual response and observer measurements, continue to make this a perplexing area of investigation. A direct correlation of multiple flow parameters to the HVPG remains elusive. Vascular impedance Arterial vascular impedance can be estimated as the RI, which represents the ratio of the difference between the peak systolic and end-diastolic velocities to the peak systolic velocity. This can be measured directly in the superior mesenteric or hepatic artery. In addition to pharmacologic agents, however, numerous factors on the capillary and venous side can affect the RI. These include alteration of blood flow in the portal veins following a meal and the extent of development of collateral vessels, in addition to increased resistance from fibrosis or hepatic congestion because of fatty infiltration or right-sided heart failure. Screening for focal hepatic masses US has an established role in screening for focal hepatic masses, despite rather low specificity (see Images 35-37, Images 57-59). Demonstration of shunt vascularity by Doppler US enables a diagnosis to be made with high specificity (see Image 64, Image 69), but neovascularization occurring in small lesions may be below the threshold of detection of even sophisticated US systems. Multifocal lesions occasionally may be obscured (see Images 33-34), but in general, the lesions can be appreciated as tumor masses that either have vascularity (see Image 66, Image 69) or are avascular, but displacing, vessels (see Image 68). Pulse Doppler US is useful in demonstrating shunt velocity (see Image 64, Image 69), which in the author's population has been found to be highly specific for HCCA when in excess of 2.4 kHz. Portal vein thrombosis Portal vein thrombosis can be diagnosed with relative confidence if a distended portal vein is found that contains echogenic material in the absence of Doppler signal (see Image 31). Malignant invasion of the portal vein may be detectable as neovascularity within the thrombus, occasionally with direct contiguity with an intrahepatic lesion (compare Image 71 with Image 72). Low flow within the portal vein may be misinterpreted as thrombus, and careful attention to technique is necessary to ensure that the sensitivity of the Doppler signal is optimized. Harmonic imaging/intravascular contrast agents The development of intravascular contrast agents (which have little or no toxicity) initiated a re-evaluation of ultrasonographic sensitivity and specificity, which early investigations have suggested are greatly improved. The technical performance of ultrasonographic systems concomitantly has been modified to insonate tissue optimally, as well as to detect and process vascular and parenchymal signals from contrast agents. Techniques that are used include harmonic imaging, which is designed to capture nonlinear resonant frequencies from tissue and microbubbles with enhanced signal compared to background noise. The microbubbles can be disrupted by insonation at a high mechanical index (MI), which represents the peak negative pressure of the transmitted ultrasonographic pulse, and this produces a strong, very brief echo. The microbubbles can then be visualized at a lower MI intensity (<0.5) without causing further disruption. The bubbles can be seen within vessels and are detectable within capillaries in which conventional Doppler techniques cannot detect flow. HCCAs have variable enhancement patterns on contrast-enhanced harmonic US. Homogeneous and heterogeneous enhancement have been described by Kim and colleagues, correlating with CT-scan enhancement patterns.55 Three of 8 patients in this study also had linear tumor vessels in the lesions, but globular or peripheral enhancement seen in hemangioma and metastases, respectively, were not shown. Wilson and colleagues described perilesional and intralesional vessels. In a pilot study of 3 patients with biopsy-proven HCCA, the authors found variable characteristics, including identification of tumor vessels within the lesion and increased echogenicity within the center of the tumor (see Image 73). The use of harmonic power Doppler US remains in the investigational phase, as researchers study the impact of technical parameters, such as pulse repetition frequency, wall filter settings, and injection rates on lesion detection. The decreased sensitivity of harmonic power Doppler US, in comparison with conventional power Doppler US on precontrast, is more than compensated for on contrast-enhanced imaging (see Image 74). Real-time elastography Real-time elastography is a promising technique for the noninvasive evaluation of the severity of hepatic fibrosis. This technique has been commercially developed by Hitachi Medical Systems and was used by Friedrich-Rust and colleagues to assess liver fibrosis in 79 patients with chronic viral hepatitis. Using a stepwise logistic regression analysis in patients and controls to define a tissue elasticity score, diagnostic accuracy was 0.75 for significant fibrosis, 0.73 for severe fibrosis, and 0.69 for cirrhosis, with a highly significant correlation (Spearman's correlation coefficient = 0.48) between the elasticity scores and the histologic fibrosis stage (p <0.001).57 Degree of ConfidenceThe presence of portal hypertension can be inferred based on the measurement of portal vein diameter; a sensitivity of 75% and a specificity of 100% for a diameter greater than 1.3 cm have been claimed. As previously noted, however, measurements of flow and vessel diameter are only indirectly related to portal pressure, and the degree and level of intrahepatic obstruction (presinusoidal or postsinusoidal), arterial flow to the liver, and capacitance of the collateral flow may affect flow parameters. Other findings, such as loss of respiratory variation in the diameter of the main portal vein or the presence of collaterals, are considered by Zimmerman and coauthors to be approximately 80% sensitive.60 Such a wide range of variability exists among patients that measurements of this nature should be considered useful only in research settings. If no other corroborative evidence has been obtained, caution should be used in interpreting these measurements as determinants of the presence of portal hypertension. Ultrasonic characteristics The ultrasonographic characteristics of HCCAs are variable, reflecting the diversity of neoplastic differentiation. However, certain pathologic characteristics occur with greater frequency and are helpful in characterizing hepatic lesions on ultrasonographic examination. For example, a pseudocapsule may be identified as a halo on ultrasonographic imaging. Neovascularity with arterial-venous shunting, the hallmark of malignant transformation, can be identified by current ultrasonographic systems once a lesion has reached approximately 2 cm. Contrast agents that increase the signal-to-noise ratio enable tumor vascularity to be detected with greater sensitivity. Ultrasonographic sensitivity In patients with cirrhosis attributed to multiple risk factors, Fasani and colleagues report that, compared with CT scanning, US appears to understage patients with multinodular lesions.61 The sensitivity of US is also reduced in patients with heterogeneous livers. This understaging may be significant when considering patients for transplantation or ablative therapy, indicating that corroborative imaging with MRI or CT scanning may be of benefit in patients with advanced cirrhosis or a multifactorial etiology. US combined with intravascular contrast agents US appears to be very promising, particularly when combined with intravascular microbubble contrast agents, in assessing the effectiveness of tumor ablation. Choi studied the tumor characteristics of 40 patients with 45 nodular HCC lesions 1-3.8 cm in diameter.62 The patients were undergoing US-guided, percutaneous RF ablation with power Doppler US before and after intravenous injection of a microbubble contrast agent. In 33 of the 45 HCCAs, intratumoral flow was seen at power Doppler US before the administration of a contrast agent. After administration of the contrast agent, an increase in the degree of visualized flow was observed. After RF ablation, none of the ablated tumors showed intratumoral flow signals at unenhanced power Doppler US, whereas 6 showed marginal intratumoral flow signals at contrast agent–enhanced power Doppler US. This correlated with enhancing foci that were suggestive of viable tumor in corresponding areas, as found at immediate follow-up with contrast-enhanced CT scanning. Thus, these preliminary data suggest that contrast-enhanced power Doppler US can be a promising noninvasive technique for assessing therapeutic response. False Positives/NegativesRegenerative nodules, dysplastic nodules, focal fat, and fatty sparing may mimic focal HCCA. Other nonmalignant hepatic neoplasms, such as hemangioma, may appear similar to HCCA, although arteriovenous (AV) shunts are uncommon. Focal nodular hyperplasia and liver cell adenoma may have extensive AV shunting, with this occurring most often in females. The development of US contrast agents should further increase sensitivity; evidence suggests that the combination of advanced ultrasonographic imaging techniques (harmonic imaging) can increase the conspicuity of liver lesions (hence, the sensitivity of US when combined with microbubble contrast). NUCLEAR MEDICINESection 8 of 12
FindingsFunctional imaging techniques using 99mTc-labeled sulfur colloid provide some indication of hepatic function. The agent is taken up by reticuloepithelial (RE) cells, and colloid shift to the other RE organs (bone marrow, spleen) provides indirect evidence of portal hypertension. In addition, heterogeneous uptake enables recognition of underlying hepatic dysfunction (see Image 17). Volumetric estimates of the liver can be made but have been superseded by other imaging techniques. Fluorine-18 fluorodeoxyglucose (18F-FDG) is taken up by tumor cells, but the use of this agent in conjunction with positron emission tomography (PET) scanning appears to be more suited to larger, better-differentiated lesions. Therefore, at present, Trojan and colleagues believe that 18F-FDG PET is unlikely to replace the other techniques.63 Sensitivity appears in the range of only 55%, compared with the 90% sensitivity of CT scanning, and Khan and coauthors report that better-differentiated tumors tend to have a lower level of uptake.64 The prognostic implications of this finding have not been elucidated. In an investigation, Kim and colleagues expressed hope that functional imaging techniques may be able to predict tumor response to chemotherapy.65 Degree of ConfidenceSince the sensitivity of PET is relatively low, this modality is not at present recommended as a clinical screening tool for HCCA, and its use remains investigational. Kurtaran and coauthors report that it may be helpful in discriminating benign hepatic lesions, such as focal nodular hyperplasia (FNH), from malignant lesions, because there is reduced uptake in FNH.66 ANGIOGRAPHYSection 9 of 12
FindingsAngiography has evolved from an invasive modality used in the diagnostic evaluation of tumors and other complications of cirrhosis (in the decades prior to the introduction of noninvasive, cross-sectional imaging modalities) to an imaging method with a far more sophisticated interventional and therapeutic use. The angiographic characteristics of the hepatic circulation in cirrhosis (see Image 10) and of tumor vascularity, including the demonstration of AV shunting characteristic of HCCA, were described several decades ago, and the knowledge of these characteristics now forms the cornerstone of our understanding of dynamic hepatic imaging by US, CT scanning, and MRI. Angiographic techniques are currently used in the placement of catheters for CTA and for CTAP, as well as in the administration of chemotherapy (chemoembolization). The angiographic demonstration of hepatic perfusion remains essential in transplant assessment, given the remarkable variability of the liver's arterial and venous drainage, although Smith and colleagues suggest that the development of computer-based, 3-dimensional rendering techniques may make this obsolete.67 It is accepted that angiography, although useful in demonstrating vascular anatomy, is not the most sensitive technique available for the diagnosis of small, occult HCCAs. An accurate assessment of portal hemodynamics of the patient with cirrhosis is necessary for prognostic purposes. Such assessment requires the measurement of hepatic wedge pressures, the direct measurement of right atrial pressure, and the measurement of inferior vena caval pressures above, within, and caudal to the liver (see Images 75-79). Wide individual variation was described by Bosch and Garcia-Pagan in response to pharmacologic agents administered to reduce portal pressures, which means that it is important to obtain follow-up measurements during the course of therapy.68 As yet, no noninvasive substitutes for the HVPG have been identified. Degree of ConfidenceEscorsell and colleagues determined that portal pressure (evaluated as the HVPG) is an independent prognostic factor in variceal bleeding risk. Their evidence indicated that such risk is very low in patients in whom a reduction in variceal pressure of 20% or greater is achieved.69 The measurement of portal pressures is necessary in patients who are undergoing pharmacologic intervention designed to reduce portal pressure gradients. INTERVENTIONSection 10 of 12
Of those patients with cirrhosis and varices, 25-40% experience bleeding. The management of portal hypertension and upper tract GI bleeding has been revolutionized by endoscopic and angiographic treatment. The use of the intravascularly placed transjugular intrahepatic portosystemic shunt (TIPS) has provided a second-line therapy for the management of portal hypertension, with reduced mortality and morbidity compared with that associated with the open surgical procedure. Management of GI bleeding with TIPS In the management of GI bleeding, Grace, Kerlan, and colleagues recommended that the TIPS generally be reserved for patients in whom a combined approach of vasoactive pharmacologic agents and endoscopic sclerotherapy or ligation has failed.70, |