Introduction
Patient with cirrhosis showing tortuous hepatic arteries in addition to enlarged left lobe and caudate (C)
More advanced cirrhosis. Computed tomography (CT) scan with a portal venous–phase image shows a markedly enlarged left lobe (L) and caudate (C), with an area of focal fibrosis and atrophy of the posterior right lobe, deforming contour (open arrow). Incidental note of prominent collaterals in lesser curvature region (white arrow)
Typical appearance of cirrhosis (in a 22-year-old female) on angiography. Injection of the celiac trunk demonstrates an enlarged hepatic artery. Intrahepatic branches are tortuous, with a "corkscrew" configuration.
Background
Cirrhosis 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.
For excellent patient education resources, visit eMedicine's Hepatitis Center and Liver, Gallbladder, and Pancreas Center. Also, see eMedicine's patient education articles Hepatitis A, Hepatitis B, Hepatitis C, and Cirrhosis.
Related eMedicine topic:
Cirrhosis [in the Gastroenterology section]
Pathophysiology
Cirrhosis 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.
Hepatocellular carcinoma (HCCA) is a frequent and usually fatal complication. Patients with cirrhosis caused by primary sclerosing cholangitis may develop cholangiocarcinoma, which also is invariably fatal.
Related eMedicine topics:
Portal Hypertension
Hepatocellular Carcinoma [Radiology]
Hepatocellular Carcinoma [Pediatrics: Oncology]
Hepatic Carcinoma, Primary
Frequency
United States
Using 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
International
Cirrhosis 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/Morbidity
Since 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:
- Incidence of HCCA - Although this trend appears encouraging, El-Serag and colleagues report that the incidence of HCCA in the United States actually has increased markedly from 1980-1995, rising from a rate of 1.4 persons with the disease per 100,000 from 1976–1980 to 2.4 per 100,000 between 1990 and 1995.5 Also observed is a trend toward development of HCCA in younger patients, who were most likely infected with hepatitis B or C in the 1960s and 1970s.
- Prevalence of hepatitis C - At least 4 million people in the United States are estimated to have chronic hepatitis C infection, which is associated with a 100-fold increase in the risk of developing HCCA. Based on molecular evolutionary studies in Japan and the United States, Mizokami and coauthors predicted that the incidence of this complication would peak by about 2020.6
- The hepatitis C virus is transmitted primarily through the transfusion of blood and blood products, as well as through injection drug use. Among persons infected with the virus, 80-85% develop chronic hepatitis C, which can lead to cirrhosis and, subsequently, to HCCA; alcohol abuse and co-infection with hepatitis B are additional risk factors. In patients with hepatitis C, the estimated risk of developing HCCA after 20 years is 1-5%.
Race
Generally, 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.
Sex
The 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.
Age
Age-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.
Anatomy
Hepatic 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).
Often, concomitant volume loss occurs in the right lobe because of progressive fibrosis (see Image 4). The degree of scarring is variable and occasionally results in regions of retraction that extend to the capsule in wedge-shaped or irregular patterns
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, butnot with splenomegaly or varices.
The development of splenomegaly and collaterals from portal hypertension is readily evident when any cross-sectional technique is used and is discussed in the following section. Nodular iron deposition within the spleen, as seen on seen on MRI scans (Gamma-Gandy bodies), is highly suggestive of portal hypertension.
Functional imaging techniques, such as the use of technetium-99m (99m Tc)–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.
Endoscopic evaluation provides a visual window on esophageal varices, which can be graded for prognosis. However, noninvasive techniques are useful in demonstrating collateral vessels beyond the reach of the endoscope. Three-dimensional CT scanning is particularly helpful in demonstrating the development and pattern of collateral flow in portal venous hypertension (see Images 84-88).
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).
Presentation
Patients 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.
A study of 123 patients by Chawla and coauthors determined that the prevalence of gallstones was not affected by sex, race, or the presence of underlying diabetes, but that the prevalence of gallbladder disease was increased in patients with autonomic neuropathy (51% vs 35%, P = 0.08).18 In persons with Child C cirrhosis, gallstones (P = 0.018) and gallbladder disease (P = 0.03) were seen more commonly in patients with autonomic neuropathy. The authors hypothesized that such patients may have impaired gallbladder contractility and sphincter of Oddi dysmotility.
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 Examination
US 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 Techniques
Real-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.
Differential Diagnoses
Cirrhosis
Hepatocellular Carcinoma
Portal Hypertension
Portal Vein Thrombosis
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Further Reading
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
